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With the arrival of two new polypill studies overcoming some of the limitations of the existing literature, some are convinced that it's time for the guidelines to incorporate fixed-dose combination therapies in cardiovascular disease (CVD) prevention.

First, the randomized QUARTET trial showed that use of a fixed "quadpill" was a better strategy for blood pressure (BP) control than was standard monotherapy for hypertension. Notably, the uptitration of therapy over time did not diminish the difference in BPs achieved between intervention and control groups.

The second study, a meta-analysis of three large and well-known polypill trials, was able to show that polypills consistently conferred clinical benefit in primary prevention -- regardless of a person's cardiometabolic risk factors, and no matter the specific drugs chosen for combination therapy.

Both studies were presented as late-breakers at the European Society of Cardiology (ESC) virtual meeting and were simultaneously published in the Lancet.

"Guideline writers and policy makers should consider how to incorporate this evidence base into guidelines and policies," urged Jonathan Mant, MD, of University of Cambridge, and Richard McManus, MBBS, PhD, of University of Oxford, both in England, in an .

QUARTET and Blood Pressure

A single pill combining tiny doses of four antihypertensives was successful at reducing BP without raising safety concerns, according to a .

Patients assigned to the quadpill had a 6.9-mmHg bigger drop in unattended office systolic BP at 12 weeks compared with peers receiving irbesartan monotherapy on intention-to-treat analysis (P<0.0001), reported Clara Chow, PhD, of University of Sydney, and colleagues.

"In QUARTET, this BP reduction was achieved largely in one step -- this simplicity is a key potential advantage. Implementation research is now required to understand how ultra-low dose combinations can best be integrated into current treatment algorithms globally," they said.

"Clinical practice guidelines should be updated to incorporate evidence on the effectiveness and safety of strategies that use low-dose combination medications as initial or early treatment of patients with hypertension," the authors added.

The proportion of QUARTET participants achieving office BP <140/90 mmHg at 12 weeks was 76% of the quadpill group versus 58% of controls (RR 1.30, 95% 1.15-1.47).

Trial protocol allowed people who didn't push BP low enough on their assigned therapy to get additional medications, starting with amlodipine at 5 mg. At 12 weeks, these additional drugs were given to 15% vs 40% of the quadpill and monotherapy arms, respectively.

"The quadpill strategy is simple and effective. In this study, most of the intervention participants only needed the quadpill to achieve BP control," the QUARTET group emphasized.

Investigators had 591 people randomized to the polypill (containing irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg, and bisoprolol 2.5 mg) or a monotherapy control (irbesartan 150 mg).

In the subgroup of 417 patients who stayed in the study out to 12 months, the control arm experienced more frequent uptitration of their medications but did not catch up to the quadpill group in BP control or BP levels. Systolic BP remained on average 7.7 mmHg lower after a year of the intervention.

The phase III double-blind was conducted from 2017-2020. Participants entered the study at an average 59. Three in five were men, and 82% of patients were white. Baseline mean unattended office BP was 141/85 mmHg. Study participants were not treated for their hypertension in 54% of cases; the rest were already on some kind of monotherapy.

Quadpill and control groups shared similar baseline characteristics.

Chow's group demonstrated the quadpill's safety and tolerability by reporting no excess adverse event-related treatment withdrawals at 12 weeks (4.0% vs 2.4%, P=0.27) and similarly low rates of serious adverse events between groups (3% vs 1%).

"Initial monotherapy remains the most used strategy globally, and as a result BP control rates remain suboptimal, often due to treatment inertia. This study supports a greater focus by clinicians, medication manufacturers, and consumers on using combination therapy," Chow and colleagues concluded.

Yet COVID-19 had thrown a wrench in recruitment for the trial, leaving the investigators short of their 650-person recruitment target, they cautioned. In addition, they lacked data on long-term CV outcomes and couldn't tell how adherent patients really were to their assigned antihypertensive medications.

Studies like the following, however, bolster the case that the magnitude of BP reduction by the quadpill may be linked to clinical benefit.

Putting the Big Trials Together

A showed that polypills conferred big reductions in incident CVD for most patients despite modest improvements in lipid and BP levels.

In a large primary prevention cohort, the composite of CVD, myocardial infarction, stroke, or arterial revascularization over a median 5 years reached 3.0% of people assigned polypills vs 4.9% of controls receiving placebo or usual care (HR 0.62, 95% CI 0.53-0.73). Each component of this primary endpoint supported significant benefit with fixed-dose therapy.

With 18,162 people pooled from the TIPS-3, HOPE-3, and PolyIran trials, the meta-analysis is the largest study to date showing the effect of polypill therapy in CVD prevention -- the estimated number needed to treat to prevent the primary outcome being as low as 52 at 5 years, according to Philip Joseph, MD, of the Population Health Research Institute at Hamilton Health Sciences and McMaster University in Ontario, Canada.

"There is a striking consistency in the results of the three individual trials, despite the different drugs used, providing further confidence in the conclusion that a fixed-dose combination strategy is effective," commented Mant and McManus.

Study authors also noted that the clinical effects of polypills were unchanged by cardiometabolic risk factors: results were similar at different lipid and BP levels, and in the presence or absence of diabetes, smoking, or obesity.

The polypills studied in these three trials comprised at least two BP-lowering agents plus a statin. The combined medications were associated with a modest 4.7-mmHg drop in systolic BP and 22-mg/dL reduction in LDL cholesterol compared with controls.

People randomized to have aspirin added to their fixed-dose treatment saw a particularly large drop in incident CVD -- a 47% reduction over 5 years, Joseph's group reported. As for safety, this aspirin subgroup of the polypill arm showed a modest increase in gastrointestinal (GI) bleeding (0.4% vs 0.2%, P=0.15) as well as dizziness (11.7% vs 9.2%, P<0.0001).

With a number needed to harm of 554 to cause one GI bleed, however, "the balance of benefit compared with potential harm is in favour of the use of a fixed-dose combination strategy that includes aspirin," the authors maintained.

Otherwise, the occurrence of hemorrhagic stroke, fatal bleeding, and peptic ulcer disease was low and did not differ significantly between polypill and control groups.

Across the three trials, study participants had a mean age of 63. The cohort, split between men and women, had an estimated 10-year CVD risk of 17.7% at enrollment.

The meta-analysis was limited by the studies' differing methods for adverse event collection. GI bleeding not requiring hospitalization or intervention might have been underreported, according to Joseph and colleagues.

Nonetheless, they said that the body of evidence favors the integration of polypills into clinical practice for many populations, which can be expected to prevent "several tens of millions of CVD events and related cardiovascular deaths over the next decade."

"Many people with indications for pharmacotherapy, even those with existing CVD, in low-income and middle-income countries are not taking it. This suggests that strategies to initiate and maintain these drugs need to be as simple as possible. Such strategies might also have a role in high-income countries," said Mant and McManus.