US Study Points Way to Polypill for CVD Prevention

Patrice Wendling

September 18, 2019

New research shows that a single fixed-dose pill combining a statin and three antihypertensive drugs reduced cardiovascular disease (CVD) risk by about 25% compared with usual care in underserved Americans without CVD, bringing the promise of the polypill for the first time to the land of precision medicine.

Various formulations of the polypill for primary and secondary CVD prevention have been around for close to two decades but most of the clinical trial work has taken place in lower- and middle-income countries. Robust results were reported in recent weeks from the PolyIran study and HOPE-4 study, conducted in Columbia and Malaysia.

The present study, published online today in the New England Journal of Medicine, is the first randomized trial to test a fixed-dose polypill strategy in the United States.

"What our results shine some light on is that for patients who are socioeconomically and medically vulnerable, an easy to understand, practical tactic like the polypill can be empowering," lead author Daniel Muñoz, MD, MPA, a cardiologist at Vanderbilt University Medical Center, Nashville, Tennessee, told | Medscape Cardiology.

"One of the most promising pieces of our results was that at 12 months we estimate adherence to the polypill — as measured by pill counts — was 86% in this population," he said. "For context, there is a literature base out there that for US patients with hypertension who require drug therapy, fewer than half are adherent to that therapy at 1 year."

Commenting on the study, long-time polypill advocate Salim Yusuf, MD, DPhil, director of the Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada, said, "This is showing that low-cost simple medicine is better than the usual care. So to me, this is a landmark because this is being done in the land of the skeptics."

The US Food and Drug Administration (FDA) convened an advisory panel in 2014 to debate the possibility of a polypill, focusing primarily on its use in secondary prevention. No firm conclusions were reached but concerns were raised about returning to a one-size-fits-all approach and the inability to titrate the individual components.

"Our entire approach — that is physician-based, individualized medicine — may have a role in certain complex situations, but not necessarily in common conditions that affect 40% of the adult population," observed Yusuf. "No country in the world can afford to do it and no country in the world does it well anyway.

"And the other fact is that physicians in reality don't up-titrate that often," he said. "So this is overcoming physician inertia, the need for up-titration is lessened. It's possible in the future we will have polypills in two tracks, low- and half-dose and full-dose; so instead of having it take 10 steps at titration, we could have two or three steps."

Muñoz said a polypill with fixed doses may fly against all the trends in precision medicine but it doesn't have to be an either/or proposition.

"One could imagine the deployment of a polypill strategy in the real world where it's entirely permitted and encouraged to layer additional therapy as a clinician may deem appropriate, but the polypill provides what may be a critical base or foundation of cardiovascular prevention," he said. "And that base and foundation may be all the more critical for patients who have a hard time attending frequent follow-up visits and having their medications adjusted in an intensive way. So it's not an either/or. I think there can be gains from combining both population-based approaches and all the virtues of precision medicine."

Community-Based Trial

The SCCS Polypill Pilot Trial was conducted in a community health center in Alabama among 303 participants in the SCCS, which was initiated in 2001 to examine health disparities in cancer. Three quarters of patients reported an annual household income of $15,000, 60% were women, 96% were African American, and the average age was 56 years.

Entry criteria included systolic blood pressure (BP) 120-160 mmHg, low-density lipoprotein (LDL) cholesterol < 190 mg/dL, and an estimated glomerular filtration rate ≥ 60 mL/min/1.73m2.

Half the patients were randomly provided free of charge 90-day refillable supplies of the polypill, which contained atorvastatin 10 mg, amlodipine 2.5 mg, losartan 25 mg, and hydrochlorothiazide (HCZ) 12.5 mg. The remaining patients received routine care at the community center on top of any ongoing care from a primary care physician.  

At baseline, 53% of the polypill group were taking a hypertensive, 18% a statin, 21% amlodipine, 4% losartan, and 18% HCZ, with similar numbers reported in the usual-care group. Average BP was 140/83 mmHg in both groups. LDL cholesterol levels averaged about 114 mg/dL and average high-density lipoprotein cholesterol was 61 mg/dL.

After 12 months, results showed that systolic BP declined by an average of 9 mmHg in the polypill group compared with 2 mmHg in the usual-care group (95% CI, –12 to –2; P = .003).

LDL cholesterol fell by an average of 15 mg/dL vs 4 mg/dL, respectively (95% CI, –18 to –5; P <.001). Taken together the findings translate into a 25% reduction in risk of experiencing a CV event over 10 years, according to Muñoz.

It is unlikely that free medication in the polypill group contributed to the results as the community center had a 340B pharmacy program that provided free or nearly free medications to all uninsured patients, the authors note. Thus, the only expense in the usual-care group would have been at most a $3 copayment for a 90-day supply.

As for safety, rates of myalgia and hypotension/light-headedness were each 1% among the 148 patients in the polypill group. No abnormal liver function results were reported. Five deaths and one coronary bypass surgery occurred during the study, but none of the events were judged to be study related.

Muñoz said they specifically chose 10 mg atorvastatin and not to include an angiotensin-converting enzyme inhibitor to reduce the potential risk of side effects. Aspirin was also avoided because of its increasingly questionable role in primary prevention.

