Polypill could change secondary prevention strategies for US cardiologists

The concept of a fixed-dose, combination strategy for CVD prevention has long been a topic of discussion in the cardiology community.

Medication adherence continues to be an issue worldwide for patients with CVD. Patients with a history of MI or stroke are recommended to take preventive medications including aspirin, cholesterol-lowering and BP-lowering therapies. However, 60% of people in the United States and other high-income countries and more than 90% of people in low-income countries are not taking the medications they need for secondary prevention, according to current estimates.

“When we look at community-based surveys of people in the United States who have had MI, which include those who are not necessarily coming to a doctor, only one in four takes a combination of aspirin, a statin and other recommended medications,” Mark D. Huffman, MD, MPH, FACC, FAHA, assistant professor of preventive medicine and medicine-cardiology at Northwestern University Feinberg School of Medicine and staff cardiologist at Bluhm Cardiovascular Institute at Northwestern Medicine, told Cardiology Today. “Combination therapy is an effective strategy that makes it easier for patients to remember to take life-saving drugs. The data tend to be consistent that fixed-dose combination therapy can improve adherence.”

The “polypill,” most commonly a combination of low-dose aspirin, a statin and at least one other medication, usually an ACE inhibitor or beta-blocker, has been developed to address issues of adherence. ACE inhibitors or beta-blockers are not used because they lower BP, but rather because they are associated with survival benefit and prevent recurrent MI even in the absence of lowering BP, experts told Cardiology Today.

Several polypills are known to be in development, two of which have been approved: Trinomia/Sincronium (Ferrer Laboratories/Centro Nacional de Investigaciones Cardiovasculares Carlos III) is available in 21 countries in Europe and the Americas and PolyCap (Cadila/Population Health Research Institute) is available in India and Zambia. Approval in the United States may not be far off, after an FDA Cardiovascular and Renal Drugs Advisory Committee meeting in September 2014 offered suggestions for a regulatory pathway.

However, acceptance of the polypill in the United States would result in a different practice of medicine for cardiologists, and perhaps a changed mindset as well. Instead of titrating individual medications, doctors would prescribe a combination pill containing multiple drugs, likely chosen from a few dose options, with tailoring on top; in the future, there may be different combination and dosing options of polypills, which would allow customization for those with specific contraindications. The emphasis would be on long-term adherence to all recommended drug classes, with less focus on the possibly diminishing marginal returns of tailoring to a single risk factor.

“It would not surprise me if there are some bumps in the road for the reception of the polypill as a prevention strategy, because it is not always easy to effect change,” Sidney C. Smith Jr., MD, FACC, FAHA, FESC, professor of medicine at the heart and vascular center of the University of North Carolina at Chapel Hill and past president of the American Heart Association and World Heart Federation, said in an interview. “It would have to be positioned as an optional approach to treating patients.”

The “starting point” is key, according to Anthony Rodgers, MD, PhD, professor of global health at the George Institute for Global Health, Sydney, Australia. “If all patients are started on the right drugs at the right doses and unwaveringly continue them long term, there wouldn’t be much need for polypills. However, in a world where most people, even in the United States, aren’t taking core recommended medicines even a year after MI, most would agree that there is a need for adherence-improving strategies like the polypill.”

Study data show benefit

One advantage of a polypill is that its components are proven to save lives and are relatively safe and inexpensive for secondary prevention of CVD in patients who have had MI. So, increased adherence to the medications will lead to better outcomes, Valentin Fuster, MD, PhD, physician-in-chief at The Mount Sinai Hospital, director of the Mount Sinai Heart Institute and general director of Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, told Cardiology Today. Via CNIC, Fuster has been involved with research and development of Trinomia/Sincromium, a polypill composed of aspirin, simvastatin or atorvastatin, and ramipril.

“The pills used separately are already a standard, proven to be Class I, given to any patient with MI,” Fuster said.

The FOCUS I study evaluated adherence to the three separate medications by patients in different countries. “What we found is that medication adherence is low following MI. Less than 50% of people are taking the medications they are supposed to,” said Fuster, a researcher for that trial.

