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Initial treatment with a single capsule containing half-dose quadruple therapy vs standard-dose dual therapy in hypertensive patients (QUADUAL): a randomized, blinded, crossover trial

BMC Medicine volume 23, Article number: 56 (2025) Cite this article

Abstract

Background

Guidelines recognized dual combination in initial antihypertensive therapy. Studies found that low-dose quadruple combination were superior to monotherapy. However, whether low-dose quadruple therapy is better than dual combination is unknown.

Methods

A randomized blinded crossover trial was conducted to compare the efficacy and safety of low-dose quadruple antihypertensives (irbesartan 75 mg + metoprolol 23.75 mg + amlodipine 2.5 mg + indapamide 1.25 mg) with standard-dose dual antihypertensives (irbesartan 150 mg + amlodipine 5 mg), both in a single pill, in the initial treatment of patients with mild to moderate hypertension. Patients were randomly assigned in a 1:1 ratio to two crossover sequences. Each sequence received four-weeks of either half-dose quadruple antihypertensives or standard-dose dual antihypertensives, followed by a two-week washout and crossover for four-weeks. Participants and researchers were blinded. The main outcomes were the reduction of blood pressure and safety outcomes. Analyses were per intention to treat.

Results

A total of 90 eligible participants were randomized between July 13, 2022, and April 20, 2023. The mean age was 43.88 years (SD 10.31), and 25.6% were women. The mean baseline 24-h blood pressure was 145.59/93.84 mm Hg. Compared to the standard-dose dual treatment, the half-dose quadruple treatment resulted in a further reduction in mean 24-h blood pressure by 4.72/4.17 mm Hg (P < 0.001 for both systolic and diastolic blood pressure), mean daytime blood pressure by 5.52/4.73 mm Hg (P < 0.001 for both), mean nighttime blood pressure by 2.37/2.25 mm Hg (P = 0.034 and 0.014, respectively), and mean office blood pressure by 2.91/1.73 mm Hg (P < 0.001 and 0.014, respectively). Apart from significant increases of fasting blood glucose (P = 0.029) and blood uric acid (P < 0.001) in the half-dose quadruple group, no other adverse events or changes in laboratory values differed significantly between the two treatments.

Conclusions

Initiating treatment with half-dose quadruple combination therapy was more effective in lowering blood pressure than standard-dose dual therapy. The safety of half-dose quadruple therapy was comparable.

Trial registration

ClinicalTrials.gov Identifier: NCT05377203.

Peer Review reports

Background

Hypertension is the most common cardio-cerebrovascular disease worldwide and often coexists with other cardiovascular risk factors, causing damage to important organs [1, 2]. Globally, hypertension is the leading risk factor for deaths, accounting for 10.8 million deaths in 2019 [3], and it also places a significant economic burden on China [4]. However, despite its prevalence and impact, the awareness, treatment, and control rates of hypertension remain suboptimal, with some data showing corresponding metrics to be as low as 50.0%, 38.1%, and 11.1%, respectively [5].

Current hypertension guidelines recognized the efficacy of dual combination therapy as an initial antihypertensive treatment [1, 2, 6,7,8,9]. However, hypertension involves multiple mechanisms [10, 11], and the goal of blood pressure control has become more stringent. Dual combination therapy may not be sufficient to meet the needs of patients. Several studies have investigated the use of low-dose three-drug or four-drug combinations in initial treatment [12,13,14,15,16], which showed promising results in terms of antihypertensive effects and safety profiles compared to monotherapy. However, these studies employed monotherapy or placebo or usual care as controls, which are not consistent with current guidelines for initial hypertension treatment or not a fixed comparison. These studies did not demonstrate whether low-dose multidrug (≥ 3) combinations were more effective than the current recommended dual combinations, and studies conducted in a predominantly Asian/Chinese population are still lacking.

Therefore, the QUADUAL trial aimed to address these gaps in research by evaluating the efficacy and safety of half-dose quadruple therapy compared to standard-dose dual therapy.

