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Quad-pill more effective than mono-therapy in hypertension

An anti-hypertensive quad-pill has been shown to provide better blood pressure control than the standard initial approach with mono-therapy.

According to the World Health Organization (WHO), the number of adults aged 30–79 years with hypertension is estimated to be 1.28 billion. However, perhaps more concerning are the WHO statistics suggesting that approximately 46% of adults are unaware that they have hypertension and that only 21% of patients have their condition under control. Various hypertension guidelines recognise that adequate blood pressure control is often only achieved with several medicines, yet guidance from NICE, for example, still recommends initiating mono-therapy. The potential value of using combination therapy as an initial approach to the management of hypertension, was explored in a small trial with 55 patients in 2017. A research team from the George Institute for Global Health, Camperdown, Australia, examined the value of using a single quad-pill with four anti-hypertensives, at a quarter of the normal treatment dose, as an initial therapy for patients with high blood pressure compared with placebo. After only 4 weeks, all patients given the quad-pill achieved a satisfactory blood pressure control (<140/90mmHg). However, these results were not surprising given the findings of a 2009 meta-analysis, which concluded that the additional blood pressure reduction from combining drugs from two different classes was approximately five-times greater than doubling the dose of one drug.

Now, the same Australian team has published the results of a randomised trial which they termed Quadruple UltrA-low-dose tReaTment for hypErTension (QUARTET). This randomised, double-blind study in adults with hypertension, allocated individuals, on a 1:1 basis, to either the quad-pill, which contained irbesartan (37.5mg), amlodipine (1.25mg), indapamide (0.625mg) and bisoprolol (2.5mg), or an indistinguishable, mono-therapy with irbesartan 150mg. The primary outcome was the difference in unattended office systolic blood pressure at 12 weeks. Moreover, a sub-cohort of patients from the trial continued with treatment for up to 52 weeks.


A total of 591 patients with a mean age of 59 years (60% male) and a mean baseline unattended blood pressure of 141mm/85mmHg, were randomised to quad-pill (300) or mon-therapy with irbesartan . By week 12 only 15% of those receiving the quad-pill compared to 40% on mono-therapy, required additional blood pressure medication. Furthermore, at week 12, a higher proportion of patients given the quad-pill (76% vs 58%) achieved a blood pressure < 140/90mmHg (relative risk, RR = 1.30, 95% CI 1.20–1.50, p < 0.0001). In addition, a blood pressure of less than 120/80mmHg, was also achieved by more patients in the quad-pill group (46% vs 26%, RR = 1.75, 95% CI 1.38–2.22, p < 0.0001). After 52 weeks, mean unattended systolic blood pressure remained 7.7mmHg lower in the intervention group. At 12 months, blood pressure control rates were also higher for the intervention group (81% vs 62%, RR 1.32, 95% CI 1.16–1.50) as were the proportion achieving a blood pressure < 120/80mmHg (53% vs 25%, intervention vs control, RR = 2.1 95% CI 1.60–2.8, p < 0.0001).

The authors concluded that “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 mono-therapy.”


Chow CK et al. Initial treatment with a single pill containing quadruple combination of quarter doses of blood pressure medicines versus standard dose mono-therapy in patients with hypertension (QUARTET): a phase 3, randomised, double-blind, active-controlled trial. Lancet 2021