Four Drugs, One Pill: QUARTET USA Supports New Strategy for BP-Lowering

An ultralow-dose “quadpill” has again shown promise, this time in a low-income, diverse US population.

Four Drugs, One Pill: QUARTET USA Supports New Strategy for BP-Lowering

Photo Credit: AHA/Scott Morgan 2022. Used with permission.

An ultralow-dose quadruple-combination pill has again outperformed standard-dose monotherapy at lowering blood pressure, according to data from the small, randomized QUARTET USA trial. The difference did not quite reach statistical significance for systolic BP at 12 weeks, though it did for diastolic BP.

“Persistently low hypertension control rates around the world, including in the United States, demonstrate the urgent need for a new approach to managing our patients,” Mark D. Huffman, MD (Washington University in St. Louis, MO), said when presenting the late-breaking clinical trial findings at the American Heart Association 2022 Scientific Sessions in Chicago, IL.

“Ultralow-dose combination therapy has a favorable balance between the blood pressure-lowering effect—a lot of which is observed at very low doses—tolerability [with fewer side effects], and adherence, by simplifying the medication regimen,” Huffman told AHA attendees.

Previously, the Australia-based QUARTET trial, which also tested a four-drug pill but a slightly different formulation and control (irbesartan rather than candesartan), provided evidence that by 12 weeks systolic BP was 6.9 mm Hg lower with the “quadpill.” And while more study-drug patients than controls withdrew due to side effects, the benefit was sustained through 12 months, Huffman noted.

“However, this is a large effect that was studied in a generally white and East Asian population in Australia,” he pointed out. QUARTET USA, which enrolled patients with mild-to-moderate hypertension, sought to understand how the results would play out in a more-diverse US population.

There is the question, though, of whether the fixed nature of doses and components in a combo pill would have downsides.

Huffman told TCTMD this question is a common one. The combination approach “is great, because it works really well, it’s simple. But you lose some of the flexibility,” he observed. On the flip side, having too many choices comes at the risk of “decision fatigue,” with so many products for BP-lowering on the market.

Some people might need more-tailored medication regimens, Huffman allowed. Still, he said, “look at our current approach—is it working? No. Is this the answer? It could be part of it.”


The trial randomized 62 patients (mean age 52 years; 45% female) receiving care in a Chicago-area health network over a 3-year period ending in May 2022. Fully 73% were Hispanic, and 18% were Black. More than half had an annual household income below $25,000. Around three-quarters were already on monotherapy with systolic BP < 160 mm Hg and diastolic BP < 100 mm Hg, and the rest were treatment-naive with systolic BP < 180 mm Hg and diastolic BP < 110 mm Hg.

Mean systolic BP was 138.7 mm Hg for controls and 137.6 mm Hg for the intervention group at baseline, while mean diastolic BP was 84.3 mm Hg in both groups.

Study participants were randomly assigned, in a double-blind fashion, to receive either candesartan 8 mg or the combination therapy (candesartan 2 mg, amlodipine 1.25 mg, indapamide 0.625 mg, and bisoprolol 2.5 mg). At 6 weeks, patients with BP still above 130/80 mm Hg received add-on amlodipine 5 mg daily—this occurred in 53% of controls and 19% of the intervention group.

We’re hearing [about] these big implementation gaps because of the approach of starting the medicine, titrating it up, having patients come back. We’re trying to get to lower goals faster, safer through lower-dose combination therapy. Mark D. Huffman

Unadjusted data showed “earlier and greater reductions in blood pressure in the intervention group,” said Huffman, such that with the quadpill, mean systolic BP was 122.9 mm Hg by 6 weeks and 121.2 mm Hg by 12 weeks. With candesartan 8 mg, these values were 130.1 and 124.2 mm Hg, respectively.

Mean change in automatic office systolic BP at 12 weeks after adjustment for baseline values, the study’s primary endpoint, was -4.8 mm Hg (95% CI -10.7 to 1.2) greater with the quadpill than with control. The nonsignificant difference between groups was likely do to the small sample size.

Adjusted mean change in diastolic BP, a secondary endpoint, was -4.9 mm Hg (95% CI -8.6 to -1.1).