In the FOCUS II study, patients with acute MI assigned a polypill exhibited better adherence at 9 months compared with those assigned the three medications separately, both in an intention-to-treat population (50.8% vs. 41%; P = .019) and a per-protocol population (65.7% vs. 55.7%; P = .012).

In the UMPIRE study, participants with or at high risk for CVD had a higher rate of medication adherence if assigned a polypill composed of aspirin, simvastatin, lisinopril and atenolol or hydrochlorothiazide compared with usual care (86% vs. 65%; RR for adherence = 1.33; 95% CI, 1.26-1.41).

A systematic review of nine trials published from 2009 to 2013 covering 7,047 participants and six different polypill formulations found that improvement in adherence was as high as 33%. Although individual polypill trials have been underpowered to compare polypills and separate medications in terms of CV outcomes, the review found no difference between a polypill or comparator therapy in mortality (RR = 1.26; 95% CI, 0.67-2.38), fatal/nonfatal CVD events (RR = 1.38; 95% CI, 0.91-2.1) or serious adverse events, although the polypill was associated with a higher rate of overall adverse events (RR = 1.19; 95% CI, 1.09-1.3), Huffman and colleagues reported.

CNIC is currently coordinating a large clinical trial to compare the effectiveness of Trinomia on CV outcomes in 3,200 patients in Europe with prior MI. The trial is being funded by the European Commission and recruitment is expected to begin in late 2015, Fuster said.

When Rodgers and colleagues performed a meta-analysis of the UMPIRE, Kanyini-GAP and IMPACT trials, they found “surprisingly” that the benefits of the polypill appeared to be higher in younger people compared with elderly adults, and that most of the benefits could be attributed to “getting people started or restarted on all recommended medications, rather than in reducing pill burden among those already taking lots of medications,” Rodgers said.

Another oft-cited benefit of the polypill — and a reason why there has been much focus on bringing it to lower-income countries — is cost.

“The polypill evolved for two reasons. One is because we want to improve adherence, and we think one pill a day is easier to take than three pills a day,” said Fuster, who also is editor-in-chief of the Journal of the American College of Cardiology and past president of the AHA and World Heart Federation. “Second, is the economic basis. Effectively, improved adherence translates into reduction of CV events and consequently in reduced associated costs. In this respect, polypills should be considered cost-effective treatments.”

A question of titration

A theoretical trade-off with the polypill is that health care providers cannot tailor a specific drug regimen to a specific patient, but can be assured that the patient is more likely to take all the medications necessary to help prevent future CV events. However, “at present, most patients don’t have all the drugs prescribed and, in real life, few patients are titrated up to the full doses of the medications,” Salim Yusuf, MBBS, DPhil, professor of medicine at McMaster University, Hamilton, Ontario, Canada; executive director of the Population Health Research Institute, Hamilton; and president of the World Heart Federation, told Cardiology Today.

“The key thing is that the individual components matter less because there are overlapping effects of the different drugs, so that slight variations of what you use, so long as they are compatible with each other, will not make a difference,” Yusuf said in an interview. “What matters more is that we use BP-lowering agents, a statin at some dose — the incremental benefits of higher doses are far more modest than the benefits of using low doses — and, in secondary prevention, aspirin.”

Rodgers agreed. “The specific components do matter, but not nearly as much as expected,” he said. “Most formulations would be expected to lower CV risk by 50% to 75%. Different components would help for people who cannot take certain medications due to side effects.”

It will be important for doctors to keep on top of any adverse events associated with the polypill because “there is a risk that if people stop taking the polypill for problems with one component, they will miss out on taking all components,” said Rodgers, who has been involved with development of the Red Heart Pill (George Institute for Global Health). However, that has rarely been seen in trials, he added.

Yusuf noted that “some polypills are available with only some of the components, which then can be used in patients with a specific side effect. For example, a polypill without an ACE inhibitor can be used in those with a cough.”