Methods

Study design

We conducted an investigator-initiated, prospective, randomized double-blind 2 × 2 crossover clinical trial, comparing the effectiveness and safety of low-dose quadruple antihypertensives with standard-dose dual drugs in initial antihypertensive treatment in patients with mild to moderate hypertension (140–179/90–109 mm Hg), in the Third Xiangya Hospital of Central South University, Hunan Province, China. The protocol (Additional file 1) and statistical analysis plan have been published previously [17, 18]. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.

Participants

Participants were eligible for inclusion in the trial if they were 1) ≥ 18 and < 80 years old; 2) had never taken antihypertensive medications or had not taken antihypertensive medications in the past one month; 3) met the diagnostic criteria of hypertension: a) office blood pressure: systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg, in three separate measurements on different days; and b) ABPM: 24-h average blood pressure ≥ 130/80 mmHg or daytime average blood pressure ≥ 135/85 mmHg or nighttime average blood pressure ≥ 120/70 mmHg; 4) participated voluntarily and signed a written informed consent. Patients were excluded from the trial if 1) they were confirmed or highly suspected secondary hypertension; 2) had severe hypertension; 3) other conditions not appropriate for participating in this trial. Detailed inclusion and exclusion criteria were listed in the Additional file 2: Expanded Methods.

Randomization

Randomization and blinding were established by an independent statistician using blocked randomization and individual random crossover method. Except for randomizing, blinding, and drug coding investigators, who were not involved in any other process of the trial, all others were blinded to patient grouping and drug assignment [17]. The blind allocation was sealed in opaque envelopes.

Interventions

Participants were randomized into two crossover sequences in 1:1 ratio. One sequence was given low-dose quadruple antihypertensive drugs for four weeks, washed out with a placebo for two weeks, and then switched to standard-dose dual drugs for four weeks. The other sequence went the other way (Additional file 2: Fig. S1).

The combination drugs were put into one identical capsule. Half-dose quadruple capsule contained irbesartan 75 mg, metoprolol 23.75 mg (metoprolol tartrate sustained-release tablet), amlodipine 2.5 mg, indapamide 1.25 mg in total (referred to as “1/2 (A + B + C + D)”) and standard-dose dual capsule contained irbesartan 150 mg and amlodipine 5 mg in total (“A + C” for short), advised to take once daily, in the morning on an empty stomach.

Study outcomes

The primary outcome was established as the reduction in mean 24-h systolic blood pressure (SBP) by ABPM after four weeks of drug administration.

Secondary outcomes were the change in mean daytime and nighttime SBP in ABPM; 24-h, daytime, and nighttime mean diastolic blood pressure (DBP) in ABPM; morning blood pressure surge in ABPM; office blood pressure; home blood pressure; and heart rate after four-week treatment. Blood pressure control rate after treatment was also concerned. Time in target range (TTR) of home blood pressure = days met target / days of medication × 100% [19]. Medication compliance = (total number of dispensed medication pills—number of returned medication pills) / number of days medication should be taken * 100%.

Safety outcomes were adverse events, adverse drug reactions after treatment and changes in biochemistry results and QT interval of the electrocardiogram.

Certified medical electronic upper arm sphygmomanometer [Omron HBP-1300, OMRON (DALIAN) Co., Ltd.] was used for clinic blood pressure and certified ambulatory blood pressure monitor [DMS-ABP, DM SYSTEMS (Beijing) Co., Ltd.] for ambulatory blood pressure. Home blood pressure was measured at home by patients themselves or their family members with upper arm sphygmomanometers calibrated by physicians when enrolling. Blood pressure measurement methods were detailed in Additional file 2: Expanded Methods.

