Hypertension is the leading preventable risk factor for all‐cause death globally. 1 Despite this, blood pressure (BP) continues to be poorly managed. The QUARTET (Quadruple Ultra‐Low‐Dose Treatment for Hypertension) trial was a multicenter, double‐blind, randomized controlled trial of 591 participants with hypertension. 2 The trial demonstrated greater reduction in BP among participants assigned to receive an ultra‐low‐dose combination of 4 antihypertensive agents known as the “quadpill” (irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg, bisoprolol 2.5 mg) compared with “standard‐of‐care” monotherapy (control group treated with irbesartan 150 mg). Here, we report the results of the imaging substudy that evaluates alterations in structural and functional echocardiographic parameters after 12 months of therapy in both groups.
The methods and primary results of the QUARTET trial have been previously reported. 2 Data supporting this substudy are available from the corresponding author upon reasonable request. Participants were recruited from 3 sites across Australia (Westmead Hospital, Sydney; Royal Perth Hospital and Curtin University Health Service, Perth) with capacity to perform comprehensive, research‐focused transthoracic echocardiograms before commencement of treatment and at 12‐month follow‐up. Ethics approval was obtained from the Human Research Ethics Committee, and all participants gave informed consent.
Transthoracic echocardiograms were performed using the E95 (General Electric, Norway) ultrasound system. Left ventricular (LV) and left atrial (LA) volumes, LV wall thickness, and LV mass derived using the Devereux formula indexed to body surface area (LVMi) and LV ejection fraction were measured offline according to American Society of Echocardiography guidelines 3 by an expert observer, blinded to treatment allocation. All investigators were blinded to treatment allocation, with unblinding occurring only after final analysis. Changes in LVMi between the groups was the primary outcome determined a priori.
Cardiac magnetic resonance imaging was performed at baseline and 12 months in a subset of patients (n=23). Cine imaging was by steady‐state free precession (short‐axis stack with whole‐heart coverage, parallel imaging factor 2). LV mass including papillary muscle was measured, and LA appendage was excluded from LA volumes. Cardiac magnetic resonance imaging scans were assessed by an expert observer. Due to small numbers, only aggregated data from all 23 patients are presented. Statistical analysis was performed on SPSS version 23 (IBM Corporation, Armonk, NY). Continuous variables are presented as mean and within‐patient analysis performed using a paired t test.
Seventy‐six participants from the QUARTET trial were enrolled in this substudy. Two without baseline transthoracic echocardiogram were excluded; thus, 74 patients were included in final analysis, with 37 patients per group after unblinding. Average heart rate in the quadpill group was 68 versus 59 bpm (baseline and 12 months, respectively; P<0.001) and in the control group was 73 versus 72 bpm (P=0.519). Average 24‐hour ambulatory systolic BP was 142 versus 128 mm Hg (baseline and 12 months; P<0.001) in the quadpill group and 139 versus 134 mm Hg (P=0.009) in the control group.
Treatment with the quadpill was associated with significant reduction in LVMi at 12 months, not evident in the control group (80.1 versus 73.8 g/m2, P=0.007; 78.9 versus 76.9 g/m2, P=0.409; Figure). The quadpill group demonstrated a significant increase in LV ejection fraction (60.7% versus 63.6%, P=0.009; 61.1% versus 63.1%, P=0.072). Maximum LA volume index increased significantly over 12 months in both the quadpill and control groups (28.6 versus 33.4 mL/m2, P<0.001; 27.7 versus 31.0 mL/m2, P=0.006). Cardiac magnetic resonance imaging in 23 patients from both the quadpill and monotherapy groups demonstrated a trend toward reduction in LV mass (115.3 versus 111.4 g, P=0.089) and increasing LA volumes (72.3 versus 75.9 mL, P=0.290) over 12 months.
Figure 1. Change in LV indexed mass in the quadpill treated and monotherapy groups at baseline and at 12‐month follow‐up.
The area shaded green includes patients with <10 g/m2 increase in LV indexed mass at 12 months. LV indicates left ventricular; and LVMi, left ventricular mass indexed to body surface area.
