New trials elevate focus on polypill strategy for CVD prevention
Treatment with a polypill — generally combining statins, BP-lowering drugs and sometimes aspirin — is not a new concept for CVD. Two recent successful trials have brought the use of a polypill for primary and secondary prevention of CVD into the spotlight again, one of which extended the applicability of the concept to the United States.
In the cluster-randomized PolyIran trial published in The Lancet in August, a polypill with 12.5 mg hydrochlorothiazide, 81 mg aspirin, 20 mg atorvastatin and 5 mg enalapril prevented major CV events with high medication adherence rates and low adverse event rates rates compared with standard care in patients living in Iran requiring primary or secondary prevention.
“For clinical practice, the main message is that we should not wait until heart attack or stroke [occurs] and then start treatment,” Reza Malekzadeh, MD, director of the Digestive Disease Research Institute at the Tehran University of Medical Science, Iran, told Cardiology Today. “Rather, we should prevent heart attack and stroke in apparently healthy people who have one or more risk factors by starting prevention with a once-daily polypill, which is very safe.”
Another trial, published a month later in The New England Journal of Medicine, found that a polypill with 10 mg atorvastatin, 2.5 mg amlodipine, 25 mg losartan and 12.5 mg hydrochlorothiazide contributed to greater reductions in systolic BP and LDL compared with usual care in a socioeconomically vulnerable minority population living in Mobile, Alabama.
“It was important for us to take this pragmatic clinical research question to where the need was greatest,” Daniel Muñoz, MD, MPA, assistant professor of cardiovascular medicine at the Vanderbilt Translational and Clinical Cardiovascular Research Center at Vanderbilt University Medical Center and lead author of the Alabama study, told Cardiology Today.“If we’re going to understand what works and what doesn’t, we need to study these patients so that we can help bend the needle in terms of health outcomes in these vulnerable populations.”
Advantages, challenges of polypill
Studies of the polypill strategy go back as far as 2009.
A meta-analysis of early polypill studies found the strategy improved medication adherence by 44% (95% CI, 26-65), and subsequent studies have shown similar results.
Several advantages to a polypill strategy for CVD prevention include convenience, simplicity and evidence on the effectiveness of components typically found in polypills.
Although this approach seems novel, it stems from old strategies.
“The fixed-dose combination concept of polypill therapy is an old idea, if you think about multivitamins. The idea is to put multiple medications into a simpler delivery system,” Mark Huffman, MD, MPH, Quentin D. Young Professor of Health Policy, associate professor of preventive medicine and medicine-cardiology and director of the Center for Global Cardiovascular Health at Northwestern University Feinberg School of Medicine and also associate professor of food policy at The George Institute for Global Health at the University of New South Wales in Kensington, Australia, said in an interview. “It makes sense to be able to use a similar strategy to tackle CVD — the leading cause of death globally — just like how HIV, tuberculosis and malaria are treated all over the world every day.”
This strategy can, however, pose the risk for adverse drug reactions or events depending on components of the combination pills, which may include statins, aspirin and BP-lowering drugs. Researchers for the PolyIran study had a second variation of a polypill on hand for patients who developed cough; this pill contained 40 mg valsartan instead of 5 mg enalapril. Cough is a common adverse event tied to ACE inhibitors.
“This program of need for pill switching could happen in a real-life situation,” Bart S. Ferket, MD, PhD, assistant professor of population health science and policy at the Institute for Healthcare Delivery Science at Mount Sinai Icahn School of Medicine, told Cardiology Today. “The question of the optimal combination of drugs and who might benefit most from a polypill for CVD is still open for debate.”
A study published in Heart in 2017 by Ferket and colleagues suggested that patients older than 40 years would benefit with regard to increased life expectancy and improved quality-adjusted life expectancy through the prevention of CV events. Beyond that, experts said that patients with medication adherence issues or those from socioeconomically vulnerable populations could see a benefit with a polypill-based strategy.
“It remains an open question of where else, in what other communities, in what other types of patients might this concept be applied successfully,” Muñoz told Cardiology Today.
Cost-effectiveness of a polypill-based strategy is dependent upon who the pill is prescribed to. According to the study by Ferket and colleagues, the polypill strategy would not be cost-effective in patients with low risk, but would offer the greatest cost-effectiveness in patients aged 60 years or older.
“We know that the cost-effectiveness would improve on an individual level when people with high risk are treated, but the price of the polypill itself would also alter the cost-effectiveness of the strategy,” Ferket said.
Several trials are currently in progress to further assess the benefits of a poly-pill strategy for CVD, including TIPS-3, which includes patients without heart disease or prior stroke in 10 countries, and SECURE, which enrolled older patients with recent MI.
Muñoz and colleagues have submitted a grant funding application for a study that would be conducted in a network of community health centers across the U.S.
“It will be valuable to understand whether a polypill strategy can be effective and can be implemented across a diverse array of settings,” he said.
Although more research is needed in this area, some experts believe that focus should be placed on the potential behind a polypill strategy rather than the individual components of it.
“Rather than debating about the nuances of individual drugs within various drug classes, polypills can help patients, especially those with low adherence, be more likely to achieve some of the ambitious clinical targets that we have not just in low- and middle-income countries where hypertension control rates are quite low, but also even here in the United States,” Huffman told Cardiology Today. “That is the power of this Southern Community Cohort Study polypill trial. This is a global solution that’s applicable to us here in Chicago, not just people in Iran or Delhi or other low- and middle-income country settings.” – by Darlene Dobkowski
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- Ferket BS, et al. Heart. 2017;doi:10.1136/heartjnl-2016-310529.
- Muñoz D, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1815359.
- Roshandel G, et al. Lancet. 2019;doi:10.1016/S0140-6736(19)31791-X.
- Secondary Prevention of Cardiovascular Disease in the Elderly Trial. ClinicalTrials.gov. Available at: clinicaltrials.gov/ct2/show/NCT02596126. Accessed Oct. 11, 2019.
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- The International Polycap Study 3. ClinicalTrials.gov. Available at: clinicaltrials.gov/ct2/show/NCT01646437. Accessed Oct. 11, 2019.
- Thom S, et al. JAMA. 2013;doi:10.1001/jama.2013.277064.
- For more information:
- Bart S. Ferket, MD, PhD, can be reached at firstname.lastname@example.org.
- Mark Huffman, MD, MPH, can be reached at email@example.com; Twitter: @mark_huffman.
- Reza Malekzadeh, MD, can be reached at firstname.lastname@example.org.
- Daniel Muñoz, MD, MPA, can be reached at email@example.com.
Disclosures: Ferket, Malekzadeh and Muñoz report no relevant financial disclosures. Huffman reports he received funding from the NHLBI where he is the principal investigator for a four-drug, quarter-dose BP-lowering combination pill, and has a secondary appointment at The George Institute for Global Health, which has a company called George Medicines that has a license and has received investments to commercials some drug combinations, although he is not directly involved with those studies.