There have been concerns about risk factor control with the polypill. “The biggest concerns seems to be lack of flexibility in tailoring doses, which might translate to worse risk factor control. However, the trials showed clearly that improvements in adherence more than made up for this issue. One can still tailor ‘on top,’ and several of the polypills have dose versions,” Rodgers said.

A range of polypills with different medications and dosages available may help allay some concerns, experts said.

When the idea of the polypill was first proposed in 2001, “it was envisioned that multiple polypills and multiple fixed-dose combinations would be available for patients with different needs and different specifications,” Huffman said. “So it is not unexpected that some patients might be better suited for some combinations. For example, some patients can tolerate a beta-blocker or ACE inhibitor, while others have a hard time based on side effects.”

The likelihood of problems with the polypill is no greater than those with individual drugs, according to Yusuf, who has been involved with development of the PolyCap polypill. “The beauty of the polypill is that it overcomes the defects of tailoring,” he said. “We often get it wrong, and we don’t treat people to the extent we should. The only tailoring I would do is if there was an obvious contraindication or side effect to a particular component.”

Growing availability

At least five polypills are available worldwide or in development, and several are currently going through the FDA regulatory process. Examples include CardiaPill (CardioPharma), Polycap, PolyIran (University of Teheran Medical Sciences), Red Heart Pill and Trinomia/Sincronium. Rodgers anticipates that CardiaPill will be the first polypill approved by the FDA. Ferrer is also planning to enter the U.S. market with Trinomia/Sincronium, Fuster said.

To date, India is the only country that has approved a polypill for primary prevention; the other approvals have been for secondary prevention.

The polypill has not yet been available in the United States because of uncertainty about the regulatory process. However, this was addressed at the recent meeting of the FDA Cardiovascular and Renal Drugs Advisory Committee, experts said.

“Part of the impediment was that there was not a clear regulatory route for approval,” Yusuf said. “The FDA meeting provided some guidance and actually made it reasonably straightforward to get an approval. These components are drugs we have used for decades. I think the FDA has removed one major obstacle, and we will see a lot of people developing it. In a decade, I expect the polypill to be widely used worldwide.”

During the FDA meeting, advisory committee members told FDA officials that randomized controlled trials with CV endpoints should not be required for approval of a polypill. The panel did not come to consensus on what should be required beyond potential for pharmacokinetic and pharmacodynamics interaction.

The target population identified was anyone who requires secondary prevention of CVD, has indications for all components and is able to tolerate all components of the polypill. FDA officials had suggested that a target population be specified as those who cannot get the follow-up necessary for titration, but advisory committee members said doctors will not be interested in identifying who is and is not likely to get follow-up for titration. Panel members also said concerns about consequences for patients who could receive follow-up for titration but instead take the polypill are unfounded because underutilization of necessary medications is the bigger concern.

“The people most likely to benefit are those unable to follow a regimen of multiple therapy,” Smith said. “As patients get older, sometimes it becomes difficult for them to remember all of their different medications. So those who are older, those with lower educational status, and those with multiple comorbidities and diseases would be the people that would have the highest benefit from the polypill.”

Primary prevention less certain

Much less certain is whether the polypill is appropriate for primary prevention; that issue was not discussed at the FDA panel meeting last year. If a polypill were approved by the FDA for primary prevention of CVD, it would likely not contain aspirin, as the FDA in 2013 issued a public health advisory cautioning against using aspirin for primary prevention, experts said.

Fuster said the problem with a polypill for primary prevention is that, unlike with secondary prevention, where it is well known what everyone who has had MI should take to prevent another one, there is no single medication strategy known to work for those who have not yet had a CV event.

In contrast, “for some high-risk primary prevention populations, such as those with diabetes or hypertension, both BP-lowering medications and statins have been clearly proven to save lives and prevent MI and stroke,” Yusuf said.

