Use of potassium-binder patiromer for up-titration of renin-angiotensin-aldosterone system inhibition therapy in a patient with chronic heart failure and reduced ejection fraction followed in a multidisciplinary integrated chronic care management programme: a case report.
ABSTRACT: Background:Chronic heart failure (CHF) is a growing epidemic. The cornerstone of pharmacological therapy in CHF patients with reduced ejection fraction (HFrEF) is the inhibition of the renin-angiotensin-aldosterone system (RAAS). One of the adverse effects of RAAS blockade is the development of hyperkalaemia, which often limits the optimization of recommended, Class I treatments. In this context, potassium binders patiromer or sodium zirconium cyclosilicate (ZS-9) provide an opportunity to optimize the pharmacological management of these patients. Case summary:We present a case report illustrating our real-life experience using the potassium-binder patiromer in a patient with HFrEF, in whom recurrent hyperkalaemia (up to 6.3?mmol/L with low doses of enalapril) was preventing titration of RAAS inhibition therapies. Use of patiromer allowed re-introducing ramipril (subsequently switched to sacubitril/valsartan) and eplerenone. Serum potassium levels remained normal with patiromer 16.8?g/24 h, and the patient's tolerance to patiromer was excellent. Discussion:In patients with HFrEF and recurrent hyperkalaemia, optimal RAAS inhibition is often discontinued. In this context, novel potassium binders such as patiromer or ZS-9 have been shown to be effective in lowering potassium and maintaining normokalaemia, with a good safety profile and patient tolerance, all of which make them promising alternative options. Our preliminary experience suggests that patiromer may be a helpful and well-tolerated treatment option, which may aid in achieving optimal RAAS inhibition in HFrEF patients with recurrent hyperkalaemia. Registries of HFrEF patients will help better understand whether therapies such as patiromer have prognostic benefits through facilitating optimal RAAS blockade.
Project description:Medications that affect the renin-angiotensin-aldosterone system (RAAS) form the mainstay of current heart failure (HF) therapy in patients with reduced ejection fraction. Concerns about the risk of hyperkalaemia have created a significant barrier to optimal RAAS inhibitor therapy in patients with HF, however, and many patients are discontinuing or receiving suboptimal doses of these lifesaving therapies. This has serious health and economic implications due to adverse renal and cardiovascular events. There is therefore an important unmet need for novel therapeutic options for the long-term management of patients with, and at risk for, hyperkalaemia. Two new potassium-binding agents, patiromer and ZS-9, have been shown to be effective and safe for the treatment of hyperkalaemia, as well as the maintenance of normokalaemia, without dose reduction or discontinuation of RAAS inhibitors. In addition, the fast onset of ZS-9 action suggests that it may be useful in the treatment of acute hyperkalaemia. These agents may allow for dose optimisation of RAAS inhibitors for the long-term maintenance and protection of the renal and cardiovascular system.
Project description:Among patients with proteinuric chronic kidney disease (CKD), current guideline recommendations mandate the use of agents blocking the renin angiotensin aldosterone system (RAAS) as first-line antihypertensive therapy based on randomized trials demonstrating that RAAS inhibitors are superior to other antihypertensive drug classes in slowing nephropathy progression to end-stage renal disease. However, the opportunities for adequate RAAS blockade in CKD are often limited, and an important impediment is the risk of hyperkalemia, especially when RAAS inhibitors are used in maximal doses or are combined. Accordingly, a large proportion of patients with proteinuric CKD may not have the anticipated renoprotective benefits since RAAS blockers are often discontinued due to incident hyperkalemia or are administered at suboptimal doses for fear of the development of hyperkalemia. Two newer potassium binders, patiromer and sodium zirconium cyclosilicate (ZS-9), have been shown to effectively and safely reduce serum potassium levels and maintain long-term normokalemia in CKD patients receiving background therapy with RAAS inhibitors. Whether these novel potassium-lowering therapies can overcome the barrier of hyperkalemia and enhance the tolerability of RAAS inhibitor use in proteinuric CKD awaits randomized trials.
