Low-dose polypill: Another step forward in hypertension management?

A polypill comprising ultra-low doses of four antihypertensive drugs shows promise in reducing blood pressure (BP) levels compared with standard monotherapy, according to a small study presented at AHA 2022.

“Initiating a four-drug, quarter-dose BP-lowering combination led to a –4.8/–4.9 mm Hg greater reduction in change in BP from baseline to 12 weeks compared with standard-dose [angiotensin receptor blocker] monotherapy in patients with mild to moderate hypertension,” remarked study author Dr Mark Huffman, an adjunct professor at the Feinberg School of Medicine, Northwestern University, Chicago, Illinois, US.

Participants in the QUARTET* USA trial were 62 patients (mean age 52 years, 45 percent female, 73 percent Hispanic) with hypertension who were either treatment-naïve (BP: 140–179/90–109 mm Hg) or on monotherapy (BP: 130–159/85–99 mm Hg). They were randomized 1:1, double-blind, to receive the intervention comprising four drugs at low doses (candesartan [2 mg] + amlodipine [1.25 mg] + indapamide [0.625 mg] + bisoprolol [2.5 mg]) or candesartan monotherapy (8 mg/day) for 12 weeks. Patients with BP levels ≥130/80 mm Hg at the 6-week mark could receive add-on amlodipine (5 mg/day). 

Twenty-nine and 24 patients in the intervention and monotherapy groups, respectively, completed the 12 weeks of follow up. Mean BP levels at baseline were 137.6/84.3 and 138.7/84.3 mm Hg, respectively. Mean heart rate was 72 beats per minute and 24 patients in each group were on monotherapy. Nineteen and 53 percent of patients in the intervention and monotherapy groups, respectively, received add-on amlodipine at week 6.

At 12 weeks, patients in the intervention group experienced a reduction in systolic BP levels compared with those on monotherapy (adjusted mean change, –4.8 mm Hg (95 percent confidence interval [CI], –10.7 to 1.2). [AHA 2022, session LBS.04]

There was also a reduction in diastolic BP at 12 weeks in the intervention vs monotherapy group (adjusted mean change, –4.9 mm Hg (95 percent confidence interval [CI], –8.6 to –1.1).

The small sample size may have been responsible for the lack of statistical significant difference in systolic BP levels between groups, said Huffman.

The reductions in systolic and diastolic BP levels (unadjusted values) were rapid in the intervention group (systolic BP levels: mean 122.9 and 121.2 mm Hg at 6 and 12 weeks, respectively; diastolic BP levels: mean 72.3 and 73.2 mm Hg, respectively). In the monotherapy group, systolic BP levels were 130.1 and 124.2 mm Hg at 6 and 12 weeks, respectively, and diastolic BP levels 78.9 and 77.0 mm Hg, respectively.

Adverse events (AEs) occurred in 62.5 and 46.7 percent of patients in the intervention and monotherapy groups, respectively, with 25 and 10 percent, respectively, possibly related to trial regimen. Two and eight patients, respectively (6.3 percent vs 26.7 percent), discontinued treatment due to AEs. Two serious AEs were reported in the intervention arm, though neither was considered related to study drug.

“New approaches are needed to achieve lower BP targets, especially for patients and communities with a high burden of hypertension and hypertension-related diseases,” said Huffman.

According to discussant Assistant Professor LaPrincess Brewer from the Mayo Clinic College of Medicine, Rochester, Minnesota, US, the upfront low-dose drug combination therapy is likely to be a more effective and efficient approach to reducing BP in patients with uncontrolled hypertension.

The difference in systolic BP may not be statistically significant but it is clinically meaningful, she said.