Quarter-dose quadruple combination therapy for initial treatment of hypertension: placebo-controlled, crossover, randomised trial and systematic review.

Chow, CK; Thakkar, J; Bennett, A; Hillis, G; Burke, M; Usherwood, T; Vo, K; Rogers, K; Atkins, E; Webster, R; Chou, M; Dehbi, H-M; Salam, A; Patel, A; Neal, B; Peiris, D; Krum, H; Chalmers, J; Nelson, M; Reid, CM; Woodward, M; Hilmer, S; Thom, S; Rodgers, A

Quarter-dose quadruple combination therapy for initial treatment of hypertension: placebo-controlled, crossover, randomised trial and systematic review.

Chow, CK Thakkar, J Bennett, A Hillis, G Burke, M Usherwood, T Vo, K Rogers, K

Atkins, E Webster, R

Chou, M Dehbi, H-M Salam, A Patel, A Neal, B Peiris, D Krum, H Chalmers, J Nelson, M Reid, CM Woodward, M Hilmer, S Thom, S Rodgers, A

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Publisher:: Elsevier
Publication Type:: Journal Article
Citation:: The Lancet, 2017, 389, (10073), pp. 1035-1042
Issue Date:: 2017-03-11

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Field	Value	Language
dc.contributor.author	Chow, CK
dc.contributor.author	Thakkar, J
dc.contributor.author	Bennett, A
dc.contributor.author	Hillis, G
dc.contributor.author	Burke, M
dc.contributor.author	Usherwood, T
dc.contributor.author	Vo, K
dc.contributor.author	Rogers, K https://orcid.org/0000-0001-5497-4298
dc.contributor.author	Atkins, E
dc.contributor.author	Webster, R https://orcid.org/0000-0002-7444-3037
dc.contributor.author	Chou, M
dc.contributor.author	Dehbi, H-M
dc.contributor.author	Salam, A
dc.contributor.author	Patel, A
dc.contributor.author	Neal, B
dc.contributor.author	Peiris, D
dc.contributor.author	Krum, H
dc.contributor.author	Chalmers, J
dc.contributor.author	Nelson, M
dc.contributor.author	Reid, CM
dc.contributor.author	Woodward, M
dc.contributor.author	Hilmer, S
dc.contributor.author	Thom, S
dc.contributor.author	Rodgers, A
dc.date.accessioned	2022-08-22T05:12:58Z
dc.date.available	2017-01-17
dc.date.available	2022-08-22T05:12:58Z
dc.date.issued	2017-03-11
dc.identifier.citation	The Lancet, 2017, 389, (10073), pp. 1035-1042
dc.identifier.issn	0140-6736
dc.identifier.issn	1474-547X
dc.identifier.uri	http://hdl.handle.net/10453/160683
dc.description.abstract	BACKGROUND: Globally, most patients with hypertension are treated with monotherapy, and control rates are poor because monotherapy only reduces blood pressure by around 9/5 mm Hg on average. There is a pressing need for blood pressure-control strategies with improved efficacy and tolerability. We aimed to assess whether ultra-low-dose combination therapy could meet these needs. METHODS: We did a randomised, placebo-controlled, double-blind, crossover trial of a quadpill-a single capsule containing four blood pressure-lowering drugs each at quarter-dose (irbesartan 37·5 mg, amlodipine 1·25 mg, hydrochlorothiazide 6·25 mg, and atenolol 12·5 mg). Participants with untreated hypertension were enrolled from four centres in the community of western Sydney, NSW, Australia, mainly by general practitioners. Participants were randomly allocated by computer to either the quadpill or matching placebo for 4 weeks; this treatment was followed by a 2-week washout, then the other study treatment was administered for 4 weeks. Study staff and participants were unaware of treatment allocations, and masking was achieved by use of identical opaque capsules. The primary outcome was placebo-corrected 24-h systolic ambulatory blood pressure reduction after 4 weeks and analysis was by intention to treat. We also did a systematic review of trials evaluating the efficacy and safety of quarter-standard-dose blood pressure-lowering therapy against placebo. