Quadruple, Quarter Dose Antihypertensive Combination Therapy More Effective vs Monotherapy

Fixed-dose, quadruple combination antihypertensive therapy initiated early may be more effective than monotherapy for patients with hypertension.

A multicenter, double-blind, randomized, phase 3 trial found that early initiation of quadruple quarter-dose combination therapy was more effective at lowering blood pressure (BP) than monotherapy. These findings were published in The Lancet.

The quadruple ultra-low-dose treatment for hypertension (QUARTET) trial recruited patients (N=591) with hypertension who were untreated or receiving monotherapy from 10 centers across Australia between 2017 and 2020. Patients were randomized to receive either a quadpill (n=300) containing quarter-standard doses of irbesartan (37.5 mg), amlodipine (1.25 mg), indapamide (0.625 mg), and bisoprolol (2.5 mg) or irbesartan (150 mg) monotherapy (n=291) for 12 weeks. At week 6, patients who had blood pressure >140/90 mm Hg were given additional 5 mg daily amlodipine. At week 12, participants were invited to extend treatment up to 12 months.

The intervention and control cohorts comprised individuals aged mean 58 (standard deviation [SD], 12) and 59 (SD, 11) years, 59% and 61% were men, BMI was 31 (SD, 6) and 30 (SD, 6) kg/m2, 83% and 80% were White, 57% and 51% were untreated at baseline, unattended systolic BP (SBP) was 142 (SD, 13) and 140 (SD, 13) mm Hg, and unattended diastolic BP (DBP) was 86 (SD, 10) and 83 (SD, 10) mm Hg, respectively.

At week 12, the recipients receiving the quadpill had a mean unattended SBP of -6.9 (95% CI, -4.9 to -8.9) mmHg compared with controls (P <.001). Which was similar to unattended DBP (mean, -5.8; 95% CI, -4.4 to -7.2 mmHg; P <.001).

The quadpill cohort was more likely to achieve BP control at <140/90 mmHg (76% vs 58%; relative risk [RR], 1.30; 95% CI, 1.2-1.5; P <.0001) and tight BP control at <120/80 mmHg (46% vs 26%; RR, 1.75; 95% CI, 1.38-2.22; P <.0001) by week 12.

Among the 417 patients who extended participation to 12 months, the mean unattended SBP was -7.7 (95% CI, -5.2 to -10.3 mmHg; P <.0001) and DBP was -6.0 (95% CI, -4.3 to -7.6 mmHg) among the quadpill recipients compared with controls.

After 12 months of therapy, more of the intervention cohort achieved BP control (81% vs 62%; RR, 1.3; 95% CI, 1.2-1.5; P <.0001) and tight BP control (53% vs 25%; RR, 2.1; 95% CI, 1.6-2.8; P <.0001).

Treatment withdrawal due to any reason occurred among 4.0% of the intervention and 2.4% of the control cohorts. Serious adverse events were reported by 7 of the intervention (ankle fracture, cholecystitis, migraine, non-cardiac chest pain, positional vertigo, shortness of breath, and tonic clonic seizure) and 3 of the control (myocardial infarction, non-cardiac chest pain, and pneumonia) recipients.

This study was limited by not reaching recruitment targets due to the COVID-19 pandemic.

These data indicated that compared with a standard monotherapy for hypertension, BP was more effectively controlled with a quadpill-based strategy which comprised a quadruple quarter-dose combinatorial therapy of common hypertension medications.

“The findings add further weight to the existing trend in guideline recommendations to actively discourage the use of monotherapy while encouraging the greater use of effective and safe combination therapies,” the study authors concluded.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.


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;398(10305):1043-1052.