• Becky McCall—United Kingdom

Polypill or poly-problem? Probing a many-sided debate

The decades-old disagreement on the polypill, available in many countries, refuses to die down as not everyone sees it as the solution to the world’s leading cause of death—cardiovascular disease. Will the findings of a new major study give it wider acceptance?

Nearly 20 years ago, a landmark study published in the BMJ concluded that the polypill—a combination of medications commonly used to treat heart disease and high blood pressure—could largely prevent heart attacks and stroke if taken by everyone aged 55 and older and those with cardiovascular disease [CVD].

As far as public health interventions go, this was a bold claim that promised to reform population health on a national and, indeed, global level. In fact, the authors, from the University of London, went so far as to say that the polypill “would have a greater impact on the prevention of disease in the Western world than any other single intervention”.

Arguably, the key to the clinical success of the polypill is simple: it improves medication adherence. Many patients have trouble taking all their individual pills consistently, but when combined in a polypill they can adhere better to treatment.

However, the polypill is still not widely prescribed globally. Yet, it has neither disappeared from the medical landscape. After decades of study, the evidence is starting to reach a critical mass, and even the United States’ Food and Drug Administration (FDA) may soon be convinced enough to approve it.

The first randomised controlled trial of polypill use in secondary care, called SECURE, which was published recently in the New England Journal of Medicine (NEJM), found that when taken after a heart attack it prevents further heart problems when compared to taking each medication separately.

With CVD still the world's leading cause of death, data on the use of the polypill—whether as a primary prevention tool (for people with CVD risk factors) or secondary prevention tool (for those with a history of CVD)—needs careful scrutiny to help resolve one of public health's biggest global challenges.

Benefits to many at low cost

CVD accounted for 32% of all global deaths in 2019, according to the World Health Organization (WHO). There were an estimated 17.9 million deaths, and this figure is expected to grow to 23.6 million by 2030. Of current CVD deaths, 85% are due to heart attack and stroke, and over three quarters are in low- and middle-income countries (LMICs).

Debate around the polypill largely centres on the value of individual risk-based strategies versus population-based strategies.

Similar to the polypills developed for diabetes and metabolic syndrome, the CVD polypill is a one-stop shop for common heart medications, usually aspirin, statins (cholesterol-lowering medication), beta-blockers (which make the heart beat with less force) and ACE inhibitors (which relax blood vessels and decrease blood volume to lower the blood pressure).

Debate around the polypill largely centres on the value of individual risk-based strategies versus population-based strategies.

In theory, a population-based approach aims to lower the overall risk by distributing it across a population. It should be low-cost and with minimal adverse effects—ideal for LMICs and even high-income countries, say some.

At first glance, given the widespread effects of CVD globally, a population-based approach where polypills are prescribed to at-risk groups might seem the obvious answer, but some cardiovascular specialists argue that risk factors and disease require a more nuanced and individualised approach. There is also the fundamental question of whether the polypill should be used for primary or secondary prevention, or both.

Professor Salim Yusuf, a professor of medicine at McMaster University in Canada and past president of the World Heart Federation, supports a population-based approach. He says the polypill is not just a low-cost solution, but also encourages compliance.

"It's a solution that overcomes physicians' reluctance to prescribe, as well as patients' reluctance to take multiple medications,” he says. Even if half the number of heart patients take a polypill, “about two million premature deaths will be prevented, and three times as many people will avoid non-fatal strokes and [heart attacks] each year. This is substantial.”

Yusuf says the polypill offers "substantial value in all countries, irrespective of economic levels, for both primary and secondary prevention”.

He agrees that the potential for the polypill is greater in LMICs owing to its affordability, but points out that "even in high-income countries, fewer than 50% of people in secondary prevention and fewer than 25% of people in primary prevention receive appropriate prevention medications."

Primary versus secondary prevention

A slew of key trials underpin the case for the polypill but there is limited consensus among experts on the preferred healthcare setting. Professor Salim co-authored a 2021 meta-analysis, published in The Lancet, of three primary prevention trials demonstrating significant benefits of the polypill.

Plus, he says, the SECURE study in secondary prevention “expands on these findings and indicates that using the same drugs in a single pill is more effective than prescribing them separately".

Yet distinguished cardiologist and lead investigator on SECURE, Professor Valentin Fuster, who is physician-in-chief at The Mount Sinai Hospital in New York, firmly believes that optimal use of the polypill is in secondary prevention rather than primary prevention.

"It would be very difficult to have a polypill for primary prevention and give people drugs like aspirin, which is not indicated for those without prior cardiovascular events,” he says.

Fuster advocates a role for the polypill in both high-income countries, where medication adherence can be low, and LMICs, where he says it is cost-effective. "In fact, the reason I started developing the polypill was because I was involved with low-income countries, and I saw that the polypill would make the necessary drugs much cheaper,” he says.

