Four-in-one pill
Worldwide, hypertension control is poor, Dr. Chow said, because of the need for multiple medications, treatment inertia, and concerns about adverse events.
The researchers hypothesized that initial antihypertensive treatment with a four-in-one pill with quarter doses of each medication would minimize side effects, maximize BP lowering, and overcome these treatment barriers and concerns. A pilot study of this strategy published by the group in 2017 showed promise.
QUARTET randomized 591 adults with hypertension, seen at clinics in four states in Australia from June 2017 through August 2020.
Patients were either receiving no antihypertensive medication and had an unattended standard office BP of 140/90 to 179/109 mm Hg or daytime ambulatory BP greater than 135/95 mm Hg, or they were on BP-lowering monotherapy and had a BP of 130/85 to 179/109 mm Hg or daytime ambulatory BP greater than 125/80 mm Hg. Patients who were taking antihypertensive therapy entered a washout period before the trial.
The researchers randomized 291 participants to receive 150 mg irbesartan daily (usual care or control group).
The other 300 participants received a daily quadpill containing 37.5 mg irbesartan, 1.25 mg amlodipine, 0.625 mg indapamide, and 2.5 mg bisoprolol. The first three drugs are the most commonly prescribed angiotensin II receptor blocker, calcium channel blocker, and thiazide or thiazidelike diuretic in Australia, and the last drug, a beta-blocker, has a long duration of action, the study protocol explains.
Patients in both groups had similar baseline characteristics. They were a mean age of 58 years, 40% were women, and 82% were White. They also had a mean body mass index of 31 kg/m2. About 8% were current smokers, and about 54% were not taking a BP-lowering drug.
Participants had clinic visits at baseline, 6 weeks, and 12 weeks, and if they continued the study, at 26 weeks and 52 weeks.
If a patient’s blood pressure was higher than 140/90 mm Hg, clinicians could add another medication, starting with amlodipine 5 mg.
At 12 weeks, 15% of patients in the intervention group and 40% in the control group had stepped up treatment.
Despite greater up-titration in the usual care group, BP control remained higher in the quadpill group, Dr. Chow pointed out. That is, patients in the quadpill group were more likely than patients in the usual care group to have a BP less than 140/90 mm Hg (76% vs. 58% respectively; P < .0001).
Patients in the quadpill group also had lower daytime and nighttime ambulatory systolic BP.
At 12 months, among the 417 patients who continued treatment, patients in the quadpill group had a 7.7 mm Hg greater drop in systolic BP, compared with patients in the control group, (P < .001).
There were no significant differences in adverse events, which were most commonly dizziness (31% and 25%) or muscle cramps, gastrointestinal complaints, headache, or musculoskeletal complaints.
At 12 weeks, there were seven serious adverse events in the intervention group versus three in the control group. There were 12 treatment withdrawals in the intervention group versus seven in the control group (P = .27).
Remaining questions, upcoming phase 3 U.S. study
“While the [QUARTET] results are impressive, we are left with a number of questions,” Dr. Yusuf said.
Would the results be the same with a three-drug combo or even a two-drug combo at half doses? In the HOPE 3 trial, a two-drug combo at half doses provided similar results to the current study, over a much longer mean follow-up of 5.6 years, he noted.
Also, is the quadpill associated with higher rates of diabetes or higher creatinine levels in the long term? “Given that we do not have any data on long-term clinical outcomes from a four-drug combination,” Dr. Yusuf said, “caution should be utilized.”
Would the reduced risk of CVD be greater with a combination of low doses of two BP-lowering drugs plus a statin plus aspirin? That may be superior, he said, “based on recent information published on the polypill indicating a 50% relative risk reduction in CVD events.”
The related phase 2 QUARTET US trial should shed further light on a quadpill strategy. Patients with hypertension are being randomized to a daily quadpill containing 2 mg candesartan, 1.25 mg amlodipine besylate, 0.625 mg indapamide, and 2.5 mg bisoprolol, or to usual care, 8 mg candesartan daily.
Investigators plan to enroll 87 participants in the Chicago area, with estimated study completion by March 31, 2023.
The study was supported by an Australian National Health and Medical Research Council grant. The George Institute for Global Health has submitted patent applications for low–fixed-dose combination products to treat CV or cardiometabolic disease. Dr. Chow and coauthor Kris Rogers, PhD, senior biostatistician at The George Institute for Global Health, Newtown, Australia, are listed as inventors, but they do not have direct financial interests in these patent applications.
A version of this article first appeared on Medscape.com.