Project description:PURPOSE OF REVIEW:Hyperkalemia is increasingly prevalent in the heart failure population as more people live with heart failure and comorbid conditions such as diabetes and chronic kidney disease. Furthermore, renin-angiotensin-aldosterone (RAAS) inhibitors are a key component of clinical therapy in these populations. Until now, we have not had any reliable or tolerable therapies for treatment of hyperkalemia resulting in inability to implement or achieve target doses of RAAS inhibition. This review will focus on two new therapies for hyperkalemia: patiromer and sodium zirconium cyclosilicate (SZC). RECENT FINDINGS:Patiromer and SZC have been studied in heart failure and both agents have demonstrated the ability to maintain normokalemia for extended periods of time with improved side effect profiles than existing potassium binders such as sodium polystyrene sulfate, though no direct comparisons have occurred. SZC has also shown promise in the treatment of acute hyperkalemia with its quick onset of action. SUMMARY:Patiromer and SZC will be useful adjuncts in the clinical care of heart failure patients with hyperkalemia. These agents will allow clinicians to maintain patients on RAAS inhibitors and uptitrate their guideline directed medical therapy to target doses without the additional concern for recurrent hyperkalemia and its untoward effects.
Project description:To compare and contrast the efficacy and safety of patiromer and sodium zirconium cyclosilicate (ZS-9) in the treatment of hyperkalemia.A systematic review and meta-analysis of phase II and III clinical trial data was completed.Eight studies (two phase II and four phase III trials with two subgroup analyses) were included in the qualitative analysis, and six studies (two phase II and four phase III trials) were included in the meta-analysis.Significant heterogeneity was found in the meta-analysis with an I2 value ranging from 80.6-99.6%. A random-effects meta-analysis was applied for all end points. Each clinical trial stratified results by hyperkalemia severity and dosing; therefore, these were considered separate treatment groups in the meta-analysis. For patiromer, a significant -0.70 mEq/L (95% confidence interval [CI] -0.48 to -0.91 mEq/L) change was noted in potassium at 4 weeks. At day 3 of patiromer treatment, potassium change was -0.36 mEq/L (range of standard deviation 0.07-0.30). The primary end point for ZS-9-change in potassium at 48 hours-was -0.67 mEq/L (95% CI -0.45 to -0.89 mEq/L). By 1 hour after ZS-9 administration, change in potassium was -0.17 mEq/L (95% CI -0.05 to -0.30). Analysis of pooled adverse effects from these trials indicates that patiromer was associated with more gastrointestinal upset (7.6% constipation, 4.5% diarrhea) and electrolyte depletion (7.1% hypomagnesemia), whereas ZS-9 was associated with the adverse effects of urinary tract infections (1.1%) and edema (0.9%).Patiromer and ZS-9 represent significant pharmacologic advancements in the treatment of hyperkalemia. Both agents exhibited statistically and clinically significant reductions in potassium for the primary end point of this meta-analysis. Given the adverse effect profile and the observed time-dependent effects, ZS-9 may play more of a role in treating acute hyperkalemia.
Project description:<h4>Aims</h4>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.<h4>Methods and results</h4>Chronic kidney disease (CKD) patients on renin-angiotensin-aldosterone system inhibitors (RAASi) with serum K(+) levels ?5.1 mEq/L to <6.5 mEq/L (n = 243) received patiromer (4.2 g or 8.4 g BID initially) for 4 weeks (initial treatment phase); the primary efficacy endpoint was mean change in serum K(+) from baseline to week 4. Eligible patients (those with baseline K(+) ?5.5 mEq/L to <6.5 mEq/L and levels ?3.8 mEq/L to <5.1 mEq/L at the end of week 4) entered an 8-week randomized withdrawal phase and were randomly assigned to continue patiromer or switch to placebo; the primary efficacy endpoint was the between-group difference in median change in the serum K(+) over the first 4 weeks of that phase. One hundred and two patients (42%) had heart failure (HF). The mean [± standard error (SE)] change in serum K(+) from baseline to week 4 was -1.06 ± 0.05 mEq/L [95% confidence interval (CI), -1.16,-0.95; P < 0.001]; 76% (95% CI, 69,84) achieved serum K(+), 3.8 mEq/L to <5.1 mEq/L. In the randomized withdrawal phase, the median increase in serum K(+) from baseline of that phase was greater with placebo (n = 22) than patiromer (n = 27) (P < 0.001); recurrent hyperkalaemia (serum K(+), ?5.5 mEq/L) occurred in 52% on placebo and 8% on patiromer (P < 0.001). Mild-to-moderate constipation was the most common adverse event (11%); hypokalaemia occurred in 3%.<h4>Conclusion</h4>In patients with CKD and HF who were hyperkalaemic on RAASi, patiromer was well tolerated, decreased serum K(+), and, compared with placebo, reduced recurrent hyperkalaemia.
