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Use of a combination antihypertensive product containing quarter doses of four different drugs could be an effective strategy to get patients to target blood pressures in one step, a new study suggests. 

The study, QUARTET-USA, warfarin vs aspirin for blood clots showed a reduction in blood pressure of almost 5 mm Hg more than the comparator of one antihypertensive agent at standard dose over the 12-week follow up period in patients with mild to moderate hypertension.

The QUARTET-USA study was presented at the American Heart Association (AHA) Scientific Sessions 2022 by Mark Huffman, MD, professor of medicine at Washington University School of Medicine, St Louis, Missouri. 

It builds on a previous trial, QUARTET, conducted in Australia, which first showed benefits with this approach.

In the new US study, which was considerably smaller than the Australian trial, the four-drug combination, including candesartan, amlodipine, indapamide, and bisoprolol, led to a -4.8/-4.9 mm Hg greater reduction in blood pressure from baseline to 12 weeks compared with standard-dose candesartan monotherapy.

Differences in systolic blood pressure were not statistically significant, which is likely because of limited power related to the sample size, Huffman noted.  

Adverse events were more common in the four-drug intervention group, but the rate of discontinuation was higher in the comparator group. No severe adverse events were deemed related to the study drug.

“The direction and magnitude of blood pressure-lowering effect were similar between the previous Australian study and this American study, despite different populations with lower baseline blood pressure in the current study, thus strengthening the case for this new approach,” Huffman concluded.

“The two studies together show that the approach of using four drugs in quarter doses is more effective in lowering blood pressure than a single standard dose antihypertensive agent and has an acceptable safely profile,” he commented to theheart.org | Medscape Cardiology.

He said the four-drug combination could be an effective way of getting patients to target without multiple appointments.  

“If you think about how many visits to the doctor’s office it takes to get patients to goal blood pressures, this combination gets patients down to new guideline target levels in one step, whereas in the SPRINT trial it took three or more visits to get down to these levels. And in practice we lose people — they don’t come back,” he said.

Huffman explained that the rationale for the study was the persistently low hypertension control rate, which demonstrates the need for a new approach.

The previous Australian QUARTET study suggested that ultra-low-dose combination therapy has a favorable balance between blood pressure-lowering effect, tolerability, and adherence.

That study, conducted in 591 patients and reported in 2021, demonstrated a greater blood pressure-lowering effect with a four-drug combination at quarter doses (irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg, bisoprolol 2.5 mg) at 12 weeks compared with irbesartan 150 mg daily. Systolic blood pressure was reduced by more than 6.9 mm Hg and diastolic blood pressure by 5.8 mm Hg than full dose irbesartan alone, both significant differences. 

The current study, QUARTET-USA, aimed to see if a similar strategy could produce comparable results in a US population.

The US study included 62 patients from the Access Community Health Network, Chicago, who were either treatment naive with blood pressures above 140/90 mm Hg, or already taking antihypertensive monotherapy with blood pressures above 130/85 mm Hg.

The mean systolic blood pressure at baseline was 138 mm Hg and the mean diastolic pressure was 84 mm Hg.

Study participants were mainly from ethnic minorities (90% Hispanic or Black) and over half were from low-income households (annual household income less than $25,000).

They were randomly assigned to daily administration of a four-drug combination at quarter doses (candesartan 2 mg, amlodipine 1.25 mg, indapamide 0.625 mg, bisoprolol 2.5 mg) or a full dose of candesartan 8 mg (the comparator arm).

Amlodipine 5 mg daily could be added on to treatment if blood pressure remained above 130/80 mm Hg at 6 weeks. This occurred in 18% of the study group vs 53% of the comparator group.

Results showed that at 12 weeks the adjusted mean change in systolic blood pressure weeks was -4.8 mm Hg (95% CI, -10.7 to 1.2), and the adjusted mean change in diastolic blood pressure was -4.9 mm Hg (95% CI, -8.6 to -1.1) in the four-drug combination group compared with the comparator arm.

Average blood pressures at the end of 12-week study period were 121 mm Hg systolic and 73 mm Hg diastolic in the four-drug intervention group compared with 124 mm Hg systolic and 77 mm Hg diastolic in the comparator group.

Any adverse events that were possibly related to drug therapy occurred in 25% of the intervention group vs 10% of the comparator group. But adverse events leading to discontinuation occurred in 6.3% of the study group vs 26.7% of patients in the comparator arm.

“New approaches are needed to achieve lower blood pressure targets, especially for patients and communities with a high burden of hypertension and hypertension-related diseases. QUARTET-USA was the first trial of a four-drug, ultra-low dose, blood pressure lowering combination therapy in the US,” Huffman said.

“We showed reductions in blood pressure similar in magnitude to those in the Australian study. It is useful to know that the direction of the effect is similar across varied populations. Now that we have that signal of efficacy and tolerability, we can move to actually getting it into the hands of patients and providers,” he added.

Noting that further studies will be required to attain marketing authorization, Huffman suggested that a pharmaceutical company would need to complete that process.

“These are promising results for companies who may be interested in partnering,” he said.  

“A More Efficient Approach” 

LaPrincess C. Brewer, MD, assistant professor of medicine at Mayo Clinic College of medicine, Rochester, Minnesota, and discussant of the study, said the QUARTET-USA study suggests the four-drug, low-dose combination shows promise in lowering blood pressure compared with the standard dose, and while the reduction in systolic pressure was not quite significant, it was clinically meaningful.

“Most US adults with hypertension do not have it under control. This is due to unfavorable social and structural determinants of health which limit adherence to antihypertensive medication,” Brewer noted.  

From a patient point of view, the multiple visits needed to attain goals are a burden and there is also the issue of clinical inertia and lack of medication intensification by clinicians, she commented. 

“Of patients with uncontrolled hypertension, 40% are taking just one antihypertensive medication, so up-front, low-dose combination therapy is likely a more efficient approach,” she said.

“This study builds the evidence base for the need for tailored interventions that address the social determinants of health and the intentional prioritization of diverse population in clinical trials,” Brewer concluded.

QUARTET was an investigator-initiated study, Huffman reports a pending patent for a heart failure polypill.  The George Institute for Global Health, Sydney, Australia, where Huffman has a secondary appointment, has a patent, license, and has received investment funding with intent to commercialize fixed-dose combination therapy. Brewer reports research support from the  National Institutes of Health, Centers for Disease Control and Prevention, American Heart Association, and Bristol-Meyers Squibb Foundation.

American Heart Association (AHA) 2022 Scientific Sessions: Presentation 19617. Presented November 6, 2022.  

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