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Managing Hyperkalemia in High-Risk Patients in Long-Term Care
Rajeev Kumar, MD, FACP; Leo Kanev, MD; Steven D. Woods, PharmD; Melanie Brenner, PharmD; and Bernie Smith, RPh, MBA, MHA

Managing Hyperkalemia in High-Risk Patients in Long-Term Care

Rajeev Kumar, MD, FACP; Leo Kanev, MD; Steven D. Woods, PharmD; Melanie Brenner, PharmD; and Bernie Smith, RPh, MBA, MHA
Clinical Efficacy of Patiromer in the Treatment of Hyperkalemia
In a multicenter, open-label, randomized, 52-week study (AMETHYST-DN), patiromer was shown to significantly reduce the serum K+ level in hyperkalemic patients with diabetic nephropathy and hypertension with or without HF who were taking RAASIs (Figure 191).91 Daily administration of patiromer resulted in the reduction of mean serum K+ to normokalemic levels (<5.0 mEq/L) in approximately 48 hours for patients with mild hyperkalemia and in one week for patients with moderate hyperkalemia. Serum K+ level was significantly decreased at week 4 and remained in the target range (3.8–5.0 mEq/L) through week 52.

OPAL-HK was a multicenter, single-blind, randomized study that comprised 2 phases: a 4-week, single-group initial treatment phase and an 8-week, placebo-controlled, randomized withdrawal phase.86 In the treatment phase, hyperkalemic patients with CKD who were on a stable dose of RAASI therapy were treated with patiromer. This resulted in a significant decrease in mean serum K+ level from baseline to week 4. In the randomized withdrawal phase, the median serum K+ level remained unaltered from the start of the withdrawal phase to week 4 in patients who continued taking patiromer, whereas it increased by 0.72 mEq/L in patients who switched to placebo. By week 8 of the withdrawal phase, a significantly higher proportion of patients given placebo had at least one event of recurrent hyperkalemia compared with those given patiromer. Of note, a significantly higher proportion of patients who received patiromer (94%) remained on RAASI therapy compared with those who received placebo (44%).86 Similar findings were observed in a prespecified analysis of the subgroup of patients with HF in OPAL-HK, with 100% of patients with HF taking patiromer still receiving RAASI therapy at the end of the randomized withdrawal phase, compared with 55% of patients taking placebo.89

Safety and Tolerability of Patiromer in the Treatment of Hyperkalemia
In OPAL-HK, patiromer was reported to be generally safe and well tolerated, with 47% of patients reporting at least one AE during the initial patiromer treatment phase, and 47% of the patients who continued taking patiromer and 50% of those who switched to placebo reporting at least one AE during the withdrawal phase.86 Serious AEs—none determined by the investigators to be related to patiromer—were reported in 1% of patients during the treatment phase and in 2% of patients given placebo and none given patiromer during the withdrawal phase.86 In the AMETHYST-DN study, the most common AEs over 52 weeks of patiromer treatment were worsening of CKD (9%; none related to patiromer), hypomagnesemia (9%; related to patiromer, 7%), worsening of hypertension (8%; related to patiromer, 0.3%), constipation (6%; related to patiromer, 5%), and diarrhea (6%; related to patiromer, 3%).91 None of the patients developed severe hypomagnesemia (serum magnesium level <1.0 mg/dL) and none had cardiac arrhythmias or neuromuscular abnormalities temporally associated with hypomagnesemia.91

To assess safety and tolerability in patients (n = 666) treated with patiromer across all clinical studies, an integrated safety analysis was conducted.65 The results were generally consistent with those from OPAL-HK and AMETHYST-DN. Of the 666 patients, 219 (32.9%) received patiromer daily for at least 6 months and 149 (22.4%) for at least one year. Patiromer was generally well tolerated in these patients, including those with CKD, HF, and/or diabetes. The majority of AEs were mild or moderate. The most common individual AEs that resulted in discontinuation of patiromer were GI-related (2.7%), including vomiting (0.8%), diarrhea (0.6%), flatulence (0.5%), and constipation (0.5%). Based on prespecified laboratory criteria, hypokalemia (serum K+ level <3.5 mEq/L) occurred in 4.7% of patients; no patient developed a serum K+ level less than 3.0 mEq/L.65 A serum magnesium level less than 1.2 mg/dL was reported in 2.0% of patients; no patient developed a serum magnesium level less than 1.0 mg/dL. There were no patiromer-related serious AEs or deaths in any of the trials.65,86,88,91 There were no clinically meaningful changes in renal function or mean serum electrolyte (calcium, sodium, magnesium, phosphate) levels.65

Patiromer is not systemically absorbed87; therefore, the potential for drug-drug interactions related to effects on cytochrome P450 isoenzymes or systemic drug transporters is not a clinical concern when patiromer is coadministered with other drugs. Recently, in a series of in vivo studies in healthy volunteers, patiromer was evaluated for potential drug-drug interactions with 12 drugs administered at the same time as patiromer or 3 hours apart. The 12 drugs were selected based on results of in vitro tests, in which patiromer had demonstrated potentially clinically relevant binding in 14 of 28 drugs.84 Results from the phase one studies revealed that no reduction in absorption was observed for any of the 12 drugs tested with a 3-hour dose separation from patiromer. Based on these study results, the FDA recently approved a supplemental New Drug Application for patiromer with important updates to the prescribing information, which no longer includes a boxed warning regarding the separation of patiromer and other oral medications, and recommends that patients take patiromer at least 3 hours before or 3 hours after other oral medications.84

Efficacy and Safety of Patiromer in Elderly Patients
An additional post hoc analysis of 41 patients at least 75 years of age from the OPAL-HK study assessed the same end points as in the primary study.86 Treatment with patiromer resulted in a mean (standard error [SE]) decrease in serum K+ level of −0.99 (0.10) mEq/L (95% CI, −1.19 to −0.80; P <.001) from baseline to week 4 of the initial treatment phase. Figure 2 shows mean serum K+ level during the initial treatment phase for patients 75 years and older and those less than 75 years of age. In the randomized withdrawal phase, serum K+ level was essentially unchanged from the start of the phase to week 4 in patients aged 75 years and older who remained on patiromer (median change [quartiles], −0.10 [−0.3, 0.3] mEq/L), whereas it increased considerably (0.60 [0.40, 1.10]) in patients who were switched to placebo; the difference in the median change between the groups (0.70; 95% CI, 0.06-1.34) was signficant (P <.001) (Figure 3). The results were generally similar in patients less than 75 years of age (Figure 3).

Treatment with patiromer was generally safe and well tolerated in patients 75 years and older and those less than 75 years of age. Table 2 summarizes the safety parameters during the initial treatment phase. A total of 46% of patients 75 years and older and 47% of those less than 75 years of age had at least one AE. Mild-to-moderate constipation was the most common AE and it was the most common patiromer-related AE in these patients (Table 2). AEs led to study discontinuation in 10% of patients 75 years and older and in 5% of those less than 75 years of age. Serious AEs—none considered to be related to patiromer—occurred in 2% of patients 75 years and older and 1% of those less than 75 years of age. Hypokalemia (predefined as a serum K+ level <3.5 mEq/L) occurred in 8% of patients 75 years and older and in 2% of those less than 75 years of age (Table 2).



 
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