Statistical analysis

Based on results of previous trial [16] that the 1/4 dose quadruple combination further reduced SBP by 6.9 mm Hg (95% CI 4.9–8.9) compared to single drug, with an estimated standard deviation of 15 mm Hg, and our previous clinical observation results on low-dose quadruple combination and standard-dose dual combination, it was estimated that the difference in 24-h mean SBP reduction between the two groups was 6 ± 15 mm Hg. Considering 20% loss to follow-up and the random factors of the block group, a final sample size of 90 participants with 45 in each crossover sequence would provide the trial 90% power (at a two-sided alpha level of 0.05).

Continuous variables were presented as mean and standard deviation (SD) or median and interquartile range (IQR) and categorical variables as frequencies and percentages. All efficacy results were statistically analyzed in full analysis set according to the intention-to-treat principle. The primary outcome and continuous variables of secondary outcomes were analyzed using a linear mixed-effects model that included all pre-specified covariates to analyze the treatment effect, stage effect, and sequence effect (residual carryover effect), with participant as a random effect [20, 21]. Longitudinal linear models were used to estimate the differences in home blood pressure. The proportion of participants achieving target blood pressure was analyzed by McNemar chi-square test. Safety outcomes were analyzed using chi-square tests or Fisher's exact probability method in safety set.

Prespecified subgroups included age (< 45 years or ≥ 45 years), sex, and diabetes. Prespecified sensitivity analysis were conducted 1) in per protocol set for analysis of primary and secondary outcomes; and 2) in different ways of managing missing data for analysis of home blood pressure.

All statistical significance tests were conducted using a two-sided type I error rate of 5%. All statistical analyses were performed using R Studio 2023.06.0 + 421.

Results

Study participants

A total of 90 eligible participants were randomized between July 13, 2022, and April 20, 2023, with final study visits completed on July 4, 2023. The mean age of the study population was 43.88 years, 25.6% were women, and 93.3% were Han Chinese. The mean baseline 24-h systolic/diastolic blood pressure was 145.59/93.84 mm Hg. Prior to randomization, median duration of hypertension was 12 months, and 4.4% of participants had ever taken blood pressure-lowering treatment. 4.4% had diabetes and 71.1% had mild sleep apnea, with no participants complicated with coronary heart disease, cerebrovascular disease, and peripheral vascular disease (Table 1). The mean duration of the trial last for 75.40 days and medication compliance was more than 95% (Additional file 2: Table S1). After excluding one participant for low blood pressure, two for using drugs that affected the trial, one for COVID-19, and two for voluntary withdrawal, a total of 84 participants completed stage one treatment (full analysis set). In stage two treatment, one participant voluntarily withdrew and one withdrew due to COVID-19, leaving 75 participants who completed the whole treatment (Fig. 1), with 63 participants included in the per protocol set.

Table 1 Characteristics of the patients at baseline
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Fig. 1
figure 1

Trial profile. Only one participant withdrew in the quadruple therapy stage with a blood pressure below 90/60 mmHg and changed the treatment to losartan 50 mg per day. “Use of drugs affecting the test”: one participant in quadruple treatment was hospitalized with SAE and switched to a different blood pressure medication to facilitate medication adjustment; the others were using other antihypertensive drugs by themselves

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Primary outcomes

After four-week treatment, the mean change in 24-h systolic blood pressure was −22.61 mm Hg (95% CI, −24.57 to −20.65 mm Hg) in half-dose quadruple treatment group and −17.94 mm Hg (95% CI, −19.99 to −15.89 mm Hg) in the standard-dose dual treatment group (Table 2). The mean 24-h systolic blood pressure difference between groups was −4.72 mm Hg (95% CI –7.60 to –1.84; P < 0.001). Tests for both a carry-over effect (P = 0.656) and a stage effect (P = 0.484) were not significant. The sensitivity analyses based on per protocol set also confirmed the significant difference in mean 24-h systolic blood pressure (Additional file 2: Table S2).

