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.

Chow, CK; Atkins, ER; Hillis, GS; Nelson, MR; Reid, CM; Schlaich, MP; Hay, P; Rogers, K; Billot, L; Burke, M; Chalmers, J; Neal, B; Patel, A; Usherwood, T; Webster, R; Rodgers, A; QUARTET Investigators,

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.

Chow, CK Atkins, ER Hillis, GS Nelson, MR Reid, CM Schlaich, MP Hay, P Rogers, K

Billot, L Burke, M Chalmers, J Neal, B Patel, A Usherwood, T Webster, R

Rodgers, A QUARTET Investigators,

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Publisher:: Elsevier BV
Publication Type:: Journal Article
Citation:: Lancet, 2021, 398, (10305), pp. 1043-1052
Issue Date:: 2021-09-18

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Field	Value	Language
dc.contributor.author	Chow, CK
dc.contributor.author	Atkins, ER
dc.contributor.author	Hillis, GS
dc.contributor.author	Nelson, MR
dc.contributor.author	Reid, CM
dc.contributor.author	Schlaich, MP
dc.contributor.author	Hay, P
dc.contributor.author	Rogers, K https://orcid.org/0000-0001-5497-4298
dc.contributor.author	Billot, L
dc.contributor.author	Burke, M
dc.contributor.author	Chalmers, J
dc.contributor.author	Neal, B
dc.contributor.author	Patel, A
dc.contributor.author	Usherwood, T
dc.contributor.author	Webster, R https://orcid.org/0000-0002-7444-3037
dc.contributor.author	Rodgers, A
dc.contributor.author	QUARTET Investigators,
dc.date.accessioned	2022-02-20T00:36:24Z
dc.date.available	2021-08-11
dc.date.available	2022-02-20T00:36:24Z
dc.date.issued	2021-09-18
dc.identifier.citation	Lancet, 2021, 398, (10305), pp. 1043-1052
dc.identifier.issn	0140-6736
dc.identifier.issn	1474-547X
dc.identifier.uri	http://hdl.handle.net/10453/154697
dc.description.abstract	BACKGROUND: Treatment inertia is a recognised barrier to blood pressure control, and simpler, more effective treatment strategies are needed. We hypothesised that a hypertension management strategy starting with a single pill containing ultra-low-dose quadruple combination therapy would be more effective than a strategy of starting with monotherapy. METHODS: QUARTET was a multicentre, double-blind, parallel-group, randomised, phase 3 trial among Australian adults (≥18 years) with hypertension, who were untreated or receiving monotherapy. Participants were randomly assigned to either treatment, that started with the quadpill (containing irbesartan at 37·5 mg, amlodipine at 1·25 mg, indapamide at 0·625 mg, and bisoprolol at 2·5 mg) or an indistinguishable monotherapy control (irbesartan 150 mg). If blood pressure was not at target, additional medications could be added in both groups, starting with amlodipine at 5 mg. Participants were randomly assigned using an online central randomisation service. There was a 1:1 allocation, stratified by site. Allocation was masked to all participants and study team members (including investigators and those assessing outcomes) except the manufacturer of the investigational product and one unmasked statistician. The primary outcome was difference in unattended office systolic blood pressure at 12 weeks. Secondary outcomes included blood pressure control (standard office blood pressure <140/90 mm Hg), safety, and tolerability. A subgroup continued randomly assigned allocation to 12 months to assess long-term effects. Analyses were per intention to treat. This trial was prospectively registered with the Australian New Zealand Clinical Trials Registry, ACTRN12616001144404, and is now complete. FINDINGS: From June 8, 2017, to Aug 31, 2020, 591 participants were recruited, with 743 assessed for eligibility, 152 ineligible or declined, 300 participants randomly assigned to intervention of initial quadpill treatment, and 291 to control of initial standard dose monotherapy treatment. The mean age of the 591 participants was 59 years (SD 12); 356 (60%) were male and 235 (40%) were female; 483 (82%) were White, 70 (12%) were Asian, and 38 (6%) reported as other ethnicity; and baseline mean unattended office blood pressure was 141 mm Hg (SD 13)/85 mm Hg (SD 10). By 12 weeks, 44 (15%) of 300 participants had additional blood pressure medications in the intervention group compared with 115 (40%) of 291 participants in the control group. Systolic blood pressure was lower by 6·9 mm Hg (95% CI 4·9-8·9; p<0·0001) and blood pressure control rates were higher in the intervention group (76%) versus control group (58%; relative risk [RR] 1·30, 95% CI 1·15-1·47; p<0·0001). There was no difference in adverse event-related treatment withdrawals at 12 weeks (intervention 4·0% vs control 2·4%; p=0·27). Among the 417 patients who continued, uptitration occurred more frequently among control participants than intervention participants (p<0·0001). However, at 52 weeks mean unattended systolic blood pressure remained lower by 7·7 mm Hg (95% CI 5·2-10·3) and blood pressure control rates higher in the intervention group (81%) versus control group (62%; RR 1·32, 95% CI 1·16-1·50). In all randomly assigned participants up to 12 weeks, there were seven (3%) serious adverse events in the intervention group and three (1%) serious adverse events in the control group. INTERPRETATION: A strategy with early treatment of a fixed-dose quadruple quarter-dose combination achieved and maintained greater blood pressure lowering compared with the common strategy of starting monotherapy. This trial demonstrated the efficacy, tolerability, and simplicity of a quadpill-based strategy. FUNDING: National Health and Medical Research Council, Australia.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Elsevier BV
dc.relation	http://purl.org/au-research/grants/nhmrc/1100377
dc.relation	http://purl.org/au-research/grants/nhmrc/1125044
dc.relation.ispartof	Lancet
dc.relation.isbasedon	10.1016/S0140-6736(21)01922-X
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	11 Medical and Health Sciences
dc.subject.classification	General & Internal Medicine
dc.subject.mesh	Amlodipine
dc.subject.mesh	Antihypertensive Agents
dc.subject.mesh	Australia
dc.subject.mesh	Bisoprolol
dc.subject.mesh	Blood Pressure
dc.subject.mesh	Double-Blind Method
dc.subject.mesh	Drug Therapy, Combination
dc.subject.mesh	Female
dc.subject.mesh	Humans
dc.subject.mesh	Hypertension
dc.subject.mesh	Indapamide
dc.subject.mesh	Irbesartan
dc.subject.mesh	Male
dc.subject.mesh	Middle Aged
dc.subject.mesh	Treatment Outcome
dc.subject.mesh	Humans
dc.subject.mesh	Hypertension
dc.subject.mesh	Bisoprolol
dc.subject.mesh	Indapamide
dc.subject.mesh	Amlodipine
dc.subject.mesh	Antihypertensive Agents
dc.subject.mesh	Treatment Outcome
dc.subject.mesh	Drug Therapy, Combination
dc.subject.mesh	Double-Blind Method
dc.subject.mesh	Blood Pressure
dc.subject.mesh	Middle Aged
dc.subject.mesh	Australia
dc.subject.mesh	Female
dc.subject.mesh	Male
dc.subject.mesh	Irbesartan
dc.title	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.
dc.type	Journal Article
utslib.citation.volume	398
utslib.location.activity	England
utslib.for	11 Medical and Health Sciences
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Health
pubs.organisational-group	/University of Technology Sydney/Faculty of Health/Centre for Health Economics Research and Evaluation
utslib.copyright.status	closed_access	*
dc.date.updated	2022-02-20T00:36:23Z
pubs.issue	10305
pubs.publication-status	Published
pubs.volume	398
utslib.citation.issue	10305