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12614001057673. The trial ended after 1 year and this report presents the final analysis. FINDINGS: Between November, 2014, and December, 2015, 55 patients were screened for our randomised trial, of whom 21 underwent randomisation. Mean age of participants was 58 years (SD 11) and mean baseline office and 24-h systolic and diastolic blood pressure levels were 154 (14)/90 (11) mm Hg and 140 (9)/87 (8) mm Hg, respectively. One individual declined participation after randomisation and two patients dropped out for administrative reasons. The placebo-corrected reduction in systolic 24-h blood pressure with the quadpill was 19 mm Hg (95% CI 14-23), and office blood pressure was reduced by 22/13 mm Hg (p<0·0001). During quadpill treatment, 18 (100%) of 18 participants achieved office blood pressure less than 140/90 mm Hg, compared with six (33%) of 18 during placebo treatment (p=0·0013). There were no serious adverse events and all patients reported that the quadpill was easy to swallow. Our systematic review identified 36 trials (n=4721 participants) of one drug at quarter-dose and six trials (n=312) of two drugs at quarter-dose, against placebo. The pooled placebo-corrected blood pressure-lowering effects were 5/2 mm Hg and 7/5 mm Hg, respectively (both p<0·0001), and there were no side-effects from either regimen. INTERPRETATION: The findings of our small trial in the context of previous randomised evidence suggest that the benefits of quarter-dose therapy could be additive across classes and might confer a clinically important reduction in blood pressure. Further examination of the quadpill concept is needed to investigate effectiveness against usual treatment options and longer term tolerability. FUNDING: National Heart Foundation, Australia; University of Sydney; and National Health and Medical Research Council of Australia.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Elsevier
dc.relation.ispartof	The Lancet
dc.relation.isbasedon	10.1016/S0140-6736(17)30260-X
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	11 Medical and Health Sciences
dc.subject.classification	General & Internal Medicine
dc.subject.mesh	Administration, Oral
dc.subject.mesh	Amlodipine
dc.subject.mesh	Antihypertensive Agents
dc.subject.mesh	Atenolol
dc.subject.mesh	Biphenyl Compounds
dc.subject.mesh	Blood Pressure
dc.subject.mesh	Cross-Over Studies
dc.subject.mesh	Double-Blind Method
dc.subject.mesh	Drug Combinations
dc.subject.mesh	Female
dc.subject.mesh	Humans
dc.subject.mesh	Hydrochlorothiazide
dc.subject.mesh	Hypertension
dc.subject.mesh	Irbesartan
dc.subject.mesh	Male
dc.subject.mesh	Medication Adherence
dc.subject.mesh	Middle Aged
dc.subject.mesh	Review Literature as Topic
dc.subject.mesh	Tetrazoles
dc.subject.mesh	Treatment Outcome
dc.subject.mesh	Administration, Oral
dc.subject.mesh	Amlodipine
dc.subject.mesh	Antihypertensive Agents
dc.subject.mesh	Atenolol
dc.subject.mesh	Biphenyl Compounds
dc.subject.mesh	Blood Pressure
dc.subject.mesh	Cross-Over Studies
dc.subject.mesh	Double-Blind Method
dc.subject.mesh	Drug Combinations
dc.subject.mesh	Female
dc.subject.mesh	Humans
dc.subject.mesh	Hydrochlorothiazide
dc.subject.mesh	Hypertension
dc.subject.mesh	Irbesartan
dc.subject.mesh	Male
dc.subject.mesh	Medication Adherence
dc.subject.mesh	Middle Aged
dc.subject.mesh	Review Literature as Topic
dc.subject.mesh	Tetrazoles
dc.subject.mesh	Treatment Outcome
dc.subject.mesh	Humans
dc.subject.mesh	Hypertension
dc.subject.mesh	Atenolol
dc.subject.mesh	Biphenyl Compounds
dc.subject.mesh	Tetrazoles
dc.subject.mesh	Amlodipine
dc.subject.mesh	Hydrochlorothiazide
dc.subject.mesh	Antihypertensive Agents
dc.subject.mesh	Drug Combinations
dc.subject.mesh	Treatment Outcome
dc.subject.mesh	Administration, Oral
dc.subject.mesh	Cross-Over Studies
dc.subject.mesh	Double-Blind Method
dc.subject.mesh	Blood Pressure
dc.subject.mesh	Middle Aged
dc.subject.mesh	Female
dc.subject.mesh	Male
dc.subject.mesh	Review Literature as Topic
dc.subject.mesh	Medication Adherence
dc.subject.mesh	Irbesartan
dc.title	Quarter-dose quadruple combination therapy for initial treatment of hypertension: placebo-controlled, crossover, randomised trial and systematic review.
dc.type	Journal Article
utslib.citation.volume	389
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/Public Health
pubs.organisational-group	/University of Technology Sydney/Faculty of Health/Centre for Health Economics Research and Evaluation
utslib.copyright.status	closed_access	*
pubs.consider-herdc	false
dc.date.updated	2022-08-22T05:12:56Z
pubs.issue	10073
pubs.publication-status	Published
pubs.volume	389
utslib.citation.issue	10073