Table 2 Effects of quadruple and dual treatments
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Secondary outcomes

After four-week treatment, the mean differences of 24-h diastolic blood pressure (−17.09 mm Hg vs. −13.15 mm Hg), daytime ambulatory blood pressure (−24.16/−18.12 mm Hg vs. −18.81/−13.73 mm Hg), nighttime ambulatory blood pressure (−18.35/−13.84 mm Hg vs. −15.56/−11.43 mm Hg), and office blood pressure (−25.99/−16.20 mm Hg vs. −23.36/−14.99 mm Hg) were significantly different between the half-dose quadruple treatment group and the standard-dose dual treatment group (Table 2, Additional file 2: Fig. S2). While two treatments did not show obvious difference on home blood pressure in the fourth week (Table 2, Additional file 2: Fig. S2), half-dose quadruple treatment reduced patients' home blood pressure in longitudinal change within 4 weeks, especially systolic blood pressure, more significantly than standard-dose dual treatment (Fig. 2). The sensitivity analyses based on per protocol set confirmed the significant difference in mean 24-h diastolic blood pressure, daytime ambulatory blood pressure, office blood pressure and longitudinal home systolic blood pressure difference between groups (Additional file 2: Table S2, Fig. S3). The sensitivity analyses in home blood pressure enhanced the significant difference in mean home blood pressure difference between groups, even in home diastolic blood pressure (Additional file 2: Fig. S4-S6).

Fig. 2
figure 2

Effects on home blood pressure of two treatments. P was for interaction effect of treatment and days based on linear mixed effect model, adjusted for stage, sequence, sex, age, nation, diabetes, OSAS, smoke, alcohol, ever treated, time of hypertension, BMI and eGFR, with participants and treatments as randomized effect. I bars represent 95% confidence intervals

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The difference between the effects of the two treatment regimens on heart rate was inconclusive and not clinically significant (Table 2). The mean morning surge differences between groups were not significant (Table 2).

A greater proportion of participants taking half-dose quadruple capsule achieved their blood pressure target at 4th week compared with taking standard-dose dual capsule (Additional file 2: Table S3, Table S4). TTR of home blood pressure was significantly higher in half-dose quadruple treatment group than standard-dose dual treatment group (56.91 ± 37.06% vs. 46.03 ± 33.70%; P = 0.025; Table 3). Difference of TTR between groups remained the same trend in the sensitivity analyses based on participants of per protocol set (Additional file 2: Table S5).

Table 3 Effects of quadruple and dual treatments on TTR of home blood pressure
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Adverse events

In total, 46 adverse events in half-dose quadruple group and 17 in standard-dose dual group were reported during the study, in which 36 and 8 adverse events, respectively, were considered related to the treatment (definite, probable and possible relationship). The most common adverse events reported in half-dose quadruple group were investigations (especially fasting blood glucose increased and blood uric acid increased), which were significantly more than standard-dose dual group (N = 9 vs. N = 2, P = 0.029; and N = 21 vs. N = 1, P < 0.001; respectively; Table 4, Additional file 2: Table S6-S7). For both treatments, the total number of dropouts in two phases was four. Only one participant withdrew in the quadruple therapy stage for his blood pressure below 90/60 mmHg and changed the treatment to losartan 50 mg per day. No any other instances where participants had to change the dose of medications taken due to intolerance.

Table 4 Adverse events during the study period
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Only one participant in half-dose quadruple group reported one serious adverse event (cerebral infarction) (Table 4), who was finally diagnosed with moyamoya disease by digital subtraction angiography.

Laboratory values

There were statistically significant between-group differences in the changes of serum potassium, serum sodium, fasting blood glucose, serum creatinine, serum uric acid, and serum urea, while not for alanine transaminase, aspartate transaminase, total bilirubin, direct bilirubin, QT interval, and QTc interval (Table 5).

Table 5 Effects of two treatments on laboratory measurements
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Subgroup analysis

There was no evidence of heterogeneity in the treatment effect for the outcomes in the prespecified subgroups of sex and age (Additional file 2: Fig. S7, Table S8). Because only four patients had diabetes mellitus, a subgroup analysis based on this condition was not performed.

