QUARTET results bolster efficacy, safety of a single pill combining quarter doses of four antihypertensive drugs

In hypertensive patients, early treatment with a fixed-dose, four-drug, quarter-dose combination of antihypertensive agents—including irbesartan, amlodipine, indapamide, and bisoprolol—lowered blood pressures (BPs) more effectively than monotherapy, according to results from the QUARTET trial published in The Lancet.

“High blood pressure remains the leading modifiable cause of disease burden globally. Even in countries where blood pressure-lowering medications are available and affordable, many—if not most—treated individuals do not achieve blood pressure control. Still, by far the most common approach to hypertension management globally is to start patients on monotherapy. Although multiple medications are usually required to achieve blood pressure control, treatment inertia and concerns regarding adverse events are common barriers to the effective use of multiple medications, resulting in persistent monotherapy for many patients with hypertension. Low-dose, single-pill combinations hold considerable promise to help overcome these barriers,” wrote Professor Clara K. Chow, PhD, of the University of Sydney, Westmead Hospital, Westmead, Australia, and fellow QUARTET investigators.

In an interview with BreakingMED, Deepak Bhatt, MD, Executive Director of Interventional Cardiovascular Programs, Brigham and Women’s Hospital Heart & Vascular Center, and professor of medicine, Harvard Medical School, Boston, explained that “Most doctors start patients with high blood pressure on one medicine at a time, max out on the dose of that drug, then add additional medicines as needed. Prior studies have shown that it is probably better to start lower doses of two drugs than a very high dose of one drug for hypertension.”

For the multicenter, double-blind, parallel-group, randomized, phase III QUARTET trial, Chow and colleagues randomized 591 hypertensive adults (mean age: 59 years; 60% male; 82% White; 12% Asian; 6% other) who were untreated or receiving monotherapy to treatment with a quadpill (n=300) comprised of quarter-doses of irbesartan (37.5 mg), amlodipine (1.25 mg), indapamide (0.625 mg), and bisoprolol (2.5 mg), or a monotherapy control (irbesartan, 150 mg; n=291). Additional medications were allowed among patients in both groups whom BP did not reach target, starting with amlodipine (5 mg).

The primary outcome of the trial was the change in unattended office systolic blood pressure at 12 weeks, and secondary outcomes included BP control (<140/99 mmHg), safety, and tolerability. A subgroup of 417 patients continued the trial to 12 months to assess long-term effects.

Baseline mean unattended office BP was 141 mmHg/85 mmHg. At 12 weeks, systolic BPs were 6.9 mmHg (95% CI: 4.9-8.9; P<0.0001) lower in patients receiving the quadpill. At this time point, BP control was higher in these patients compared with those in the control group (76% vs 58%, respectively; RR: 1.30; 95% CI: 1.15-1.47; P<0.0001).

At this same time point, 15% of patients who received quadpill treatment received additional BP medications to achieve BP control, compared with 40% of those in the control

Researchers found no difference in treatment withdrawals at 12 weeks due to adverse events (intervention: 4.0% vs control: 2.4%; P=0.27).

In the subgroup of patients who continued treatment to 12 months, up-titration was needed more often in control patients compared with the intervention group (P<0.0001). At 52 weeks, mean unattended systolic BP was 7.7 mmHg lower (95% CI: 5.2-10.3) in the intervention group, and BP control rates higher compared with the control group (81% vs 62%, respectively; RR: 1.32; 95% CI: 1.16-1.50).

At 12 weeks, 3% of patients in the intervention group experienced serious adverse events, compared with 1% of those in the control group.

“The present study nicely demonstrates that the strategy of a fixed-dose quadruple quarter-dose combination pill for hypertension results in better blood pressure control. This approach seemed safe in this modest sized trial,” Bhatt told BreakingMED. “While the data already support combination blood pressure therapy with two agents, I don’t know any doctor in clinical practice who routinely uses four medications at once. But this trial proves that such an approach (with very low doses of each of the four drugs) is effective.”

He added that these results need replication in future studies that involve more international patients, but concluded: “These results should make doctors relook at the data supporting initiation of two lower dose antihypertensives as opposed to one higher dose drug. To apply the four-drug strategy as used here would be a bit challenging right now, as it is not always easy to get quarter doses. But in the future, such combination tablets can be designed.”

Luke Laffin, MD, co-director, Center for Blood Pressure Disorders and preventive cardiologist, Cleveland Clinic, Cleveland, told BreakingMED that the findings from the QUARTET trial are not unexpected.

“Both the contemporary U.S. and European guidelines emphasize/recommend the use of fixed dose combination pills (typically 2 BP lowering medications in one pill) to treat BP >140/90 mmHg. Even though this is the guideline recommendation, the authors rightly point out that clinicians are still more likely to start monotherapy,” he said.

Laffin also pointed out some limitations:

“…contemporary U.S. and European BP management guidelines do not recommend initial monotherapy for hypertension treatment with BP >140/90, thus making the study’s findings less applicable to clinicians actually using the guidelines (of note the trial was conceived before the release of these guidelines, so that is the likely reason for the disconnect),” he said. “Also, the study population was predominantly White (performed in Australia) how this translates to U.S. population is not known—although I presume that the results may have been even compelling in a U.S. population because African American patients are more likely to have a low renin form of hypertension and do not respond to monotherapy with angiotensin-receptor blockers as robustly as White patients.”

Should these results change current clinical practice in any way?

“A pill such as the one studied in the trial is not readily available for patients. Current fixed dose combination therapy which includes three drugs at low dose are available but can be cost prohibitive based on insurance coverage. My hope is that this re-emphasizes to clinicians that monotherapy for hypertension is not particularly effective and multiple medications of different classes at low doses, do not have any more side effects and are more effective in lowering BP,” Laffin concluded.

Further study limitations listed by Chow et al include failure to reach the recruitment target, that patient compliance was assessed via pill counts only, that long-term cardiovascular outcomes were not assessed, that quarter doses were based on standard doses from published formularies without considering geographic variations in these doses, and that physicians had significantly lower rates of treatment inertia than commonly observed.

  1. A single-pill, four-drug, quarter-dose combination can achieve sustained blood pressure control quickly and safely for most hypertensive patients.

  2. Results from the QUARTET study support a greater focus by clinicians, medication manufacturers, and consumers on using combination therapy to treat patients with hypertension

Liz Meszaros, Deputy Managing Editor, BreakingMED™

The study was supported by a National Health and Medical Research Council (NHMRC) Project grant. Some investigators received support from NHMRC Program grants.

Chow is supported by an NHMRC Investigator grant, and is listed as an inventor with the George Institute for Global Health (TGI), which has submitted patent applications with respect to low fixed-dose combination products for the treatment of cardiovascular or cardiometabolic disease.

Cat ID: 6

Topic ID: 74,6,730,6,130,192,916