A low-dose, single pill that combines three antihypertensive treatments is as effective as standard-dose monotherapy — in some cases even better — for treating mild-to-moderate hypertension, according to the first phase 3 double-blind trials comparing the medications.

Investigators for the HM-APOLLO-301 and HM-APOLLO-302 phase 3 clinical trials, which were published in the Journal of the American College of Cardiology, contend there is now concrete evidence to support the efficacy of the single-pill therapy.

They argue that starting with the traditional single-agent therapy and then titrating up can delay blood pressure control, increase the possibility of adverse effects, and affect patient adherence.

Other recent studies support this concern. For example, a study in the Cleveland Clinic Journal of Medicine noted, “Starting treatment with single-pill combination therapy helps to achieve therapeutic targets faster, is more useful in controlling blood pressure in the long term, and is more efficacious in reducing blood pressure compared with monotherapy.”

Study Design

Participants in the multicenter trials conducted in South Korea were adults aged 19 years or older with mild-to-moderate hypertension.

After a 4-week placebo run-in, 610 adults with systolic blood pressure 140 to < 180 mm Hg and diastolic blood pressure < 110 mm Hg were randomized across two trials to 8 weeks of treatment with either the low-dose single-pill combination or standard-dose monotherapy. The single-pill combination included amlodipine 1.67 mg, losartan 16.67 mg, and chlorthalidone 4.17 mg. Standard-dose monotherapy was amlodipine 5 mg in Study 301 and losartan 50 mg in Study 302.

Patients with secondary hypertension, recent major cardiovascular events, advanced heart failure, severe renal impairment, significant liver disease, or major electrolyte abnormalities were excluded. Blood pressure was measured at baseline and at weeks 4 and 8.

The primary endpoint in both trials was change in systolic blood pressure at 8 weeks, tested first for noninferiority and then for superiority. Secondary endpoints included reduction in diastolic blood pressure, rates of blood pressure control, responder analyses, and safety outcomes.

Comparisons With Monotherapy

In Study 301, the single-pill combination appeared as effective as amlodipine alone. At 8 weeks, systolic blood pressure decreased by -19.1 mm Hg with the single-pill combination and -19.9 mm Hg with amlodipine. Reductions in diastolic blood pressure were also comparable (-8.9 mm Hg vs -9.7 mm Hg). Blood pressure control, defined as < 140/90 mm Hg, was achieved in 57% of participants receiving combination therapy and 60% of those receiving amlodipine.

In Study 302, however, the single-pill combination proved superior to losartan monotherapy. Systolic blood pressure decreased by -19.9 mm Hg with combination therapy compared with -16.4 mm Hg with losartan alone (P = .037). Reduction in diastolic blood pressure was also greater, with the combination therapy (-9.8 mm Hg vs -7.4 mm Hg; P = .012). Blood pressure control was achieved in 64% of participants receiving combination therapy compared with 51% of those receiving losartan (P = .042).

In sensitivity analyses using the full-analysis set, the upper confidence bound in Study 301 slightly exceeded the prespecified noninferiority margin, although results were consistent in the per-protocol population.

The study is “the first head-to-head direct comparison of blood pressure-lowering efficacy between a low-dose triple combination therapy and standard-dose monotherapy using either a calcium-channel blocker or an angiotensin receptor blocker — an approach not previously reported,” the authors wrote.

Many Possibilities

Clyde Yancy, MD, MSc, chief of Cardiology at Northwestern Medicine Bluhm Cardiovascular Institute in Chicago, sees broad opportunities for single-pill therapy.

“We don’t yet have usable options for US-based care leveraging such novel combination therapy, but as a prescribing cardiologist treating hypertension, I would readily embrace a low-dose combination pill,” he said.

The implications are even more far-reaching for global management of hypertension with an emphasis on low- and middle-income countries, Yancy added.

“The agent tested ought to be available at very low cost,” he said. “With a conservative estimate of an at least 10-mm Hg blood pressure reduction, the global burden of cardiovascular disease would diminish.”

Response to Treatment in Men vs Women

Exploratory analyses revealed sex-related differences in treatment response.

In Study 301, women experienced greater reductions in systolic blood pressure than men with both the single-pill combination and amlodipine. The differences in reduction in systolic blood pressure between women and men was 5.3 mm Hg with combination therapy and 4.8 mm Hg with amlodipine.

In Study 302, the difference between men and women was more pronounced with combination therapy. Women experienced significantly greater reductions in systolic blood pressure than men, whereas no significant sex-related difference was observed with losartan.

Among women in Study 302, the single-pill combination was superior to losartan, yielding a 5.7-mm Hg greater reduction in systolic blood pressure and a significantly greater reduction in diastolic blood pressure (-3.8 mm Hg).

Moo-Yong Rhee, MD, PhD, a professor of cardiology at the College of Medicine, Dongguk University Ilsan Hospital, Goyang, Republic of Korea, and one of the study authors, believes these differences warrant further attention.

“While this observation should be interpreted cautiously, it suggests that multi-mechanism, ultra-low-dose triple combination therapy, comprising a calcium channel blocker, an angiotensin receptor blocker and a thiazide-like diuretic, may provide particular benefit in certain subgroups, including women,” Rhee said.

“Importantly, women have historically been underrepresented in cardiovascular clinical trials, and subtle differences may become more apparent in larger pooled or integrated datasets. Continued attention to sex-specific outcomes remain essential for advancing individualized and precision-based hypertension management,” Rhee said.

This study was funded by Hanmi Pharmaceutical. Rhee reported receiving lecture honoraria from Hanmi Pharmaceutical Co. and Boryung Pharmaceutical Co. and consulting fees from Hanmi Pharmaceutical.

Lois Anzelowitz Levine is a medical and lifestyle writer living in Dallas.