Yuri Stasiv

Patiromer in Patients with Kidney Disease and Hyperkalemia Receiving RAAS Inhibitors

BACKGROUND Hyperkalemia increases the risk of death and limits the use of inhibitors of the renin-angiotensin-aldosterone system (RAAS) in high-risk patients. We assessed the safety and efficacy of patiromer, a nonabsorbed potassium binder, in a multicenter, prospective trial. METHODS Patients with chronic kidney disease who were receiving RAAS inhibitors and who had serum potassium levels of 5.1 to less than 6.5 mmol per liter received patiromer (at an initial dose of 4.2 g or 8.4 g twice a day) for 4 weeks (initial treatment phase); the primary efficacy end point was the mean change in the serum potassium level from baseline to week 4. Eligible patients at the end of week 4 (those with a baseline potassium level of 5.5 to <6.5 mmol per liter in whom the level decreased to 3.8 to <5.1 mmol per liter) entered an 8-week randomized withdrawal phase in which they were randomly assigned to continue patiromer or switch to placebo; the primary efficacy end point was the between-group difference in the median change in the serum potassium level over the first 4 weeks of that phase. RESULTS In the initial treatment phase, among 237 patients receiving patiromer who had at least one potassium measurement at a scheduled visit after day 3, the mean (±SE) change in the serum potassium level was -1.01±0.03 mmol per liter (P<0.001). At week 4, 76% (95% confidence interval, 70 to 81) of the patients had reached the target potassium level (3.8 to <5.1 mmol per liter). Subsequently, 107 patients were randomly assigned to patiromer (55 patients) or placebo (52 patients) for the randomized withdrawal phase. The median increase in the potassium level from baseline of that phase was greater with placebo than with patiromer (P<0.001); a recurrence of hyperkalemia (potassium level, ≥5.5 mmol per liter) occurred in 60% of the patients in the placebo group as compared with 15% in the patiromer group through week 8 (P<0.001). Mild-to-moderate constipation was the most common adverse event (in 11% of the patients); hypokalemia occurred in 3%. CONCLUSIONS In patients with chronic kidney disease who were receiving RAAS inhibitors and who had hyperkalemia, patiromer treatment was associated with a decrease in serum potassium levels and, as compared with placebo, a reduction in the recurrence of hyperkalemia. (Funded by Relypsa; OPAL-HK ClinicalTrials.gov number, NCT01810939.).

Effect of Patiromer on Serum Potassium Level in Patients With Hyperkalemia and Diabetic Kidney Disease: The AMETHYST-DN Randomized Clinical Trial

IMPORTANCE Hyperkalemia is a potentially life-threatening condition predominantly seen in patients treated with renin-angiotensin-aldosterone system (RAAS) inhibitors with stage 3 or greater chronic kidney disease (CKD) who may also have diabetes, heart failure, or both. OBJECTIVES To select starting doses for a phase 3 study and to evaluate the long-term safety and efficacy of a potassium-binding polymer, patiromer, in outpatients with hyperkalemia. DESIGN, SETTING, AND PARTICIPANTS Phase 2, multicenter, open-label, dose-ranging, randomized clinical trial (AMETHYST-DN), conducted at 48 sites in Europe from June 2011 to June 2013 evaluating patiromer in 306 outpatients with type 2 diabetes (estimated glomerular filtration rate, 15 to <60 mL/min/1.73 m2 and serum potassium level >5.0 mEq/L). All patients received RAAS inhibitors prior to and during study treatment. INTERVENTIONS Patients were stratified by baseline serum potassium level into mild or moderate hyperkalemia groups and received 1 of 3 randomized starting doses of patiromer (4.2 g [n = 74], 8.4 g [n = 74], or 12.6 g [n = 74] twice daily [mild hyperkalemia] or 8.4 g [n = 26], 12.6 g [n = 28], or 16.8 g [n = 30] twice daily [moderate hyperkalemia]). Patiromer was titrated to achieve and maintain serum potassium level 5.0 mEq/L or lower. MAIN OUTCOMES AND MEASURES The primary efficacy end point was mean change in serum potassium level from baseline to week 4 or prior to initiation of dose titration. The primary safety end point was adverse events through 52 weeks. Secondary efficacy end points included mean change in serum potassium level through 52 weeks. RESULTS A total of 306 patients were randomized. The least squares mean reduction from baseline in serum potassium level at week 4 or time of first dose titration in patients with mild hyperkalemia was 0.35 (95% CI, 0.22-0.48) mEq/L for the 4.2 g twice daily starting-dose group, 0.51 (95% CI, 0.38-0.64) mEq/L for the 8.4 g twice daily starting-dose group, and 0.55 (95% CI, 0.42-0.68) mEq/L for the 12.6 g twice daily starting-dose group. In those with moderate hyperkalemia, the reduction was 0.87 (95% CI, 0.60-1.14) mEq/L for the 8.4 g twice daily starting-dose group, 0.97 (95% CI, 0.70-1.23) mEq/L for the 12.6 g twice daily starting-dose group, and 0.92 (95% CI, 0.67-1.17) mEq/L for the 16.8 g twice daily starting-dose group (P < .001 for all changes vs baseline by hyperkalemia starting-dose groups within strata). From week 4 through week 52, statistically significant mean decreases in serum potassium levels were observed at each monthly point in patients with mild and moderate hyperkalemia. Over the 52 weeks, hypomagnesemia (7.2%) was the most common treatment-related adverse event, mild to moderate constipation (6.3%) was the most common gastrointestinal adverse event, and hypokalemia (<3.5 mEq/L) occurred in 5.6% of patients. CONCLUSIONS AND RELEVANCE Among patients with hyperkalemia and diabetic kidney disease, patiromer starting doses of 4.2 to 16.8 g twice daily resulted in statistically significant decreases in serum potassium level after 4 weeks of treatment, lasting through 52 weeks. TRIAL REGISTRATION clinicaltrials.gov Identifier:NCT01371747.

