Objectives

To evaluate whether treatment with a four-drug, quarter-dose combination therapy will have a greater reduction in office measured blood pressure, and with fewer side effects, compared with standard dose monotherapy in patients with hypertension.

Background

More than 1 billion adults have hypertension globally. Despite widespread availability of generic blood pressure lowering drugs for decades, hypertension control rates (defined as a blood pressure <140/<90 mm Hg) remain persistently low (<50%) among adults in the United States. Control rates are even lower (<25%) when accounting for newer, lower blood pressure targets (defined as a blood pressure <130/<80 mm Hg) recommended by national and international clinical practice guidelines. Hypertension is more prevalent in racial and ethnic minorities, in whom control rates are also lower than other groups.

Most patients with hypertension are initially treated with a single blood pressure lowering drug that is titrated up over multiple, monthly office visits with additional medications added sequentially. However, previous trials of single drug ultra-low dose (i.e., one-quarter of a standard dose) blood pressure lowering therapy demonstrated an average of −4.7 systolic and −2.4 diastolic mm Hg greater blood pressure lowering compared with placebo with no significant difference in adverse events. Each additional drug added in a combination of quarter-dose blood pressure lowering drugs demonstrated a stepwise gradient of blood pressure lowering. Two- and three-drug single pill combinations have a favorable balance between greater blood pressure lowering effect, tolerability, adherence, and persistence in blood pressure control. At the time of this study, single pill combination therapy was recommended by major clinical practice guidelines and the World Health Organization.

The QUARTET USA trial evaluated whether treatment with ultra-low-dose quadruple-combination therapy will lower in office-measured blood pressure more effectively, and with fewer side effects, compared with standard dose monotherapy in patients with hypertension.

Participants

Eligible participants were adults 18 years or older, English or Spanish speakers, and with mild to moderate hypertension that was either untreated or treated with monotherapy. Clinically measured blood pressure thresholds for inclusion were: 140–179/90–109 mm Hg for untreated participants and 130–159/85–109 mm Hg for participants on monotherapy.

62 participants were randomized, including 32 to the four-drug, quarter-dose combination therapy intervention arm and 30 to the control arm.

Design

QUARTET USA was a type I hybrid, phase II randomized (1:1), double-blind trial conducted at a federally qualified health center network in Chicago, Illinois. Participants completed baseline surveys, provided blood and urine samples, and had an electrocardiogram performed. Participants received either a quadpill of candesartan (2 mg), amlodipine (1.25 mg), indapamide (0.625 mg), and bisoprolol (2.5 mg) or candesartan (8 mg) for 12 weeks.

At the six-week follow-up visit, participants completed additional surveys, and study staff counted their pills, inquired about adverse events, and measured their blood pressure. If the systolic blood pressure was greater than 130 mm Hg or the diastolic blood pressure was greater than 80 mmHg, then participants in either arm were given open label amlodipine 5 mg daily in addition to continuing their blinded study medication. Participants returned for the final study visit at 12 weeks and completed additional surveys and had their blood pressures measured.

The primary outcome was mean change in systolic blood pressure (SBP) at 12 weeks, controlling for baseline BP. Secondary outcomes included mean change in diastolic blood pressure (DBP), serious adverse events, relevant adverse drug effects, and electrolyte abnormalities.

Conclusions

The QUARTET USA trial provides evidence of efficacy and safety of a four-drug, quarter-dose combination therapy with a similar reduction in systolic blood pressure and a greater reduction in diastolic blood pressure compared with standard dose angiotensin receptor blocker monotherapy in patients with mild to moderate hypertension.

Huffman MD, Baldridge AS, Lazar D, et al. Efficacy and safety of a four-drug, quarter-dose treatment for hypertension: the QUARTET USA randomized trial. Hypertens Res. 2024;47(6):1668-1677. doi:10.1038/s41440-024-01658-y

Publications

Quartet (Australia): https://pubmed.ncbi.nlm.nih.gov/34469767/

Translational Science Benefits Model: https://pubmed.ncbi.nlm.nih.gov/39655028/

Process Evaluation: https://pubmed.ncbi.nlm.nih.gov/38156601/

Protocol: https://pubmed.ncbi.nlm.nih.gov/36116516/

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