Project description:AIMS:Hyperkalaemia risk precludes optimal renin-angiotensin-aldosterone system inhibitor use in patients with heart failure (HF), particularly those with chronic kidney disease (CKD). Patiromer is a sodium-free, non-absorbed potassium (K+ )-binding polymer approved for the treatment of hyperkalaemia. In PEARL-HF, patiromer 25.2 g (fixed dose) prevented hyperkalaemia in HF patients with or without CKD initiating spironolactone. The current study evaluated the effectiveness of a lower starting dose of patiromer (16.4 g/day) followed by individualized titration in preventing hyperkalaemia and hypokalaemia when initiating spironolactone. METHODS AND RESULTS:This open-label 8-week study enrolled 63 patients with CKD, serum K+ 4.3-5.1 mEq/L, and chronic HF, who, based on investigator opinion, should receive spironolactone. Eligible patients started spironolactone 25 mg/day and patiromer 16.8 g/day (divided into two doses), with patiromer titrated to maintain serum K+ 4.0-5.1 mEq/L. Mean (standard deviation) serum K+ was 4.78 (0.51) mEq/L at baseline; weekly values were 4.48-4.70 mEq/L during treatment. Serum K+ of 3.5-5.5 mEq/L at the end of study treatment (primary endpoint) was achieved by 57 (90.5%) patients; 53 (84.1%) had serum K+ 4.0-5.1 mEq/L. One patient (1.6%) developed hypokalaemia, and two patients (3.2%) developed hypomagnesaemia. Spironolactone was increased to 50 mg/day in all patients; 43 (68%) patients required one or more patiromer dose titration. Adverse events (AEs) occurred in 36 (57.1%) patients, with a low rate of discontinuations [four (6.3%) patients]. The most common AE was mild to moderate abdominal discomfort [four (6.3%) patients]. CONCLUSIONS:In this open-label study, patiromer 16.8 g/day followed by individualized titration maintained serum K+ within the target range in the majority of patients with HF and CKD, all of whom were uptitrated to spironolactone 50 mg/day, patiromer was well tolerated, with a low incidence of hyperkalaemia, hypokalaemia, and hypomagnesaemia.
Project description:AIMS:Chronic kidney disease (CKD) in heart failure (HF) increases the risk of hyperkalaemia (HK), limiting angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) use. Patiromer is a sodium-free, non-absorbed potassium binder approved for HK treatment. We retrospectively evaluated patiromer's long-term safety and efficacy in HF patients from AMETHYST-DN. METHODS AND RESULTS:Patients with Type 2 diabetes, CKD, and HK [baseline serum potassium >5.0-5.5 mmol/L (mild) or >5.5-<6.0 mmol/L (moderate)], with or without HF (New York Heart Association Class I and II, by investigator judgement), on ACE-I/ARB, were randomized to patiromer 8.4-33.6 g to start, divided twice daily. Overall, 105/304 (35%) patients had HF (75%, Class II). Mean (standard deviation) ejection fraction (EF) was 44.9% (8.2) (n = 81) in patients with HF; 26 had EF ≤40%. In HF patients, mean serum potassium decreased by Day 3 through Week 52. At Week 4, estimated mean (95% confidence interval) change in serum potassium was -0.64 mmol/L (-0.72, -0.55) in mild and -0.97 mmol/L (-1.14, -0.80) in moderate HK (both P < 0.0001). Most HF patients with mild (>88%) and moderate (≥73%) HK had normokalaemia at each visit from Weeks 12 to 52. Three HF patients were withdrawn because of high (n = 1) or low (n = 2) serum potassium. The most common patiromer-related adverse event was hypomagnesaemia (8.6%). CONCLUSIONS:In patients with a clinical diagnosis of HF, diabetes, CKD, and HK on ACE-I/ARB, patiromer was well tolerated and effective for HK treatment over 52 weeks.