As part of the SECURE trial, Fuster and his colleagues recorded the proportion of cardiovascular events in participants taking a polypill—containing aspirin, an ACE inhibitor and a statin—compared to those taking similar medications individually.

All 2,500 participants had experienced a heart attack in the preceding six months and the polypill or equivalent individual medications were provided as secondary prevention. Participants were monitored for subsequent cardiovascular events for an average of three years.

The researchers found cardiovascular death, heart attack, stroke or urgent revascularisation (a procedure that can restore blood flow in blocked arteries or veins) occurred in 9.5% of patients on the polypill, compared to 12.7% in those on separate medications. Crucially, the frequency of cardiovascular death was 3.9% in the polypill group versus 5.8% in those on separate medications. Adherence to the polypill was better, compared with separate medications.

Fuster says the study was based on the hypothesis that improved adherence to the polypill would lead to reduced heart attack risk. "It's much simpler to take a polypill than separate medications [as] it is easy to miss one or the other,” he says.

An intriguing prospect for LMICs

Many heart disease experts believe that, on balance, if the polypill is to find a niche anywhere, the greatest benefit might be reaped in LMICs.

Dr Steven Nissen, chief academic officer of the Heart, Vascular and Thoracic Institute at the Cleveland Clinic in Ohio, says the polypill can help make up for shortfalls in the provision of healthcare. “In low-income countries where there's just nothing [regarding healthcare provision]…if you can get some of those people treated, you can probably save some lives."

However, he believes the polypill is unnecessary in high-income settings. "Once you get to a country with any sophistication in healthcare, doctors treat cardiovascular disease well,” Nissen says. “It isn't complicated—there are drugs to lower blood pressure, drugs to lower cholesterol and aspirin, but it should be customised to the patient's need."

"How can you individualise medicine when, globally, so few are taking the medicines in the first place?” Fuster says. “It needs to be simple and cheap for everyone.

Dr Nissen's main concern is that in a setting where good healthcare is widely accessible, some recipients of the polypill may be over-treated. There is a risk of side-effects from one or more of the medications in the fixed-dose pill, which is not individualised to patient need in primary or secondary prevention. Many patients in need of secondary prevention also have co-morbidities that may influence treatment choice, he says.

"I'm worried that some people who get this therapy will [experience] lower blood pressure and end up [passing out]. If you are on aspirin and get in a bad motor vehicle accident, then you're going to bleed, and you may die. There is a real concern about bleeding complications with aspirin."

Fuster says in the SECURE trial there was no difference in the documented adverse effects between people on the polypill and those taking medications separately. And he says medication adherence remains a significant problem across the world.

"How can you individualise medicine when, globally, so few are taking the medicines in the first place?” Fuster says. “It needs to be simple and cheap for everyone. This is not like a specific cancer, like colorectal or breast, which need personalised combinations. The polypill deals with a different spectrum of disease."

The polypill is available in 25 countries around the world, but Fuster says obtaining FDA approval in the US for secondary prevention is a fundamental next step. “Heart attack is the first entity, but now we want to move into acute coronary syndromes, including stroke. This would have a significant impact in changing medicine on a wide scale."

In the meantime, the future of the polypill remains unclear. But one thing is certain: whether the issue is overmedication or undermedication, high or low income, primary or secondary care, benefit or risk, the polypill debate looks set to remain poly-opinionated for some time to come.


Case study: Haiti reducing inequalities in CVD care

Three in four CVD deaths occur in LMICs like Haiti, where the polypill offers a glimmer of hope. Haiti is the lowest-income country in the western hemisphere, with some of the largest health disparities, says medic and researcher Dr Vanessa Rouzier, who is an assistant professor at Weill Cornell Medicine in New York and lives and works in Haiti as GHESKIO's CVD program director.

She is a co-author of a recent study in Haiti on whether the polypill might be an effective and scalable solution to close the treatment gap in LMICs. In Haiti, CVD is the leading cause of adult mortality, with recent data revealing that 29% of people have hypertension yet only 13% have their condition under control.

Poverty and lack of access to healthcare are significant barriers to improving CVD-related health outcomes. Around 80% of Haitians experience food insecurity and more than half live on less than US$2 per day. Most Haitians do not have access to quality healthcare, and the infrastructure for treatment and prevention of CVD is rudimentary, says Rouzier.

"Our patients differ from [those in] high-income settings in that we do not have high rates of smoking, diabetes, and severe obesity, yet we do have extremely high rates of early-onset hypertension—so something else must be driving hypertension in our country,” she says.

The study found that 52% of adults were eligible for the polypill under a primary prevention strategy and 6% were eligible for secondary prevention. Crucially, Rouzier says, they estimated that nearly 500,000 CVD events would occur in people aged over 40 across Haiti in a five-year period under existing conditions. But by using “a polypill strategy” in primary and secondary prevention, 148,000 projected CVD events—or 32%—could be prevented.