Abstract:

BACKGROUND: Treatment inertia is a recognised barrier to blood pressure control, and simpler, more effective treatment strategies are needed. We hypothesised that a hypertension management strategy starting with a single pill containing ultra-low-dose quadruple combination therapy would be more effective than a strategy of starting with monotherapy. METHODS: QUARTET was a multicentre, double-blind, parallel-group, randomised, phase 3 trial among Australian adults (≥18 years) with hypertension, who were untreated or receiving monotherapy. Participants were randomly assigned to either treatment, that started with the quadpill (containing irbesartan at 37·5 mg, amlodipine at 1·25 mg, indapamide at 0·625 mg, and bisoprolol at 2·5 mg) or an indistinguishable monotherapy control (irbesartan 150 mg). If blood pressure was not at target, additional medications could be added in both groups, starting with amlodipine at 5 mg. Participants were randomly assigned using an online central randomisation service. There was a 1:1 allocation, stratified by site. Allocation was masked to all participants and study team members (including investigators and those assessing outcomes) except the manufacturer of the investigational product and one unmasked statistician. The primary outcome was difference in unattended office systolic blood pressure at 12 weeks. Secondary outcomes included blood pressure control (standard office blood pressure <140/90 mm Hg), safety, and tolerability. A subgroup continued randomly assigned allocation to 12 months to assess long-term effects. Analyses were per intention to treat. This trial was prospectively registered with the Australian New Zealand Clinical Trials Registry, ACTRN12616001144404, and is now complete. FINDINGS: From June 8, 2017, to Aug 31, 2020, 591 participants were recruited, with 743 assessed for eligibility, 152 ineligible or declined, 300 participants randomly assigned to intervention of initial quadpill treatment, and 291 to control of initial standard dose monotherapy treatment. The mean age of the 591 participants was 59 years (SD 12); 356 (60%) were male and 235 (40%) were female; 483 (82%) were White, 70 (12%) were Asian, and 38 (6%) reported as other ethnicity; and baseline mean unattended office blood pressure was 141 mm Hg (SD 13)/85 mm Hg (SD 10). By 12 weeks, 44 (15%) of 300 participants had additional blood pressure medications in the intervention group compared with 115 (40%) of 291 participants in the control group. Systolic blood pressure was lower by 6·9 mm Hg (95% CI 4·9-8·9; p<0·0001) and blood pressure control rates were higher in the intervention group (76%) versus control group (58%; relative risk [RR] 1·30, 95% CI 1·15-1·47; p<0·0001). There was no difference in adverse event-related treatment withdrawals at 12 weeks (intervention 4·0% vs control 2·4%; p=0·27). Among the 417 patients who continued, uptitration occurred more frequently among control participants than intervention participants (p<0·0001). However, at 52 weeks mean unattended systolic blood pressure remained lower by 7·7 mm Hg (95% CI 5·2-10·3) and blood pressure control rates higher in the intervention group (81%) versus control group (62%; RR 1·32, 95% CI 1·16-1·50). In all randomly assigned participants up to 12 weeks, there were seven (3%) serious adverse events in the intervention group and three (1%) serious adverse events in the control group. INTERPRETATION: A strategy with early treatment of a fixed-dose quadruple quarter-dose combination achieved and maintained greater blood pressure lowering compared with the common strategy of starting monotherapy. This trial demonstrated the efficacy, tolerability, and simplicity of a quadpill-based strategy. FUNDING: National Health and Medical Research Council, Australia.

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http://hdl.handle.net/10453/154697