Discussion

This crossover trial demonstrated that initiating treatment with half-dose quadruple combination therapy was more effective in lowering blood pressure than starting with standard-dose dual therapy. Apart from significant increases of fasting blood glucose and blood uric acid in the half-dose quadruple group, no other adverse events or changes in laboratory values differed significantly between the two treatments.

Early attainment of target blood pressure is known to lower cardiovascular risk and lead to better prognosis [22,23,24,25]. Aggressive treatment of patients with grade 1 and 2 hypertension could reduce 803,000 cardiovascular events per year and increase 1.2 million quality-adjusted life years compared with maintaining the status quo [26], yielding considerable socioeconomic benefits. The PURE study noted that less than 1/3 of hypertensive patients achieved target blood pressure after starting with only monotherapy [27]. Compared with monotherapy, combination therapy at the initiation of antihypertensive treatment increased magnitude of blood pressure reduction and shortened time to target blood pressure [28,29,30], even in patients with grade 1 hypertension [31,32,33].

In recent years, some researchers proposed the hypothesis that low-dose multidrug combinations (≥ 3) offered better antihypertensive effects and fewer side effects in initial treatment, and conducted preliminary investigations into this field [12,13,14,15,16], further breaking the stereotyped thought that the current antihypertensive regimen started with a combination of two drugs, based on which 2023 ESH hypertension guidelines mentioned the quadpill concept [34]. However, none of the above studies compared the dual therapy recommended by hypertension guidelines and involved the Chinese population. Our findings addressed these gaps, and strengthened the conclusion that small dose of quadruple drugs were more effective in lowering blood pressure than standard-dose dual drugs. In our study, half-dose quadruple therapy reduced SBP by 4.72 mmHg more than standard-dose dual therapy, which is less than the QUARTET trial [16], where quadruple quarter-dose therapy lowered SBP by 6.9 mmHg more than standard-dose monotherapy. This is consistent with the current understanding that the combination of two different medications is more effective than doubling the dose of a single drug. In addition, the primary outcome of our study was 24-h SBP, which is a better metric compared to office BP [35, 36]. This is also an advantage compared to previous research. Recent years, higher TTR was found associated with a decreased risk of death from any cause and major adverse cardiovascular events [37,38,39]. So, we added to analysed this parameter retrospectively and found that small dose of quadruple drugs could significantly increase TTR. Though the decrease of home blood pressure at the fourth week between two treatments seemed no obvious difference, the longitudinal home blood pressure within the four weeks and TTR revealed significant advantages in small dose of quadruple drugs. The suspected reason may be nervousness on the day of visit, making the home blood pressure higher on that day.

Looking at the baseline data, we could see that it was a relatively young cohort, with only 4% having diabetes. Older hypertensive patients often visited the clinic already on medication, whereas younger hypertensive patients were typically not on any treatment when they sought care. Our study primarily focused on untreated hypertensive patients, which may be why the sample mainly consisted of younger individuals with fewer comorbidities, such as diabetes. In young people, women are generally less likely to develop hypertension and other cardiovascular diseases, due to the protective effects of estrogen [40], which may be the reason the population was predominantly male. In this trial, we chose "A + C" over "A + D" as control based on evidence-based evidence and Chinese clinical practice. 2020 ISH guidelines only recommended "A + C" [1], and there was ample evidence for "A + C" [41, 42] rather than "A + D" [42, 43] in hypertension treatment. "A + C" was also the most prescribed dual combination in China [44]. Therefore, as an exploratory attempt, we chose the more obvious advantageous "A + C" combination as control. Regarding to beta-blocker, although it was no longer recognized as a priority antihypertensive drug in American guidelines [6], it was recommended as the first-line drug in Chinese [45] and European guidelines [34]. Moreover, the sympathetic nervous system and the renin-angiotensin system were significantly activated in Chinese population especially with young and middle age [46,47,48,49], so, our quadruple combination included beta-blocker.

