Amiloride may be effective for resistant hypertension, timing of BP meds doesn't matter

Amiloride, a potassium-sparing diuretic, may be an alternative to spironolactone as a fourth-line drug in patients with resistant hypertension, according to a recent study.

Researchers in South Korea randomly assigned patients with a home systolic blood pressure (SBP) of 130 mm Hg or greater after a four-week run-in period with a fixed-dose combination of an angiotensin-receptor blocker, a calcium-channel blocker, and thiazide to begin taking 12.5 mg of spironolactone or 5 mg of amiloride per day. If patients' home SBP remained at 130 mm Hg or greater and serum potassium levels were less than 5.0 mmol/L after four weeks, the respective dosages were increased to 25 mg/d and 10 mg/d. The results of the study, which was funded in part by a research grant from Daiichi Sankyo Korea Co Ltd, were published May 14 by JAMA.

Sixty patients were randomized to the spironolactone group and 58 to the amiloride group. Seventy percent were male, and the median age was 55 years. Characteristics were similar between groups, with the exception of use of alpha-blockers (8.6% in the amiloride group vs. 0% in the spironolactone group). At baseline, mean home SBP values were 141.5 (SD, 7.9) mm Hg and 142.3 (SD, 8.5) mm Hg in the amiloride and spironolactone groups, respectively. At week 12, the change in SBP from baseline was −13.6 (SD, 8.6) mm Hg and −14.7 (SD, 11.0) mm Hg, respectively (between-group difference in change, −0.68 mm Hg; 90% CI, −3.50 to 2.14 mm Hg), with amiloride demonstrating noninferiority to spironolactone. A total of 66.1% of the amiloride group and 55.2% of the spironolactone group achieved home-measured SBPs below 130 mm Hg, while 57.1% and 60.3% achieved office-based SBPs below 130 mm Hg.

The researchers noted that they did not compare the efficacy of higher doses of spironolactone and that their results might not be generalizable to patients with chronic kidney disease, among other limitations. “In this randomized clinical trial involving participants with true resistant hypertension, amiloride demonstrated noninferior efficacy in lowering BP at 12 weeks compared with spironolactone,” they concluded.

An accompanying editorial said the trial's main take-home message is that low-dose amiloride can be considered a treatment option in patients with resistant hypertension and is comparable to low-dose spironolactone for lowering BP. The editorialists also pointed out that about half of patients with true resistant hypertension will not meet their BP goals even with the addition of amiloride or spironolactone and called for developing and validating additional therapeutic options, with new drugs being studied against spironolactone or amiloride and not just placebo.

“Trial designs with active comparators are important to justify the use of these new agents as first-line therapy for resistant hypertension given their expense, invasiveness, and/or less favorable safety profiles,” the editorialists wrote, adding that unless the new agents beat amiloride or spironolactone, they should be reserved for patients who can't tolerate these drugs or need a fifth medication. “While great strides are being made, there is still much work ahead to make resistant hypertension an obsolete concept once and for all.”

Another study on hypertension, published by JAMA on May 12, looked at whether taking blood pressure medications at bedtime instead of in the morning reduces cardiovascular risk. Researchers in Canada randomly assigned primary care patients who were taking at least one once-daily antihypertensive medication to taking them all at bedtime or taking them all in the morning.

The study included 3,357 adults (56.4% female; median age, 67 years), 53.7% on monotherapy. Antihypertensive medications included angiotensin-converting enzyme inhibitors (36%), angiotensin-receptor blockers (30%), calcium-channel blockers (29%), diuretics (27%), combination pills (18%), beta-blockers (17%), and others (1%). A total of 1,677 patients were assigned to the bedtime group and 1,680 were assigned to the morning group. Median follow-up was 4.6 years.

The study's composite primary outcome, time to first occurrence of all-cause death or hospitalization/ED visit for stroke, acute coronary syndrome, or heart failure, occurred in 2.3 per 100 patient-years in the bedtime group and 2.4 per 100 patient-years in the morning group (adjusted hazard ratio, 0.96 [95% CI, 0.77 to 1.19]; P=0.70). No between-group differences were seen in the individual components of the primary outcome, all-cause hospitalizations/ED visits, or safety outcomes, including falls or fractures, new glaucoma diagnoses, or 18-month cognitive decline.

The researchers noted that the trial was stopped early because of funding constraints and that data on when participants took their medications were self-reported, among other limitations. “Among adults with hypertension in primary care, bedtime administration of antihypertensive medications was safe but did not reduce cardiovascular risk,” and thus timing “should be guided by patient preferences,” they said.

An accompanying editorial said the current trial supports previous research and should help settle questions about the timing of medications. “The addition of a subgroup of very advanced age with attention to risks of overtreatment adds additional reassurance that time of dosing is not a safety issue,” the editorialist wrote. “We can all sleep better at night whether medications are dosed before or after bedtime hours.”