Low-Dose Polypills Top Other Approaches for Initial BP Control: Meta-analysis

Fixed combinations of three or four antihypertensives get most patients under control, but many patients still have unmet needs.

Low-Dose Polypills Top Other Approaches for Initial BP Control: Meta-analysis

For the initial treatment of hypertension, polypills containing low doses of three or four antihypertensive agents are better at lowering blood pressure than monotherapy, usual care, or placebo and are generally well tolerated, according to a new meta-analysis.

These fixed-dose combinations led to significantly greater mean reductions in systolic BP within 4 to 12 weeks of treatment initiation compared with monotherapy/usual care (7.4-mm Hg greater reduction) and placebo (18.0-mm Hg greater reduction), Nelson Wang, MD (The George Institute for Global Health, University of New South Wales, Sydney, Australia), and colleagues report.

Patients who received polypills were more likely than those treated with monotherapy/usual care to have their BP controlled to below 140/90 mm Hg early on (66% vs 46%) and at 6-12 months (72% vs 59%). They were also more likely to be controlled compared with placebo-treated patients in the first 4 to 12 weeks (54% vs 18%).

The study, published online Wednesday in JAMA Cardiology, is the latest by an Australian team that has long been investigating combo-pill approaches to improving hypertension management, including taking the lead on some of the major randomized trials in this space.

Contrary to the idea that usual care—starting patients on one or two drugs and then titrating up from there—would match an initial polypill strategy in terms of BP-lowering given enough time, “this review indicated that usual care does not eventually ‘catch up’ to an initial low-dose-combination strategy, with large benefits in terms of hypertension control achieved initially and maintained at 6 to 12 months,” Wang told TCTMD via email.

Pooling results from several studies also allowed the investigators to look for safety signals that might not have been apparent in the individual analyses, and the only tolerability issue that arose was a higher rate of dizziness with the polypills versus active comparators (14% vs 11%). But that wasn’t associated with a higher rate of treatment withdrawal, senior author Anthony Rodgers, MBChB, PhD (The George Institute for Global Health, University of New South Wales), noted.

“The evidence is here to show that this would be a real step change in hypertension control,” Rodgers told TCTMD.

Consistency of Effect

Hypertension treatment guidelines typically recommend starting with one or two antihypertensives, but fixed-dose combination pills containing low doses of three or four BP-lowering medications have been developed in recent years. Results from clinical trials, including QUARTET and TRIUMPH, have been promising. “The pharmacological rationale, outlined almost 20 years ago, was that most BP-lowering effects can be maintained and most adverse effects avoided at low dosages and that there are additive effects when combining agents from different classes,” the investigators explain.

The current analysis included seven trials with a total of 1,918 patients (mean age 59 years; 38% women) who underwent initial hypertension treatment with a polypill containing three or four drugs, monotherapy, usual care, or placebo. Five trials included short-term follow-up (4-12 weeks), and two had follow-up of 6-12 months.

The evidence is here to show that this would be a real step change in hypertension control. Anthony Rodgers

The primary outcome was the mean reduction in systolic BP, which was greater in the polypill group than in the other groups. The fixed-dose combinations also achieved BP control to less than 140/90 mm Hg in most patients. The results were not affected by whether patients were already on BP-lowering therapy at baseline.

“Even though there were different drugs and doses used in all the different trials, there was a very common pattern, which obviously makes you more confident that this is going to be a broadly generalizable finding,” Rodgers said.

Although dizziness occurred in a greater number of patients in the polypill group, there were no differences in other adverse effects, including peripheral edema, headache, musculoskeletal pain, or serious adverse effects, or in treatment withdrawal.

What’s Holding Polypills Back?

Commenting for TCTMD, Niteesh Choudhry, MD, PhD (Brigham and Women’s Hospital, Boston, MA), said the paper nicely synthesizes what has been known about the impact of polypills containing low doses of multiple antihypertensive drugs—that they appear to provide superior BP-lowering effects compared with the usual approach of starting a drug, seeing how the patient responds, and then adding to it if necessary.

The fixed-dose-combination approach is likely more effective for both biological and behavioral reasons, said Choudhry, who is lead author of a 2021 American Heart Association scientific statement on medication adherence and blood pressure control.

In terms of biology, “you get most of the bang for the buck from antihypertensive therapies at their lower doses, and if you then combine a bunch of low-dose drugs that work with different mechanisms, you get the benefits of blood pressure-lowering without all of the side effects that you might otherwise see,” he said.

And on the behavior side, putting multiple drugs into a single pill can help overcome clinical inertia on the part of clinicians when it comes to intensifying therapy and make it easier for patients to adhere to their regimens, he said.

The hypertension polypill concept has not taken off, however, for a variety of reasons, Choudhry pointed out. In addition to the lack of widespread availability of such fixed-dose combinations in the market currently, a lot of physicians have concerns about how they would manage adverse events related to use of the therapies if the specific drug component causing the problem can’t be identified. Some also are worried that starting with three or four drugs may be too aggressive and may cause adverse effects, Choudhry said, noting that the increase in dizziness observed in the current study means that concern may be valid. “I think most people are conservative and cautious and won’t want to expose patients to risk, quite appropriately, and that may be holding them back.”

There may also be a lack of awareness of the state of the evidence hampering uptake of the polypill approach, Choudhry added.

All of the drugs included in the polypills are generic and widely available, he noted, “so once there are form factors that allow us to prescribe them easily and we all get comfortable doing that, then I think there will be broader adoption of this strategy.”

An ‘Excellent First Start’

But more research is needed, Choudhry indicated, pointing to lingering questions about how polypills will perform in the wider population outside of carefully controlled clinical trials and the lack of information on how this strategy might impact cardiovascular outcomes. He added, however, that “the blood pressure effects were pretty profound, and so we should reasonably expect that this would translate into cardiovascular benefits.”

Taking a broader view, Choudhry said the hypertension polypill concept is part of a larger wave of combination therapies across disease types meant to lessen the burden and costs for patients of taking a growing number of evidence-based medications.

For right now, “this is an excellent first start,” he said, pointing out that about one-third of patients still had uncontrolled BP even on a polypill. “For the routine care of patients, there’s really no reason to not think about something like this, but that doesn’t mean we’re done with this long battle of achieving better blood pressure control,” said Choudhry, adding that other drugs, like spironolactone, may be needed in certain groups. “So I think there’s really a large agenda that remains for the third of patients who wouldn’t benefit from something like this.”

Still, Rogers predicted polypills will have a big impact on improving BP control rates moving forward. The advantage over usual approaches is that up-front use of three or four agents will get patients quickly down to BP goals, he said. On the other hand, starting with one or two agents and gradually bringing down BP often results in patients and physicians taking their foot off the gas before getting down that low, meaning that even if the average BP is in the control range, some readings will bounce out of range due to typical day-to-day variability.

“How polypills work is they just get you straight past that danger zone, that decision-inertia zone, and straight into [a place] where most or all of your measures are going to be in control,” Rodgers said.

Todd Neale is the Associate News Editor for TCTMD and a Senior Medical Journalist. He got his start in journalism at …

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  • The George Institute for Global Health, with which several authors are affiliated, has submitted patent applications with respect to low fixed-dose combination products for the treatment of cardiovascular or cardiometabolic disease. George Health Enterprises and its subsidiary, George Medicines, have received investment funds to develop fixed-dose combination products, including combinations of blood pressure-lowering drugs.
  • Wang and Rodgers report no relevant conflicts of interest.