Serious adverse events occurred in two quadpill patients, though neither were deemed related to the study drug. The rate of any adverse event was higher with the intervention than with controls (62.5% vs 46.7%). The proportion of patients who had adverse events leading to drug continuation, on the other hand, was smaller with the combination pill than with monotherapy (6.3% vs 26.7%)

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

Breaching Barriers to Care

LaPrincess C. Brewer, MD (Mayo Clinic, Rochester, MN), discussant for QUARTET USA in the late-breaking session, observed that unfavorable social determinants of health are one reason why most US adults with hypertension don’t have their blood pressure under control. There also are barriers at the patient/provider level, including the need for repeat visits to adjust dosing.

Among patients with uncontrolled hypertension, 40% still are taking just one antihypertensive drug, Brewer said. “So up-front low-dose drug combination therapy is likely more effective and a more-efficient approach.”

The strategy pursued in QUARTET USA “shows promise,” she said, describing the difference in systolic BP as “not statistically significant but clinically meaningful.”

Importantly, Brewer pointed out, the trial was “conducted in federally qualified health centers, including low-income, socioeconomically disadvantaged patients,” and enrolled high proportions of women and Hispanic and Black participants.

“This study builds the evidence base for the need for tailored interventions that address social determinants of health, and intentional prioritization of diverse populations in drug clinical trials is essential,” Brewer said. The work exemplifies the AHA’s recent call to advance health equity through implementation science, she continued. “Also, we must promote pharmacoequity approaches in diverse populations through diversity and inclusion in clinical trials and drug access for all.”

This study builds the evidence base for the need for tailored interventions that address social determinants of health, and intentional prioritization of diverse populations in drug clinical trials is essential. LaPrincess C. Brewer

Keith C. Ferdinand, MD (Tulane University School of Medicine, New Orleans, LA), who moderated the late-breaking session, asked if availability of an ultralow-dose quadruple pill might have unintended consequences. “Would there be a disincentive to doctors and nurse practitioners to use effective blood pressure medications at effective doses? The idea that we need just a little bit of this, just a little bit of that tends to undermine the randomized clinical, controlled trials that have shown blood pressure medications do work and save lives.”

Huffman said he agrees BP therapies are effective. “But we’re hearing [about] these big implementation gaps because of the approach of starting the medicine, titrating it up, having patients come back,” he explained. “We’re trying to get to lower goals faster, safer through lower-dose combination therapy. I can’t predict in my patients who’s going to respond a little bit better to one drug or the other.”

Their intent is to achieve balance between the BP-lowering effect and tolerability, and to simplify care. “Combination therapy will typically improve adherence by 20-40%. We’ll be reporting those results,” said Huffman.

Next Steps

Speaking with TCTMD, Huffman pointed out that the possibility of an up-front strategy, wherein patients start out on multiple drugs at lower doses, is appealing. Even in SPRINT, with the support of a trial setting, it typically took three or four visits to get patients to target, he said. Then after the trial ended and patients returned to real-world practice, the survival benefit seen with intensive BP-lowering vanished.

He said the choice of candesartan in this study, rather than irbesartan, had to do with the production process. The company that made the quadpill for QUARTET USA used a “milling and filling approach,” he explained, “so they took the pills, they ground them down, they put them in a tumbler, weighed everything, and then did really precise quality-control measures,” which was necessary with such ultralow amounts.

Having a smaller pill, rather than larger, would be easier to swallow, he said, and the candesartan doses came in at just 2 mg in the combo pill and 8 mg in the control. By comparison, in the Australia-based QUARTET trial, irbesartan was given at a dose of 37.5 mg in the combo pill and 150 mg in the placebo.

Now, it’s time to see how the quadpill concept can come to fruition, Huffman said.

With the US Food and Drug Administration’s current regulatory pathway for combination therapies, getting “marketing authorization would require trials that would have at least five arms . . . that would show an added benefit for each component,” he said, adding, “That becomes a pretty large trial relatively quickly, [though] it doesn’t have to be necessarily long.” To pursue this, they would need to partner with a pharmaceutical company.

Caitlin E. Cox is News Editor of TCTMD and Associate Director, Editorial Content at the Cardiovascular Research Foundation. She produces the…

Read Full Bio
  • Huffman MD. Efficacy and safety of a quadruple ultra-low-dose treatment for hypertension (QUARTET USA): a randomized controlled trial. Presented at: AHA 2022. November 6, 2022. Chicago, IL.

  • The study is supported by the National Heart, Lung, and Blood Institute.
  • Huffman reports a pending patent for a heart failure polypill as well as travel with the World Heart Federation. He holds a secondary appointment at The George Institute for Global Health, the social enterprise arm of George Health, a company that has received investment funds to develop fixed-dose combination products.