Effects of 1-H-indole-3-glyoxamide (A-002) on concentration of secretory phospholipase A2 (PLASMA study): a phase II double-blind, randomised, placebo-controlled trial

BACKGROUND Secretory phospholipase A(2) (sPLA(2)) enzymes, produced and secreted in human blood vessels and hepatocytes, contribute to the development of atherosclerosis through mechanisms that are both dependent and independent of lipoprotein. We examined the effects of an sPLA(2) inhibitor on enzyme concentration and on plasma lipoproteins and inflammatory biomarkers in patients with coronary heart disease. METHODS Patients aged 18 years and older with stable coronary heart disease from the USA and Ukraine were eligible for enrolment in this phase II, randomised, double-blind, placebo-controlled, parallel-arm, dose-response study. 393 patients were randomly assigned by computer-generated sequence to receive either placebo (n=79) or one of four doses of an sPLA(2) inhibitor, A-002 (1-H-indole-3-glyoxamide; 50 mg [n=79], 100 mg [n=80], 250 mg [n=78], or 500 mg [n=77] twice daily), for 8 weeks. The primary endpoint was the change in sPLA(2) group IIA (sPLA(2)-IIA) concentration or activity from baseline to week 8. Analysis was by modified intention to treat (ITT). The ITT population consisted of all patients who received one dose of study treatment; data for patients who dropped out before the end of the study were carried forward from last observation. This trial is registered with ClinicalTrials.gov, number NCT00455546. FINDINGS All randomised patients received at least one dose and were included in the ITT population. Data for 45 patients were carried forward from last observation (36 in the A-002 group and nine in the placebo group); the main reason for dropout before completion was because of adverse events. 348 patients reached the primary endpoint (A-002 n=278, placebo n=70). Mean sPLA(2)-IIA concentration fell by 86.7%, from 157 pmol/L to 21 [corrected] pmol/L, in the overall active treatment group, and by 4.8%, from 157 pmol/L to 143 [corrected] pmol/L, in the placebo group (p<0.0001 treatment vs placebo). The reductions in sPLA(2)-IIA concentration in the A-002 groups were dose dependent (ranging from 69.2% in the 50 mg group to 95.8% in the 500 mg group) and differed significantly from placebo (p<0.0001 for all doses). In the 500 mg A-002 treatment group, there was one serious adverse event (exacerbation of underlying chronic obstructive pulmonary disease), but the proportion of patients reporting treatment-emergent adverse events did not differ from placebo. The main side-effects of the drug included headache (n=20), nausea (n=17), and diarrhoea (n=12). INTERPRETATION The reductions in sPLA(2)-IIA concentration suggest that A-002 might be an effective anti-atherosclerotic agent.