Abstract:

BACKGROUND: Globally, most patients with hypertension are treated with monotherapy, and control rates are poor because monotherapy only reduces blood pressure by around 9/5 mm Hg on average. There is a pressing need for blood pressure-control strategies with improved efficacy and tolerability. We aimed to assess whether ultra-low-dose combination therapy could meet these needs. METHODS: We did a randomised, placebo-controlled, double-blind, crossover trial of a quadpill-a single capsule containing four blood pressure-lowering drugs each at quarter-dose (irbesartan 37·5 mg, amlodipine 1·25 mg, hydrochlorothiazide 6·25 mg, and atenolol 12·5 mg). Participants with untreated hypertension were enrolled from four centres in the community of western Sydney, NSW, Australia, mainly by general practitioners. Participants were randomly allocated by computer to either the quadpill or matching placebo for 4 weeks; this treatment was followed by a 2-week washout, then the other study treatment was administered for 4 weeks. Study staff and participants were unaware of treatment allocations, and masking was achieved by use of identical opaque capsules. The primary outcome was placebo-corrected 24-h systolic ambulatory blood pressure reduction after 4 weeks and analysis was by intention to treat. We also did a systematic review of trials evaluating the efficacy and safety of quarter-standard-dose blood pressure-lowering therapy against placebo. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12614001057673. The trial ended after 1 year and this report presents the final analysis. FINDINGS: Between November, 2014, and December, 2015, 55 patients were screened for our randomised trial, of whom 21 underwent randomisation. Mean age of participants was 58 years (SD 11) and mean baseline office and 24-h systolic and diastolic blood pressure levels were 154 (14)/90 (11) mm Hg and 140 (9)/87 (8) mm Hg, respectively. One individual declined participation after randomisation and two patients dropped out for administrative reasons. The placebo-corrected reduction in systolic 24-h blood pressure with the quadpill was 19 mm Hg (95% CI 14-23), and office blood pressure was reduced by 22/13 mm Hg (p<0·0001). During quadpill treatment, 18 (100%) of 18 participants achieved office blood pressure less than 140/90 mm Hg, compared with six (33%) of 18 during placebo treatment (p=0·0013). There were no serious adverse events and all patients reported that the quadpill was easy to swallow. Our systematic review identified 36 trials (n=4721 participants) of one drug at quarter-dose and six trials (n=312) of two drugs at quarter-dose, against placebo. The pooled placebo-corrected blood pressure-lowering effects were 5/2 mm Hg and 7/5 mm Hg, respectively (both p<0·0001), and there were no side-effects from either regimen. INTERPRETATION: The findings of our small trial in the context of previous randomised evidence suggest that the benefits of quarter-dose therapy could be additive across classes and might confer a clinically important reduction in blood pressure. Further examination of the quadpill concept is needed to investigate effectiveness against usual treatment options and longer term tolerability. FUNDING: National Heart Foundation, Australia; University of Sydney; and National Health and Medical Research Council of Australia.

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http://hdl.handle.net/10453/160683