Project description:INTRODUCTION:Hyperkalemia (potassium >5.0 mEq/L) affects heart failure patients with renal disease regardless of the use of renin-angiotensin-aldosterone system inhibitors (RAASi). The open-label TOURMALINE study showed that patiromer, a sodium-free, nonabsorbed potassium binder, lowers serum potassium of hyperkalemic patients similarly when given with or without food; unlike prior studies, patients were not required to be taking RAASi. We conducted post hoc analyses to provide the first report of patiromer in patients not taking RAASi. METHODS:Hyperkalemic patients received patiromer, 8.4 g/d to start, adjusted to achieve and maintain serum potassium of 3.8 to 5.0 mEq/L. If taking RAASi, stable doses were required. The primary end point was the proportion of patients with serum potassium 3.8 to 5.0 mEq/L at week 3 or 4. This analysis presents data by patients taking or not taking RAASi. RESULTS:Demographics and baseline characteristics were similar in patients taking (n = 67) and not taking RAASi (n = 45). Baseline mean (SD) serum potassium was 5.37 (0.37) mEq/L and 5.42 (0.43) mEq/L in patients taking and not taking RAASi, respectively. Mean (SD) daily patiromer doses were similar (10.7 [3.2] and 11.5 [4.0] g, respectively). The primary end point was achieved in 85% (95% confidence interval [CI]: 74-93) of patients taking RAASi and in 84% (95% CI: 71-94) of patients not taking RAASi. From baseline to week 4, the mean (SE) change in serum potassium was -0.67 (0.08) mEq/L in patients taking RAASi and -0.56 (0.10) mEq/L in patients not taking RAASi (both P < .0001 vs baseline, P = nonsignificant between groups). Adverse events were reported in 26 (39%) patients taking RAASi and 25 (54%) not taking RAASi; the most common adverse event was diarrhea (2% and 11%, respectively; no cases were severe). Five patients (2 taking RAASi) reported 6 serious adverse events; none considered related to patiromer. CONCLUSIONS:Patiromer was effective and generally well-tolerated for hyperkalemia treatment, whether or not patients were taking RAAS inhibitors.
Project description:Hyperkalaemia is a common electrolyte abnormality, associated with higher risk of morbid events, and increasing in prevalence-in part, due to increasing rates of comorbidities such as heart failure, chronic kidney disease, diabetes mellitus, and the use of renin-angiotensin-aldosterone system inhibitors (RAASi). In spite of this growing problem, the existing treatments for chronic hyperkalaemia have been limited, and are typically confined to dietary potassium restrictions and cessation or modification of RAASi, with latter option being potentially problematic given the known morbidity and mortality benefit of RAASi therapy in certain disease states, such as heart failure. The use of sodium polystyrene sulfonate (SPS/Kayexelate) for chronic hyperkalaemia has been low, due to poor tolerability, potential gastrointestinal safety concerns, and remaining uncertainty in regards to its efficacy. Given the shortcomings of existing therapies, novel treatments are clearly needed. There are now two novel treatment options, patiromer and sodium zirconium cyclosilicate (SZC), both approved by the FDA and EMA for treatment of chronic hyperkalaemia. These novel compounds have been demonstrated in multiple studies to be efficacious in achieving and maintaining normal serum potassium levels, over an extended time period, in patients with hyperkalaemia; and appear to be relatively safe and well-tolerated. Whether the correction of hyperkalaemia with these agents will allow optimization of RAASi, which could theoretically lead to improvement in clinical outcomes, especially in patients with heart failure, remains to be determined. Several clinical trials are ongoing to address these important knowledge gaps.
Project description:New therapeutic options to treat hyperkalaemia, such as potassium binders, have been suggested as potentially beneficial by allowing the maintenance (or increase) of the dose of medications that improve outcomes in several cardiovascular conditions, but which have in common the propensity for raising serum potassium. However, potassium binding drugs have yet to prove their causal association with improvements in patients' prognosis before their widespread use can be recommended. In this review we provided an up-to-dare appraisal on potassium binders, their potential clinical applications and directions for future research.