Chow CK, Atkins ER, Hillis GS, 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 Sep 18;398(10305):1043-1052. doi: 10.1016/S0140-6736(21)01922-X. Epub 2021 Aug 29. (Original study)

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.

Discipline Area Score
Family Medicine (FM)/General Practice (GP) 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Internal Medicine 6 / 7
Endocrine 6 / 7
Nephrology 6 / 7
Cardiology 5 / 7
Comments from MORE raters

Endocrine rater

Impressive. Apparently, smaller amounts of 4 drugs that use different anti-hypertensive mechanisms are more effective than higher doses of one or several drugs that use a single mechanism. Cost-effectiveness studies will be important when the quadpill (which will probably be expensive) is approved.

General Internal Medicine-Primary Care(US) rater

This is a useful article that showed in a double-blind study of 600 patients that a combination pill of one quarter doses of 4 unique medications controlled BP better than a single normal dose of an ARB. This effect lasted for the entire 12 months of use. Poorly controlled patients had medicines added to the regimen. The side effects were similar as well.

Internal Medicine rater

Well planned and executed RCT.

Internal Medicine rater

This is pretty interesting, and builds on the polypill approach in CVD prevention. I am not sure irbesartan was the best choice for monotherapy in the comparison group; nevertheless, this should stimulate thought about the best "single pill" therapy for patients with HTN.

Internal Medicine rater

Very interesting comparison strategy. Only examined the BP surrogate outcome instead of clinical events, but the BP differences are impressive.

Nephrology rater

A relatively small study. The comparator was an ARB, but I would have preferred to see this compared with a thiazide. The resultant BP differences do not seem clinically that different. Also, I am leery about starting two drugs at the same time: this advocates four. If the patient has an adverse drug effect, how is one to know which drug is responsible?

Nephrology rater

Interesting and sensible.
Comments from EvidenceAlerts subscribers

Dr. Lim bee lin (1/2/2022 5:01 AM)

There were twice as many serious side effects in the quadpill group. I think that is a significant reason to go back to individualising treatment instead of lumping all and sundry into one homogeneous group.

Dr. Christina Richards (12/1/2021 11:08 AM)

I would need to see a study using patient-oriented outcomes to be convinced to change my practice. At very least, it seems they should have used home rather than office BP measurements as recommended by recent guidelines.

Ms. Nisha Arora (11/27/2021 10:28 PM)

There are very few patients in whom I am starting bisoprolol as a first-line medication for hypertension. I agree with Dr. Loxton - I would be leery of polypharmacy and starting 4 medications at once. I am not convinced this study has clinical utility.

Dr. paul Loxton (11/1/2021 10:53 AM)

It’s not a low dose of bisoprolol. In my view, it is most unwise to add 4 drugs together in this manner.
More polypharmacy for what is already an over-diagnosed and over-treated group of patients.