Adding amiloride effective in resistant hypertension

with fewer side effects

Sungha Park, Professor of Cardiology, Severance Hospital

Possibility rises for its use as an alternative to spironolactone...non-inferiority proven through a randomized controlled trial

“Has sufficient clinical value when considering side effects and compliance”...expectations rise on its inclusion in practice guidelines

Sungha Park, Professor of Cardiology, Severance Hospital

A new treatment option has been proposed for patients with resistant hypertension that cannot be controlled even with the existing triple combination therapy for hypertension.

 

A regimen combining an olmesartan-based triple combination therapy with the potassium-sparing diuretic ‘amiloride’ demonstrated similar blood pressure-lowering effects to spironolactone, which was previously recommended as a fourth-line treatment, with fewer side effects.

 

The SPARE study, led by Professor Sungha Park of the Department of Cardiology at Severance Hospital, was published in the international medical journal JAMA, attracting significant attention.

 

During an interview with Dailypharm, Professor Park emphasized that the amiloride-based combination therapy has established clinical evidence supporting its broader use in real-world clinical settings for resistant hypertension.

 

Difficult-to-treat ‘Resistant Hypertension’...Need for use of amiloride highlighted There are approximately 12.3 million hypertension patients in South Korea, of whom 10 -15% are classified as having “resistant hypertension,” which is defined as failing to achieve target blood pressure despite the use of three or more antihypertensive medications.

 

Patients who fail to control their blood pressure even with up to 5 antihypertensive medications are classified as having “refractory hypertension,” accounting for less than 1% of all patients.

 

According to National Health Insurance Service data, approximately 7.4% of hypertensive patients in South Korea are diagnosed with true resistant hypertension.

 

Patients with true resistant hypertension have a 1.5 to 2 times higher risk of developing cardiovascular diseases compared to general hypertensive patients, making active blood pressure control crucial for managing their prognosis.

 

Resistant hypertension is treated by adding an antihypertensive drug to the three antihypertensive drugs used to control blood pressure in general hypertensive patients: calcium channel blockers, RAS blockers, and diuretics.

 

For patients whose blood pressure remains uncontrolled even with the four-drug combination, spironolactone is recommended in the fourth line as an additional drug.

 

Spironolactone is a diuretic that acts as an aldosterone receptor antagonist, inhibiting sodium reabsorption to lower blood pressure.

 

If blood pressure remains uncontrolled even then, vasodilators such as beta-blockers, alpha-blockers, minoxidil, and hydralazine may be used.

 

Professor Park stated, “The biggest issue with spironolactone is its side effects.

 

Although spironolactone is an aldosterone antagonist, it can block sex hormones, leading to fatigue, gynecomastia in men, and menstrual irregularities in women.

 

The most serious concern is the high risk of hyperkalemia.” He added, “Due to concerns about such side effects, its use is restricted in elderly patients or those with impaired renal function, and compliance may be low.

 

Although spironolactone is recommended as a fourth-line drug in various clinical guidelines, it is not widely used in practice.” Professor Park said, “While spironolactone has been recognized as a typical potassium-sparing diuretic due to its proven efficacy in reducing the risk of cardiovascular disease after heart failure or myocardial infarction, amiloride has been relatively overlooked.

 

Amiloride is a drug that was widely used in the past, as it acts as a diuretic while also increasing potassium levels.” Amiloride demonstrates non-inferiority to spironolactone To verify this, Professor Park's research team and 14 other domestic institutions conducted a study to confirm the non-inferiority of spironolactone and amiloride.

 

This clinical trial is the first head-to-head trial comparing the two drugs.

 

Professor Park explained, “Guidelines recommend considering amiloride for patients with poor tolerability due to spironolactone’s side effects.

 

However, there was no randomized controlled trial (RCT) data to support this recommendation.

 

Against this backdrop, we decided to conduct a randomized controlled trial comparing spironolactone and amiloride.” He added, “Amiloride is a potassium-sparing diuretic that directly acts on the epithelial sodium channel (ENaC) in the distal convoluted tubule to block sodium reabsorption and preserve potassium.

 

Unlike spironolactone, which blocks aldosterone receptors, its different mechanism of action does not cause hormone-related side effects such as fatigue, gynecomastia, or menstrual irregularities.” The study, named SPARE, targeted patients whose blood pressure remained uncontrolled despite taking existing triple antihypertensive medications.

 

The study focused on patients whose systolic blood pressure remained at or above 140 mmHg after a 4-week introductory treatment with Sevikar HCT (active ingredients: olmesartan, amlodipine, and hydrochlorothiazide), The research team then divided the patients into two groups and compared them for 12 weeks: one group additionally received amiloride 10 mg and the other additionally received spironolactone 25 mg.

 

After 12 weeks of treatment, the average home systolic blood pressure and the rate of achieving target blood pressure in the clinic were measured.

 

Professor Park emphasized the importance of selecting “true resistant hypertension patients” to ensure more accurate results during this process.

 

Professor Park explained, “We focused on patients who had uncontrolled blood pressure despite taking three or more conventional antihypertensive medications.

 

We noted that a single combination therapy drug was effective in improving medication adherence, so we administered Sevikar HCT, a three-drug combination therapy containing olmesartan, amlodipine, and hydrochlorothiazide, at an appropriate dose tailored to each patient's condition for four weeks.” He added, “Sevikar HCT has already been proven to be an effective combination with excellent blood pressure-lowering effects and target blood pressure achievement rates among olmesartan-based triple combination drugs.

 

It is a combination with proven clinical evidence.” The study results showed that amiloride demonstrated non-inferiority to spironolactone in terms of blood pressure-lowering effects.

 

More specifically, the average home systolic blood pressure at week 12 compared to baseline was reduced by 14.7 mmHg in the amiloride group and 13.6 mmHg in the spironolactone group.

 

The difference in blood pressure reduction between the two groups was -0.68 mmHg, which was not statistically significant.

 

Additionally, spironolactone was particularly effective in individuals with elevated aldosterone levels, whereas amiloride demonstrated consistent efficacy across all patients, regardless of aldosterone to renin ratio.

 

It is known that an abnormally activated aldosterone-to-renin ratio can lead to elevated blood pressure.

 

Professor Park stated, “Considering drug characteristics such as medication adherence, ease of use, and side effects, amiloride could serve as an alternative to spironolactone.

 

However, further long-term follow-up studies and expanded application in practice would be necessary.” He continued, “It is uncertain whether this study can be directly applied to Caucasians, but at least in East Asian populations such as Koreans and Japanese, amiloride can be expected to provide sufficient blood pressure-lowering effects.

 

Although it was only a three-month study, side effects were significantly reduced.

 

There were no cases of hyperaldosteronism, and the incidence of hyperkalemia was low.

 

These findings also relay an important message.

 

Professor Park noted, “While amiloride has not been actively recommended in the past, major guidelines may likely incorporate this finding in the future.” The Korean Society of Hypertension is currently revising its guidelines, and there is a high likelihood that the updated guidelines will reflect this information next year.

 

Since the study involved domestic patients, the findings will likely be reflected.

 

The guidelines may include recommendations to use amiloride as an option for resistant hypertension when spironolactone cannot be used.

 

I believe it may also be reflected in other guidelines as well.”