If a polypill were to be given for primary prevention, it would have to be to those identified at high risk for CVD in the near future, Huffman said. “Some people are estimated to have short-term risk that is similar to people who have had a prior event,” he said. “For example, I had a patient whose 10-year risk was in the 24% range, which is not too far off from the expected event rate for individuals who have had a prior event. So it is possible that fixed-dose combination therapy will be a strategy to prevent MI and stroke in high-risk individuals who have not had previous events.”

Yusuf said two large trials of polypills for primary prevention are underway: the HOPE 3 trial of 12,700 people, with results expected in March 2016, and the TIPS 3 trial of 5,000 people, with results expected in 2018 or 2019.

Rodgers said primary prevention vs. secondary prevention may be a false dichotomy. “I don’t know of any drug that doesn’t work to prevent a first event, but does work to prevent a second one,” he said. “There are significant numbers of people who have not yet had an event but who are at least as high risk as someone who has, and large numbers of people who are at such low risk that treatment, polypill or otherwise, would not be warranted. That’s why I think the target group should be secondary prevention and those at similarly high risk. The challenge is in simple, reliable risk discrimination.”

Smith said use of a polypill in the United States for primary prevention may be unlikely because of personalized medicine. “I would think in developing countries where the CVD epidemic is emerging and the opportunity for personalized medicine is not as great that having a single pill that could be taken at a point when populations become at high risk for an event is something that might be considered.”

Future adoption, guideline incorporation

One question surrounding approval of polypills in the United States is about adoption. The answer to that may come down to whether they are incorporated in guidelines.

Smith, who was chair of the ACC/AHA Task Force on Practice Guidelines and the ACC/American College of Cardiology Foundation 2011 Guideline on Secondary Prevention and Risk Reduction Therapy for Patients with Coronary and Other Atherosclerotic Vascular Disease and also a member of the panel that wrote the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults, said it may be easier than some think for polypills to be incorporated into the guidelines.

“Titration to LDL targets is no longer recommended, and the recommendations are now based on statin dose,” he said. “I think that the recent guideline changes … make this a lot easier than it would have been when we were trying to titrate doses. That is a development that, although it was not done with a polypill in mind, certainly fits well.” – by Erik Swain

References:

Castellano JM, et al. J Am Coll Cardiol. 2014;doi:10.1016/j.jacc.2014.08.021.

de Cates AN, et al. Cochrane Database Syst Rev. 2014;doi:10.1002/14651858.CD009868.pub2.

Thom S, et al. JAMA. 2013;doi:10.1001/jama.2013.277064.

Webster R on behalf of the SPACE Collaboration. Late-Breaking Clinical Trials. Presented at: World Heart Federation Scientific Sessions; May 4-7, 2014; Melbourne, Australia.

For more information:

Valentin Fuster, MD, PhD, can be reached at Guggenheim Pavilion Floor GP 1 West Room 118A, 1190 Fifth Ave., New York, NY 10029; email: valentin.fuster@mssm.edu.

Mark D. Huffman, MD, MPH, FACC, FAHA, can be reached at 680 N. Lake Shore Drive, Suite 1400, Chicago, IL 60611; email: m-huffman@northwestern.edu.

Anthony Rodgers, MD, PhD, can be reached at The George Institute for Global Health, PO Box M201, Missenden Road, NSW 2050 Australia; email: arodgers@georgeinstitute.org.

Sidney C. Smith Jr., MD, FACC, FAHA, FESC, can be reached at CB #7075 Burnett Womack, 160 Dental Circle, Chapel Hill, NC 27599-7075; email: scs@med.unc.edu.

Salim Yusuf, MBBS, DPhil, can be reached at McMaster University, 1280 Main St. West, Hamilton, ON L8S 4L8, Canada.

Disclosures: Huffman reports receiving grant support from the World Heart Federation for serving as senior adviser to its emerging leaders program; the program is funded in part by Boehringer Ingelheim and the Bupa Foundation. Rodgers is employed by an institute that holds an exclusive global license for a polypill. Yusuf reports having research funded in part by Cadila. Fuster and Smith report no relevant financial disclosures.