In this trial, the half-dose quadruple combination reported more adverse events on fasting blood glucose and blood uric acid, which may be related to beta-blockers and diuretics [50,51,52,53]. The incidence of gout induced by the quadruple combination remained zero, despite increased uric acid. In addition, half-dose quadruple combination could reduce blood potassium and sodium and elevate creatinine and urea to some extent, which may all be associated with diuretics [54, 55]. However, there was no clinical meaning for these small changes compared with baseline.

Although one participant experienced a cerebral infarction when using low-dose quadruple therapy, the blood pressure of this participant was not low (approximately 150/90 mm Hg). The diagnosis was confirmed by digital subtraction angiography with Moyamoya disease, which made the patient susceptible to stroke [56]. After comprehensive analysis by the clinical end point committee and neurological physician, this serious adverse event was more related to the patient's underlying condition. For the convenience of adjusting the medication according to blood pressure, the participant withdrew from the trial.

In general, the safety of half-dose quadruple therapy was comparable with standard-dose dual therapy, and specific adverse events were related to the type of drug combinations.

Strength

The strengths of this study are that: 1) the use of dual combination as control, unlike the previous trials with single drug or placebo, could illustrate the antihypertensive advantages of quadruple combinations more effectively; 2) the use of a single capsule with identical appearance and interior could effectively ensure the implementation of blinding, guarantee the participants’ compliance with medication [57], and also reduced in the feeling of polypharmacy [57]; 3) crossover design is self-controls and can minimize bias and improve statistical power; 4) the use of a range of blood pressure measurement methods, including ABPM, office blood pressure and home blood pressure, made the results more convincing, and the treatment effects were consistent.

Limitation

Due to the single sample source and a small sample size, the study was limited in its ability to cover a broad population and geographic area, which may restrict its generalizability. The small number of patients may also make some results like target rate of blood pressure and subgroup analysis less convincing. Pill-count compliance has its limitations, including the possibility that participants may remove pills before clinic visits. In addition, the trial failed to explore the long-term antihypertensive effect and prognosis of cardiovascular outcomes for the limitations of the crossover study. Various half-dose quadruple combinations and standard-dose dual combinations were not employed in the trial, making it difficult to generalize the conclusions to all multi-drug combinations. However, the combinations in this trial were typical and representative, at least giving the concept that half-dose quadruple combinations were more effective in lowering blood pressure than standard-dose dual combinations. Therefore, more subsequent studies are needed for further exploration of the advantages of small-dose quadruple antihypertensive drugs by including more research centers, employing more kinds of combinations of quadruple and dual drugs, and observing for a longer period for prognosis of cardiovascular outcomes.

Conclusions

The QUADUAL study, to our knowledge, was the first trial to investigate the antihypertensive effect of low-dose quadruple drug initial treatment with standard-dose dual therapy as control, and it was also the first quadruple antihypertensive study conducted in the Chinese population. This study could provide a rich and solid theoretical basis for the development of possible low-dose quadruple antihypertensive combinations in the future, and provide a reference for the selection of antihypertensive programs in hypertension guidelines, thereby actively promoting the prevention and treatment of hypertension.

Data availability

Coded data (without personal identification information) used and analysed during the current study will be available to researchers one year after the publication date of the manuscript from the corresponding author on reasonable request, with the approval of the steering committee and Research Center for Clinical Trials of the Third Xiangya Hospital of Central South University, on signing of a data access agreement.

Abbreviations

ABPM:

Ambulatory Blood Pressure Monitoring

BMI:

Body Mass Index

DBP:

Diastolic Blood Pressure

eGFR:

Estimated Glomerular Filtration Rate

IDMC:

Independent Data Monitoring Committee

OSAS:

Obstructive Sleep Apnea Syndrome

SBP:

Systolic Blood Pressure

TTR:

Time in Target Range

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Acknowledgements

Acknowledgements were detailed in Additional file 2: QUADUAL team acknowledgements.