Senior author Thomas J. Wang, MD, also with Vanderbilt, said all of the components of the polypill have been proven to be safe and effective and many patients take a combination of some or all of these pills individually.

"It's reasonable to consider that the combination packaged together in the polypill would not have necessarily a different risk/benefit profile than the individual pills together from a regulatory perspective," he said.

As to whether FDA officials might look more favorably on a polypill now, Wang said the study is a step in the right direction but "it would be reasonable to conduct more studies in the United States in a broader array of populations or, at least, a broader array of sites, before it could cross the hurdle of regulatory approval."

Kausik Ray, MD, Imperial College, London, UK, said the trial is important because it covered an underserved population and that the cost to investigators of $26 a month per participant "appears to be a fairly good value, particularly in underserved populations."

Nevertheless, "One of the key things is that we need to move away from treating disease to preserving health," he told | Medscape Cardiology. "The average age here was 56, but if you went to 40-year-olds, you would think that basically 10 years of better control would have cumulative benefits."

"If we started thinking about doing things early in the vast majority of patients, it may well suit a good number, whereas in some people we would have to do additional things and individualize," Ray said. "What proportion would actually be fine with this approach versus needing an individualized approach? That would be a good study to do."

Unanswered Questions

Although "it's good to understand the magnitude of the effects" of a polypill, "what it leaves unanswered are several equally important questions," Niteesh Choudhry, MD, Brigham & Women's Hospital and Harvard University, Boston, Massachusetts, told | Medscape Cardiology.

He noted that a 2014 study in New Zealand showed the polypill compared to its components definitely improved adherence overall but there was no difference or no benefit in terms of clinical effects. In the 2009 TIPS study, there was also a suggestion that the polypill had less of an effect than simvastatin alone when it came to LDL lowering.

"So we legitimately need to understand the impact of the polypill compared to the components because when you put things together they may not be the same as taking them apart," Choudhry said.

Additional research is needed to better understand clinical outcomes with a polypill and "we also need to understand safety, especially if this is a population kind of approach, which resonates a lot with me because it's easier in some populations to give them simple strategies," Choudhry said. "But in a study of 100 people or even 1000 people, safety signals tend to be rare. All of these trials are underpowered to detect safety, so we don't know that either."

All that said, this is the first US study and most of the move in the polypill space has been in lower- and middle-income countries, he noted. "That's where the greatest benefit may be the best but there are clearly gaps in high-quality cardiovascular care in the United States, so this study begins to move us into that space. So for that reason and for that reason alone, the authors deserve tons of congratulation. But now, we need to do this again and bigger."

Two ongoing trials should provide clinical outcomes data: the TIPS-3 trial, which is being conducted in eight countries in about 5700 people and should have results in about a year, and the SECURE study from Spain, which just finished recruiting and should have results sometime in 2021.

"A More Efficient" Way

Jack Flack, MD, chair of medicine at Southern Illinois University School of Medicine in Springfield, noted that about 46% of US adults and roughly 55% of blacks are hypertensive and although blacks more often receive treatment, often their blood pressure is less controlled.

"So essentially what this study did was increase the intensity of treatment by adding three drugs that work well together and probably work well with the drugs they're on, and that's why their blood pressure fell," he said. "At its very granular level, it's telling you that more intense treatment is better. We already knew that, this is just an interesting way to do it that doesn't fit the way we typically practice."

Although this was a high-risk population, the polypill could be used in any population that doesn't have striking derangements in their blood pressure and cholesterol as either add-on therapy to a current medication regimen or as a base of therapy you would add to, Flack said.

That said, "It's absolutely true that you're not going to titrate easily with any single-pill combination," he noted. "We have two- and three-drug pills for hypertension now and we never use them until we get the patient on a stable dose because of the issue of titration. On the flipside, what this study showed in the patient population they studied is that this on top of standard therapy was better than standard therapy or usual care alone."

Flack argues that in most clinical scenarios when physicians are selecting therapy, they're not really doing precise, personalized medicine based on individual genotypes and vascular phenotypes.

"Essentially, what we're doing is looking at patterns that we take out of clinical studies and extrapolating them to entire groups," he said. "We don't practice precision medicine now. There is a promise and a hope that we are moving in that direction, but I view this as a more efficient and effective way of doing what were already doing." 

The study was funded by the America Heart Association (AHA) and National Institutes of Health, and sponsored by Vanderbilt University. Wang has reported receiving grants from the AHA during the conduct of the study and personal fees from Novartis outside the submitted work. Ray has reported acting as a consultant for Resverlogix, Amgen, Sanofi, Regeneron, Medco, Cerenis, Lilly, Ionis Pharma, Esperion, Silence Therapeutics, Bayer, Daiichi Sankyo, and AbbVie; and as a speaker for Kowa, AstraZeneca, Pfizer, Takeda, Boehringer Ingelheim, Algorithm, Cipla, Dr Reddy's, and Zuellig Pharma. He also reports receiving research grants through his institution from Sanofi, Regeneron, Amgen, MSD, and Pfizer. Yusef has reported being a co-principal investigator of TIPS-3. Flack has reported consulting with multiple device companies. Muñoz and Choudhry have reported no relevant financial relationships.

N Engl J Med. 2019;381;1114-1123. Abstract

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