Quadruple, ultra-low-dose treatment did not meet primary endpoint in hypertension

The QUARTET USA trial did not meet its primary endpoint of reducing automated systolic blood pressure (BP) after 12 weeks. Nonetheless, the quadruple (4-drug), ultra-low-dose combination therapy numerically reduced blood pressure (BP) more than candesartan monotherapy did in a predominantly Black and Hispanic study population with mild-to-moderate hypertension.

“Low hypertension control rates reflect the need for new approaches to control this condition,” argued Dr Mark Huffman (Washington University School of Medicine, USA). Previously, the Australian QUARTET study (ACTRN12616001144404) had demonstrated that a quadruple drug combination of antihypertensive medication at ultra-low doses was more efficacious than irbesartan standard-dose monotherapy in reducing the systolic BP and diastolic BP of mostly White and Asian participants in Australia [1]. Here, Dr Huffman and colleagues assessed the efficacy of quadruple, ultra-low-dose treatment for hypertension in an American population of patients with mild-to-moderate hypertension in the QUARTET USA (NCT03640312) [2]. The study randomised 62 participants (Black n=11; Hispanic n=45) 1:1 to the intervention arm (candesartan 2 mg, amlodipine 1.25 mg, indapamide 0.625 mg, and bisoprolol 2.5 mg, daily) or the control arm (candesartan 8 mg, daily). An add-on of amlodipine 5 mg daily was allowed if BP reached >130/80 mmHg at week 6. The primary outcome was the mean change in automated systolic BP after 12 weeks.

The adjusted mean change in systolic BP at week 12 was lower (Δ -4.8 mmHg; 95% CI -10.7–1.2) and the adjusted mean change in diastolic BP was also lower in the quadruple therapy compared with the control arm (Δ -4.9; 95% CI -8.6– -1.1). The safety results showed a higher rate of adverse events (AEs) in the quadruple therapy arm than in the control arm (62.5% vs 46.7%). Likewise, serious AEs were more frequently reported in the quadruple therapy arm (6.3% vs 0%), but according to the authors, these events were not related to the study drugs. In contrast to these findings, the rate of AEs leading to treatment discontinuation was higher in the control arm than in the quadruple arm (26.7% vs 6.3%).

Dr Huffman commented that the limited sample size of the study may be responsible for the fact that the observed differences in systolic BP between the 2 study groups were not statistically significant. “The QUARTET USA study confirms the BP lowering effect of a quadruple ultra-low-dose treatment previously reported for the Australian population in a different study population, with lower baseline BP. This strengthens the case for this novel approach,” concluded Dr Huffman.

1. 
   
   1. Chow CK, et al. Lancet. 2021;398(10305):1043–1052.
   2. Huffman M, et al. Efficacy and safety of a quadruple ultra-low-dose treatment for hypertension (QUARTET USA): A randomized controlled trial. LBS.04, AHA Scientific Sessions 2022, 05–07 November, Chicago, USA.

 

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Posted on 11 January, 2023