Funding

The study was supported by the Key Research and Development program of Hunan Province (NO.2022SK2029), and the National Natural Science Foundation of China Projects (NO.81800271). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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Author notes

  1. Xiaogang Li and Weihong Jiang shared last authorship.

Authors and Affiliations

  1. Department of Cardiology, The Third Xiangya Hospital of Central South University, Yuelu District, 138 Tongzipo Road, Changsha, 410013, Hunan, China

    Xiexiong Zhao, Tao Liu, Qiong Yang, Xiaohong Tang, Jingle Li, Zhongshu Liang, Anying Li, Lixiong Zeng, Juan Wen, Xiaoyan Wang, Liping Peng, Wenjuan Wang, Jingjing Cai, Ye Chen, Miao Huang, Ruixuan Li, Ru Fu, Lin Zhao, Xiaogang Li & Weihong Jiang

  2. Center of Clinical Pharmacology, The Third Xiangya Hospital of Central South University, Changsha, China

    Guoping Yang & Jingjing Cai

  3. Department of Clinical Pharmacology, XiangYa School of Pharmaceutical Sciences, Changsha, China

    Guoping Yang

  4. Department of Epidemiology, XiangYa School of Public Health, Changsha, China

    Xingli Li

  5. Hypertension Research Center of Hunan Province, Changsha, Hunan, China

    Qiong Yang, Zhongshu Liang & Weihong Jiang

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  1. Xiexiong Zhao
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Contributions

XXZ for conceptualization, writing of original draft, project administration, and supervision; TL for data curation, investigation, and writing of review & editing; QY for investigation, resources, and writing of review & editing; GPY for supervision, methodology, and writing of review & editing; XLL for formal analysis, methodology, visualization, writing of review & editing; XHT for investigation, resources, and writing of review & editing; JLL, AYL, LXZ, JW, XYW, LPP, and LZ for investigation and resources; ZSL for investigation, writing of review & editing; WJW for investigation; JJC for writing of review & editing; YC, MH, RXL, and RF for data curation; XGL for funding acquisition, writing of review & editing, and resources; WHJ for funding acquisition, supervision, and writing of review & editing. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Weihong Jiang.

Ethics declarations

Ethics approval and consent to participate

Institutional Review Board of the Third Xiangya Hospital, Central South University approved this trial (approval number R22023 and R22152). The purpose and method of the study were informed in detail and the written informed consent was obtained before enrollment from all the patients.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

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Supplementary Information

Additional file 1. Study protocol.

12916_2025_3892_MOESM2_ESM.docx

Additional file 2. Expanded Methods. Table S1. Duration of medication and medication compliance. Table S2. Effects of quadruple and dual treatments in PPS population. Table S3. Blood pressure target rate of two antihypertensive treatments. Table S4. Blood pressure target rate of two antihypertensive treatments in PPS population. Table S5. Effects of quadruple and dual treatments on TTR of home blood pressure in PPS population. Table S6. List of adverse events in system organ class. Table S7. List of relationship of adverse events and treatments. Table S8. Subgroup analysis of other indicators. Figure S1. Flow diagram of the QUADUAL trial. Figure S2. Antihypertensive effects of two treatments. Figure S3. Effects on home blood pressure of two treatments in PPS population. Figure S4. Effects on home blood pressure of two treatments after LOCF imputation. Figure S5. Effects on home blood pressure of two treatments after NOCB imputation. Figure S6. Effects on home blood pressure of two treatments after linear imputation. Figure S7. Forest plot of blood pressure according to subgroups. QUADUAL team acknowledgements.

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Zhao, X., Liu, T., Yang, Q. et al. Initial treatment with a single capsule containing half-dose quadruple therapy vs standard-dose dual therapy in hypertensive patients (QUADUAL): a randomized, blinded, crossover trial. BMC Med 23, 56 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12916-025-03892-8

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Keywords

BMC Medicine

ISSN: 1741-7015

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