We have previously reported superior BP‐lowering effect with the quadpill versus monotherapy. Here, we demonstrate that ultra‐low‐dose quadruple combination therapy further results in significant reduction in LVMi, with LV hypertrophy a well‐recognized risk factor for heart failure, arrhythmia, and death. 4 Our substudy highlights the superiority of the quadpill versus antihypertensive monotherapy, beyond BP reduction, with evidence of LV reverse remodeling, with the potential for improving long‐term cardiovascular outcomes.
An increased LV ejection fraction (albeit small and within the normal range) was noted in the quadpill group likely consequent to the reduced heart rate (given the β blocker component of the quadpill) and associated prolonged LV diastolic filling; however, a direct impact of the quadpill on LV ejection fraction via cardiac remodeling is possible.
Interestingly, we observed increased LA indexed volumes in both groups despite improved BP control over 12 months, which was confirmed in a subset on magnetic resonance imaging. As LA enlargement precedes LV hypertrophy in hypertensive heart disease, 5 we expected stabilization or possible regression of LA volumes with improved BP control. We hypothesize that LA reverse remodeling may occur only following sustained reduction in BP with consequent sustained reduction in LVMi and require longer‐term follow‐up.
Treatment of hypertension with the combination quadpill demonstrates not only superior BP control, but also LV reverse remodeling with reduction in LVMi, not apparent in those treated initially with a single agent. Structural LV change would likely improve clinical outcomes, though this requires validation in larger and longer‐term studies.
Registration
Registration: URL: https://www.anzctr.org.au/Trial; Unique Identifier: ACTRN12616001144404.
Sources of Funding
Funding for the parent study (QUARTET) was provided by the National Health and Medical Research Council, Australia.
Disclosures
None.
Acknowledgments
The authors thank Justine Chan, Kim Ireland, David Yun, and Gerald Pretorius for their contributions to this study. The authors also thank all patients and their families who helped contribute to this research.
This manuscript was sent to Tochukwu M. Okwuosa, DO, Associate Editor, for review by expert referees, editorial decision, and final disposition.
For Sources of Funding and Disclosures, see page 3.
Contributor Information
Clara K Chow, Email: clara.chow@sydney.edu.au.
Liza Thomas, Email: liza.thomas@sydney.edu.au.
References
- 1. Mills KT, Stefanescu A, He J. The global epidemiology of hypertension. Nat Rev Nephrol. 2020;16:223–237. doi: 10.1038/s41581-019-0244-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Chow CK, Atkins ER, Hillis GS, Nelson MR, Reid CM, Schlaich MP, Hay P, Rogers K, Billot L, Burke M, et al. Initial treatment with a single pill containing quadruple combination of quarter doses of blood pressure medicines versus standard dose monotherapy in patients with hypertension (QUARTET): a phase 3, randomised, double‐blind, active‐controlled trial. Lancet. 2021;398:1043–1052. doi: 10.1016/S0140-6736(21)01922-X [DOI] [PubMed] [Google Scholar]
- 3. Lang RM, Badano LP, Mor‐Avi V, Afilalo J, Armstrong A, Ernande L, Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2015;28:1–39.e14. doi: 10.1016/j.echo.2014.10.003 [DOI] [PubMed] [Google Scholar]
- 4. Bang CN, Devereux RB, Okin PM. Regression of electrocardiographic left ventricular hypertrophy or strain is associated with lower incidence of cardiovascular morbidity and mortality in hypertensive patients independent of blood pressure reduction ‐ a LIFE review. J Electrocardiol. 2014;47:630–635. doi: 10.1016/j.jelectrocard.2014.07.003 [DOI] [PubMed] [Google Scholar]
- 5. Su G, Cao H, Xu S, Lu Y, Shuai X, Sun Y, Liao Y, Li J. Left atrial enlargement in the early stage of hypertensive heart disease: a common but ignored condition. J Clin Hypertens (Greenwich). 2014;16:192–197. doi: 10.1111/jch.12282 [DOI] [PMC free article] [PubMed] [Google Scholar]