Effects of Varespladib Methyl on Biomarkers and Major Cardiovascular Events in Acute Coronary Syndrome Patients

OBJECTIVES The purpose of this study was to investigate the effects of varespladib on cardiovascular biomarkers in acute coronary syndrome patients. BACKGROUND Secretory phospholipase A(2) (sPLA(2)) represents a family of proatherogenic enzymes that hydrolyze lipoprotein phospholipids, increasing their affinity for intimal proteoglycans; contribute to cholesterol loading of macrophages by nonscavenger receptor mediated pathways; and activate inflammatory pathways. In prospective studies, high sPLA(2)-IIA levels predicted major adverse cardiovascular events in acute coronary syndrome (ACS) and stable coronary heart disease patients. METHODS This randomized, double-blind, prospective controlled clinical trial (phase 2B) was designed to investigate the effects of sPLA(2) inhibition with varespladib 500 mg daily versus placebo as adjunctive therapy to atorvastatin 80 mg daily on biomarkers (low-density lipoprotein cholesterol [LDL-C], high-sensitivity C-reactive protein [hsCRP], and sPLA(2)-IIA levels), major adverse cardiovascular events (unstable angina, myocardial infarction, death), and safety. In all, 625 ACS subjects were randomized within 96 h of the index event and treated for a minimum of 6 months. RESULTS After 8 weeks (primary efficacy end point), varespladib/atorvastatin reduced mean LDL-C levels from baseline by 49.6% compared with 43.4% with placebo/atorvastatin (p = 0.002). Respective 8-week median reductions in sPLA(2)-IIA levels were 82.4% and 15.6% (p < 0.0001), and hsCRP levels were lowered by 75.0% and 71.0% (p = 0.097). At 24 weeks, respective reductions with varespladib and placebo were as follows: LDL-C 43.5% versus 37.6% (p < 0.05), hsCRP 79.8% versus 77.0% (p = 0.02), and sPLA(2)-IIA 78.5% versus 6.4% (p < 0.0001). Major adverse cardiovascular events were not different from placebo 6 months post-randomization (7.3% varespladib vs. 7.7% placebo). No treatment differences in elevated liver function studies on >1 occasion were observed. CONCLUSIONS Varespladib therapy effectively reduced LDL-C and inflammatory biomarkers in ACS patients treated with conventional therapy including atorvastatin 80 mg daily. There were no treatment differences in clinical cardiovascular events. (FRANCIS [Fewer Recurrent Acute Coronary Events With Near-Term Cardiovascular Inflammation Suppression]-ACS Trial: A Study of the Safety and Efficacy of A 002 in Subjects With Acute Coronary Syndromes; NCT00743925).

Effect of patiromer on reducing serum potassium and preventing recurrent hyperkalaemia in patients with heart failure and chronic kidney disease on RAAS inhibitors

We evaluated the effects of patiromer, a potassium (K+)‐binding polymer, in a pre‐specified analysis of hyperkalaemic patients with heart failure (HF) in the OPAL‐HK trial.

Randomized trial of an inhibitor of secretory phospholipase A2 on atherogenic lipoprotein subclasses in statin-treated patients with coronary heart disease

AIMS To investigate the effects of secretory phospholipase A2 (sPLA(2)) inhibition on plasma lipoproteins. Secretory phospholipase A2 isoenzymes promote atherosclerosis by mechanisms that include lipoprotein modification, retention, and oxidation. METHODS AND RESULTS Phospholipase Levels And Serological Markers of Atherosclerosis II (PLASMA II) is a Phase II, randomized, double-blind, placebo-controlled parallel-arm study of two once-daily doses of the novel sPLA(2) inhibitor, 1-H-indole-3-glyoxamide or varespladib methyl (Anthera Pharmaceuticals, Hayward, CA, USA). One hundred and thirty-five stable coronary heart disease patients were treated with either varespladib methyl 250 mg once daily, varespladib methyl 500 mg once daily, or placebo for 8 weeks. Varespladib methyl treatment resulted in statistically significant dose-dependent reductions that were different from placebo in sPLA(2) concentration, low-density lipoprotein (LDL) cholesterol, and non-high-density lipoprotein (HDL) cholesterol. When compared with placebo, varespladib methyl 500 mg once daily reduced LDL cholesterol by 15% (P < 0.001), non-HDL cholesterol by 15% (P < 0.001), total very LDL (VLDL) particle concentration by 14% (P = 0.022), and small VLDL particle concentration by 24% (P = 0.030). Relative to baseline, varespladib methyl 500 mg once daily reduced total LDL particle concentration (7%, P = 0.002) and small LDL particle concentration (11%, P = 0.014). CONCLUSION Reductions in atherogenic lipoproteins suggest that varespladib methyl 500 mg once daily may be an effective anti-atherosclerotic agent. Trial registered at ClinicalTrials.gov, identifier: NCT00525954.

