A single combination pill can improve blood pressure control, reduce polypharmacy
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Key takeaways:
- Three trials showed the potential for polypills to improve uncontrolled hypertension.
- QUADRO evaluated a “quad” pill of four antihypertensive agents, while GMRx2 and VERONICA tested a triple-therapy pill.
A polypill containing multiple blood pressure-lowering drugs may be an effective solution to addressing both uncontrolled hypertension and polypharmacy causing non-adherence to antihypertensive medications, speakers reported.
At the European Society of Cardiology Congress, three international trials were presented, each demonstrating the potential for polypills to improve BP control in diverse populations: QUADRO, the GMRx2 trials and VERONICA.
In an editorial in JAMA accompanying the simultaneous publication of VERONICA, George A. Mensah, MD, FACC, FAHA, director of the Center for Translation Research and Implementation Science at the NHLBI, discussed the promise of a polypill solution to uncontrolled hypertension.
“The greatest value from [the VERONICA] study and others like it will come when the low-dose, triple-drug combination pill protocols become widely available and used sustainably in the long term by all who need it,” Mensah wrote. “As the old African proverb teaches, a sick man who eats many herbs may not know what made him well — but if the concoction is available, accessible, affordable, acceptable, safe, and effective, and if it brings him good health, he will gladly take it every time. So it will be for the low-dose combination pills for hypertension.”
The QUADRO study
QUADRO was a phase 3 trial to evaluate the efficacy and safety of a quad therapy pill containing four low-dose antihypertensive drugs for the treatment of resistant hypertension: perindopril, indapamide, amlodipine and bisoprolol.
The primary endpoint was 16-week change in office sitting systolic BP and the secondary endpoint was 16-week change in mean ambulatory systolic BP over a 24-hour period.
Office systolic BP was significantly reduced in both study arms; however, the quad therapy pill lowered office systolic BP on average 8.04 mm Hg further compared with the triple-therapy pill (P < .0001).
The results were similar for ambulatory BP, with an average 7.53 mm Hg further decrease in systolic BP with the quad therapy pill compared with the triple-therapy pill (P < .0001).
“Resistant hypertension, while leading to an increased cardiovascular risk, is difficult to treat, demanding a high number of pills with not enough safe and practical options,” Stefano Taddei, professor of internal medicine and director of the department of clinical and experimental medicine at the University of Pisa, Italy, said during a press conference. “The possibility to use four established drugs in a single combination pill may improve adherence. Thus, this is the first quadruple single-pill combination that will become available as an innovative novelty solution for resistant and difficult to treat hypertensive patients.”
GMRx2: Two pivotal trials
For the two phase 3 GMRx2 trials, researchers evaluated the safety and efficacy of single combination triple therapy pill containing low dose indapamide, amlodipine and telmisartan for the treatment of hypertension.
The first trial was designed to evaluate the efficacy and safety of ultra-low and low-dose polypills compared with placebo among 295 patients with hypertension in a placebo-controlled design. For the second active controlled trial, researchers evaluated the contribution of each component of the polypill to its efficacy and tolerability in a larger cohort of 1,295 patients with hypertension by comparing the effect of low- and standard-dose polypills with three other dual combinations of antihypertensive drugs.
In the placebo-controlled trial, which was simultaneously published in the Journal of the American College of Cardiology, the average baseline home BP was 139 mm Hg systolic/86 mm Hg diastolic.
The researchers reported least-squares mean reductions of 7.3/4 mm Hg and 8.2/5.5 mm Hg with the ultra-low and low-dose polypills, respectively, at 4 weeks.
Overall, 65% of the ultra-low dose cohort and 70% of the low-dose cohorts had an office BP of less than 140/90 mm Hg at follow-up compared with 30% of the placebo group (P < .0001).
In the active-controlled trial, 35% of participants had controlled BP — defined as BP less than 140/90 mm Hg — while taking zero to three antihypertensive drugs at baseline.
At 12 weeks, 74% of participants assigned to the polypill intervention had controlled BP. The proportion of patient who achieved control was smaller among those assigned to any of the dual combinations (amlodipine/telmisartan, 54%; amlodipine/indapamide, 61%; telmisartan/indapamide, 61%).
The researchers reported no significant differences in any safety outcome comparisons of treatment withdrawal; no increase in serious adverse events; and expected increases in nonserious events, such as symptoms of hypotension and low potassium.
“Hypertension is a global public health problem, with over 1 billion adults having high blood pressure. All countries around the world have suboptimal success rated in treatment, even in countries like the U.K. and the U.S., where access and affordability is not a major issue,” Anthony Rodgers, MD, PhD, acting director of the cardiovascular division at The George Institute, Australia and chair of clinical epidemiology, faculty of medicine, at Imperial College of London, said during the press conference. “We suggest this is hopefully a new therapeutic option for hypertension, not just in the existing uses later in life, but also initial treatment in those uncontrolled on monotherapy and hopefully part of an important advance for what is our leading cause of cardiovascular disease.”
The VERONICA trial in Nigeria
To compare the effect of a the GMRx2 trial pills with standard care in Nigeria, Dike Ojji, MBBS, PhD, FESC, head of the cardiovascular research unit at the University of Abuja in Gwagwalada, Nigeria, and colleagues designed the VERONICA trial, the results of which were simultaneously published in JAMA.
VERONICA was a randomized clinical trial that enrolled 300 Nigerian participants with uncontrol hypertension. Uncontrolled hypertension was defined as office systolic BP of 140 to 179 mm Hg and/or diastolic BP of 90 to 109 mm Hg and taking no more than one antihypertensive drug. The average age was a little over 50 years and more than half of participants were women. Most participants were not taking any antihypertensive agents at baseline.
After each month of treatment, triple-therapy pill or standard care, participants’ BP was re-measured and therapy was uptitrated with the goal of reaching long-term BP of less than 140/90 mm Hg. Uptitration in the polypill arm meant higher antihypertensive doses within the single pill. Uptitration in the standard care arm meant adding on another hypertensive agent and subsequent referral to a hypertension specialist if BP remained uncontrolled.
Ojji reported that triple therapy with the polypill produced prompt and significant long-term BP lowering to a greater extent compared with standard care among Nigerian patients with uncontrolled hypertension, with a mean difference of 5.8/3.6 mm Hg at home and 4.5/2.6 mm Hg in-office.
Overall, 62% of participants in the polypill arm achieved home BP control at 6 months — defined as BP less than 130/80 mm Hg — compared with 28% of the standard care arm (risk difference, 33%; 95% CI, 22-44; P < .001).
Similar to the GMRx2 trials, the polypill was well-tolerated and the only significant adverse event at 6 months was low serum potassium.
“Among Black African adults with uncontrolled hypertension, a low-dose triple pill protocol achieved better blood pressure lowering and control with good tolerability compared with the standard care protocol,” Ojji said during the press conference.
References:
- Ojji DB, et al. Hot line 2. Presented at: European Society of Cardiology Congress; Aug. 30-Sept. 2, 2024; London (hybrid meeting).
- Rodgers A, et al. Hot line 2. Presented at: European Society of Cardiology Congress; Aug. 30-Sept. 2, 2024; London (hybrid meeting).
- Mensah GA, et al. JAMA. 2024;doi:jama.2024.18166.
- Ojji DB, et al. JAMA. 2024;doi:10.1001/jama.2024.18080.
- Rodgers A, et al. J Am Coll Cardiol. 2024;doi:10.1016/j.jacc.2024.08.025.
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Taddei S, et al. Hot line 2. Presented at: European Society of Cardiology Congress; Aug. 30-Sept. 2, 2024; London (hybrid meeting).
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