Adding Patiromer Allows More Spironolactone in Resistant HTN, CKD: AMBER

September 20, 2019

PHILADELPHIA — Adding a potassium-sequestering agent to spironolactone in patients with treatment-resistant hypertension (HTN) and chronic kidney disease (CKD) may allow them to take more of the blood pressure (BP) med for a longer time, but with a lower risk for hyperkalemia, suggests a randomized trial.

That was apparent in the study, called AMBER, regardless of whether the patients were also in heart failure (HF). In fact, all of the evaluated patient subgroups showed results similar to the trial's population as a whole.

Spironolactone's prodigious BP-lowering effects can come at the cost of serum potassium level elevation, so it tends to be reserved as an add-on med in hypertension that hasn't responded well to more standard antihypertensive agents. But the adverse effect is even more likely in patients with compromised renal function, in whom many clinicians avoid its use.

In AMBER, coadministration of potassium-binding patiromer (Veltassa, Relypsa), compared with a placebo, "enabled the more persistent use of spironolactone by reducing hyperkalemia" in patients with resistant HTN and CKD, said Bryan Williams, MD, Sciences University College London and National Institute for Health Research UCL/UCL Hospitals Biomedical Research Centre, London, here at the Heart Failure Society of America 23rd Annual Scientific Meeting.

Those who received patiromer once daily were able to take an average of almost 400 mg/day more of spironolactone than those taking a patiromer placebo. Two-thirds of the control subjects developed hyperkalemia, and taking patiromer was associated with a reduction in that risk by about one-half, said Williams, who is also senior author on the trial, published online September 15 in the Lancet.

Even though more patients on patiromer took spironolactone for a longer time, BP fell significantly in both groups; although their BPs were about the same at the end of the study's 12 weeks.

In these patients, "you've clearly shown that you can enable use of spironolactone, which has long-term implications," Bertram Pitt, MD, University of Michigan, Ann Arbor, said to Williams after his presentation.

But the differences in BP reduction "weren't that great," Pitt added. "If you had to do this again, would you think about perhaps going to a higher dose? Because even though they had renal disease, these patients were protected by patiromer. One could have possibly shown a better effect on the blood pressure."

Potentially, the potassium sequestrant might allow the use of even higher spironolactone dosages for both BP-lowering and in heart failure, Williams replied. That is, "if we are able to overcome the anxieties that doctors often have about using spironolactone in these high doses, particularly in patients with impaired kidney function. I think that's a really important point."

"Can more patients have access to this therapy more safely? I think they showed that," Eric Velazquez, MD, Yale School of Medicine, New Haven, Connecticut, told | Medscape Cardiology.

However, the AMBER researchers "tested a strategy of patiromer with spironolactone from the get-go," said Velazquez, who is not connected to the study.

"Probably a more clinically relevant one would be to have it available to patients who can't tolerate spironolactone because of potassium."

Because the potassium sequestrant is available to clinicians, in practice it will likely be used with the aldosterone inhibitor in AMBER-like patients who "we believe will strongly benefit from spironolactone but who can't tolerate it based on monitoring that shows potassium elevation."

But, "what is its safety, and how should you monitor it? Those are the sticky problems that clinicians will have to address when integrating this option for patients in their practice," Velazquez said.

Patiromer was approved partly on the basis of the AMETHYST-DN study, in which its use appeared to safely control hyperkalemia in patients with type 2 diabetes and hypertension, with or without HF. The patients had entered the study with mild to moderate hyperkalemia secondary to treatment with renin-angiotensin-aldosterone-system (RAAS)-inhibiting drugs.

For the current study, the phase 2 AMBER trial randomly assigned 295 adults with uncontrolled resistant HTN and CKD — defined as an estimated glomerular filtration rate (eGFR) of 25 to 45 mL/min per 1.73 m² — at 62 outpatient centers in 10 countries in Eastern and Western Europe, South Africa, and the United States.

All took spironolactone on an open-label basis, initiated at 25 mg once daily (with uptitrations allowed every 3 weeks), on top of the BP-lowering meds they were taking at baseline. The 147 assigned to patiromer drank the oral suspension in water at 8.4 g once daily; uptitration was allowed after 1 week. All were told not to change their intake of foods with potassium.

After 12 weeks, about 86% of the 147 patients on patiromer and about 66% of the 148 on placebo remained on spironolactone, for an actual between-group difference — the trial's primary end point — of 19.5% (< .0001) by intention to treat.

Those on patiromer, compared with those on placebo, were able to take an average of 384.7 mg more spironolactone (P = .021). Significantly fewer patiromer patients were seen with serum potassium levels of at least 5.5 mmol/L (P < .0001).

Systolic BP dropped over the 12 weeks by 11.7 mm Hg, on average, in the patiromer group and by 10.8 mm Hg in the placebo group; both decreases were significant vs baseline (P < .0001) but the intergroup difference was not.

Decreases in eGFR of at least 30% were seen in 19% and 18% of patients, respectively.

Primarily mild or moderate adverse events, Williams said, occurred in 56% of those on patiromer and 53% of the control group, not a significant difference.

In the prespecified analysis comparing the 132 patients with a history of HF with the 163 without such a history, there was no significant difference in time to development of serum potassium of at least 5.5 mmol/L (= .212).

Primary End Point by Heart Failure Status in AMBER




P Value

History of HF, patients on spironolactone at week 12 (%)




No history of HF, patients on spironolactone at week 12 (%)




Interaction P = .8085 for history of heart failure

Among those with HF, none of the 63 in the patiromer group and 1.4% of the 69 control subjects discontinued their assigned treatment because of hyperkalemia. The corresponding rates for those without HF were 1% and 7% for the 84 on patiromer and the 79 control patients, respectively.

A trial underway called DIAMOND is exploring whether adding patiromer can enable patients with HF and reduced ejection fraction who are hyperkalemic or have a recent history of hyperkalemia to continue taking RAAS inhibitors, including spironolactone.

With a total estimated enrollment of almost 2400 and a primary end point of cardiovascular death or hospitalization, the randomized placebo-controlled DIAMOND, Williams said, will be the first trial in this arena "looking at enablement of beneficial therapy in terms of patient outcomes."

AMBER was funded by Relypsa. Williams reports consulting for Relypsa, Vascular Dynamics, and Novartis; and receiving lecture honoraria from Daichii Sankyo, Pfizer, Novartis, Servier, and Boehringer Ingelheim. Velazquez reported research grants, honoraria for speaking, and consulting or serving on an advisory board for Novartis. Pitt listed no disclosures.

Lancet. Published online September 15, 2019. Abstract

Heart Failure Society of America 23rd Annual Scientific Meeting: Late Breaking Clinical Trials. Presented September 16, 2019.

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