Patiromer induces rapid and sustained potassium lowering in patients with chronic kidney disease and hyperkalemia

Patients with chronic kidney disease (CKD) have a high risk of hyperkalemia, which increases mortality and can lead to renin–angiotensin–aldosterone system inhibitor (RAASi) dose reduction or discontinuation. Patiromer, a nonabsorbed potassium binder, has been shown to normalize serum potassium in patients with CKD and hyperkalemia on RAASi. Here, patiromers onset of action was determined in patients with CKD and hyperkalemia taking at least one RAASi. After a 3-day potassium- and sodium-restricted diet in an inpatient research unit, those with sustained hyperkalemia (serum potassium 5.5 – under 6.5 mEq/l) received patiromer 8.4 g/dose with morning and evening meals for a total of four doses. Serum potassium was assessed at baseline (0 h), 4 h postdose, then every 2–4 h to 48 h, at 58 h, and during outpatient follow-up. Mean baseline serum potassium was 5.93 mEq/l and was significantly reduced by 7 h after the first dose and at all subsequent times through 48 h. Significantly, mean serum potassium under 5.5 mEq/l was achieved within 20 h. At 48 h (14 h after last dose), there was a significant mean reduction of 0.75 mEq/l. Serum potassium did not increase before the next dose or for 24 h after the last dose. Patiromer was well tolerated, without serious adverse events and no withdrawals. The most common gastrointestinal adverse event was mild constipation in two patients. No hypokalemia (serum potassium under 3.5 mEq/l) was observed. Thus, patiromer induced an early and sustained reduction in serum potassium and was well tolerated in patients with CKD and sustained hyperkalemia on RAASis.

1-YEAR SAFETY AND EFFICACY OF PATIROMER FOR HYPERKALEMIA IN HEART FAILURE PATIENTS WITH CHRONIC KIDNEY DISEASE ON RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM INHIBITORS

Available K+-binding resins for hyperkalemia (HK) treatment are poorly tolerated, limiting long-term use. We report results by HF status from a 52-wk trial of HK treatment in CKD pts on RAASi. Multicenter, open-label trial of 304 pts with CKD, DM, HTN and serum K+ (s-K+) >5.0 mEq/L; pts randomized

Randomized, Controlled Trial of TRC101 to Increase Serum Bicarbonate in Patients with CKD

BACKGROUND AND OBJECTIVES Metabolic acidosis is common in patients with CKD and has significant adverse effects on kidney, muscle, and bone. We tested the efficacy and safety of TRC101, a novel, sodium-free, nonabsorbed hydrochloric acid binder, to increase serum bicarbonate in patients with CKD and metabolic acidosis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS One hundred thirty-five patients were enrolled in this randomized, double-blind, placebo-controlled, multicenter, in-unit study (designated the TRCA-101 Study). Patients had a mean baseline eGFR of 35 ml/min per 1.73 m2, a mean baseline serum bicarbonate of 17.7 mEq/L, and comorbidities, including hypertension (93%), diabetes (70%), and heart failure (21%). Patients ate a controlled diet and were treated for 14 days with placebo or one of four TRC101 dosing regimens (1.5, 3, or 4.5 g twice daily or 6 g once daily). After treatment, patients were discharged and followed for 7-14 days. RESULTS All TRC101 treatment groups had a mean within-group increase in serum bicarbonate of ≥1.3 mEq/L (P<0.001) within 72 hours of the first dose and a mean increase in serum bicarbonate of 3.2-3.9 mEq/L (P<0.001) at the end of treatment compared with placebo, in which serum bicarbonate did not change. In the combined TRC101 treatment group, serum bicarbonate was normalized (22-29 mEq/L) at the end of treatment in 35% of patients and increased by ≥4 mEq/L in 39% of patients. After discontinuation of TRC101, serum bicarbonate decreased nearly to baseline levels within 2 weeks. All adverse events were mild or moderate, with gastrointestinal events most common. All patients completed the study. CONCLUSIONS TRC101 safely and significantly increased the level of serum bicarbonate in patients with metabolic acidosis and CKD.