A small randomized placebo-controlled trial published in the Lancet demonstrated that treatment with ultra-low-dose combination therapy in the form of a “quadpill” significantly reduced blood pressure with few adverse effects.1
Although patients are habitually treated with monotherapy for hypertension, this typically results in a blood pressure reduction of only 9/5 mm Hg, underscoring the need for more effective approaches. Earlier findings have shown that antihypertensive treatment with half of the standard dose led to a reduction in blood pressure up to 80% of that observed with a standard dose, and fewer side effects occurred with the half-dose.2 In another trial, a combination of 4 medications was more effective than a standard dose of each single medication.3
In the present study, researchers from Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland, Imperial College in London, United Kingdom, and several Australian universities investigated the use of ultra-low-dose combination therapy — called a “quadpill” — in patients with untreated hypertension.
Adult patients (n = 18) from 4 centers were assigned to receive a daily placebo or a capsule consisting of a quarter-dose of 4 common antihypertensive agents (irbesartan 37.5 mg, amlodipine 1.25 mg, hydrochlorothiazide 6.25 mg, and atenolol 12.5 mg) for 4 weeks.
After a subsequent 2-week placebo washout period, the conditions were switched and treatment was administered for 4 additional weeks. The capsules used in both groups appeared identical, and both the patients and study staff were blinded to the treatment conditions.
Ambulatory 24-hour blood pressure monitoring was conducted at baseline, at the end of the first 4 weeks, at 6 weeks following the washout period, and at 10 weeks, which marked the end of the final 4-week treatment period. At various points, the investigators performed blood biochemistry analyses and assessed adverse events.
The primary outcome was systolic blood pressure reduction at 4 weeks per the 24-hour ambulatory monitoring results.
The following results were observed for the quadpill vs placebo periods:
- A mean difference in 24-hour systolic blood pressure of 18.7 mm Hg (95% CI, 14.3-23.0)
- A mean difference in 24-hour diastolic blood pressure of 14.2 mm Hg (95% CI, 11.5-16.9)
- A diﬀerence in oﬃce systolic and diastolic blood pressure of 22.4 mm Hg (95% CI, 16.5-28.3) and 13.1 mm Hg (95% CI, 8.9-17.3), respectively
In line with previous studies in low-dose antihypertensive therapy, the current results further show that treatment compliance was high, while adverse effects were minimal.
Compared to existing treatment strategies, a “single quadruple combination capsule is likely to achieve more blood pressure-lowering than up-titrating monotherapy, since doubling the dose for blood pressure drugs from half-dose or from standard dose provides only about 1-2 mm Hg further reduction in systolic or diastolic blood pressure,” the researchers wrote.
The quadpill approach also decreases reliance on stepped titration, increases the likelihood of treatment adherence, and “addresses the individual variation in responsiveness to diﬀerent agents through provision of a combination with a range of modes of action.”
Several investigators detail various grants, funding, and honoraria from a range of organizations and companies.
1. Chow CK, Thakkar J, Bennett A, et al. Quarter-dose quadruple combination therapy for initial treatment of hypertension: placebo-controlled, crossover, randomised trial and systematic review [published online February 9, 2017]. Lancet. doi:10.1016/S0140-6736(17)30260-X
2. Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ. 2003;326(7404):1427. doi:10.1136/bmj.326.7404.1427
3. Mahmud A, Feely J. Low-dose quadruple antihypertensive combination: more eﬃcacious than individual agents: a preliminary report. Hypertension. 2007;49:272-275. doi:10.1161/01.HYP.0000254479.66645.a3