Use RAAS inhibitors with caution in the elderly with hyperkalemia?

Due to multiple comorbidities, such as chronic kidney disease (CKD), heart failure, and type 2 diabetes (T2DM), elderly patients are more likely to develop hyperkalemia.

Patients taking renin-angiotensin-aldosterone system (RAAS) inhibitors have an increased risk of hyperkalemia.

The guidelines recommend that RAAS inhibitors should be used to delay the progression of diabetic nephropathy (DKD) regardless of age.

For elderly patients with hyperkalemia and diabetic nephropathy, how to balance the benefits and risks of RAAS inhibitors and safely treat them? Patiromer is a new type of potassium-lowering drug, which has been on the market in the United States in 2015.

In short-term and long-term clinical trials, Patiromer has been proven to be safe and can effectively reduce blood potassium.

The main results of the AMETHYST-DN trial show that the drug can significantly reduce the blood potassium levels in patients with diabetic nephropathy and hypertension.

A recently published post-mortem analysis of the AMETHYST-DN trial revealed the effect of Patiromer on lowering serum potassium in diabetic nephropathy and hyperkalemia patients 75 years of age and older who were treated with RAAS inhibitors.

Study design The AMETHYST-DN trial is a multi-center, randomized, open-label dose range trial involving 306 30-80-year-old CKD patients with diabetes and hypertension.

Patients with hyperkalemia (>5.
0–<6.
0 mEq/L) were randomly divided into groups during the screening period or after the 4-week lead-in period.

All patients received a stable dose of RAAS inhibitor treatment for ≥28 days before screening.

 Patients with hyperkalemia were randomly assigned to receive Patiromer treatment with a dose range of 4.
2-16.
8 g, twice a day.The single dose of mild hyperkalemia group (serum potassium 5.
0-5.
5 mEq/L) is 4.
2 g, 8.
4 g or 12.
6 g, and the single dose of moderate hyperkalemia group (serum potassium 5.
5-6.
0 mEq/L) It is 8.
4 g, 12.
6 g or 16.
8 g.

 This post-mortem analysis included 60 patients 75 years and older.

The researchers assessed the patient's serum potassium changes from baseline to week 4 and the entire 52 weeks, as well as the long-term safety and tolerability of Patiromer.
Outcome indicators include the incidence of adverse events, clinical laboratory indicators, and vital signs.

Research results The average age of the participants was 77 years old, 50% were males, 37% had heart failure, the average estimated glomerular filtration rate (eGFR) was 42 mL/min/1.
73 ㎡, and the median urine albumin/creatinine ratio was 127 mg/g, mean baseline blood potassium 5.
19mEq/L.

 1.
The effectiveness of Patiromer In general, from the first follow-up (day 3) to the 52nd week, the average serum potassium at each time point decreased.

In the 4th week, the least squares mean was observed to be significantly lower than the baseline (-0.
65 mEq/L; P <0.
001); in the 52nd week, the least squares mean was observed to decrease by -0.
61 mEq/L (P <0.
001).

At week 52, serum potassium of all patients was <5.
5 mEq/L, and 95% of serum potassium was <5.
0 mEq/L.

After 3, 7 and 14 days of drug withdrawal, the patients' average serum potassium was 4.
79 mEq/L, 4.
85 mEq/L and 4.
95 mEq/L, respectively.

2.
The safety of Patiromer In the subgroup of elderly patients analyzed in this analysis, Patiromer is well tolerated.

In the 52-week study, 31 (52%) patients reported at least one treatment-related emergency adverse event, and the investigators determined that 10 (17%) patients reported at least one Patiromer-related adverse event, none Serious adverse events.

 The most common treatment-related emergency adverse event was hypomagnesemia (6.
6%).
No patients discontinued treatment because of hypomagnesemia, and no severe hypomagnesemia (<1.
0 mg/dL) or hypokalemia (< 3.
5mEq/L).

The remaining adverse reactions included mild to moderate constipation (3.
3%), gastrointestinal diseases and chronic renal failure.

In addition, the patients' average serum calcium and serum magnesium levels have been maintained at normal levels.

Discussion and analysis showed that for elderly patients with diabetic nephropathy and hyperkalemia treated with RAAS inhibitors who are 75 years of age and older, Patiromer can effectively reduce serum potassium after 4 weeks of treatment, the effect lasts for 52 weeks, and it is tolerable in elderly patients good.

This result is consistent with the results observed in the overall population of the AMETHYST-DN trial.

As with the previous results, Patiromer can maintain the average serum potassium level within the normal range for up to 1 year, hardly any dose of titration, good tolerability and long-term safety, and most patients can continue to use RAAS inhibitors .

This study is the first long-term safety analysis of Patiromer for patients 75 years and older.

The guidelines recommend that CKD or DKD patients with hyperkalemia reduce the dose of ACEI or ARB by 50%, and re-measure the serum potassium level every 5-7 days, and then re-titrate the dose of ACEI or ARB based on the results.

However, some retrospective data show that many patients have not restarted ACEI or ARB treatment or titrated dose after hyperkalemia resolved.

The post-analysis results of AMETHYST-DN suggest that an effective and well-tolerated potassium binder may be beneficial to the elderly with multiple diseases.

Such drugs can give more patients with hypertension, end-stage renal disease and/or heart failure the opportunity to initiate and maintain RAAS inhibitor therapy at the recommended dose in the guidelines.

 Of course, this small subgroup analysis is not pre-set, so it is not random.
Randomized controlled trials are still needed to verify the above results. Literature index: George L.
Bakris, Steven D.
Woods, Paula J.
Alvarez, et al.
Hyperkalemia Management inOlder Adults With Diabetic Kidney Disease ReceivingRenin-Angiotensin-Aldosterone System Inhibitors: A Post Hoc Analysis of theAMETHYST-DN Clinical Trial.
Kidney Medicine .
January 17 2021.