Next question: could 4-drug tablet work in the U.S.?
Fixed-dose oral combination therapy in a single once-daily tablet reduced major cardiovascular events in a trial powered for clinical outcomes.
Fewer rural Iranians randomized to long-term "polypill" use had a hospitalization for acute coronary syndrome, fatal MI, sudden death, heart failure, coronary artery revascularization, or stroke over 5 years than did controls (5.9% vs 8.8%, adjusted HR 0.66, 95% CI 0.55-0.80).
Longer duration polypill use was associated with a stronger protective effect in the 6,838-person PolyIran trial.
"The polypill strategy could be considered as an additional effective component in controlling cardiovascular diseases, especially in low-income and middle-income countries," concluded Reza Malekzadeh, MD, of Tehran University of Medical Sciences, and collaborators in the Aug. 24 issue of The Lancet.
The once-daily polypill included low-dose aspirin, moderate-dose atorvastatin, and half-dose hydrochlorothiazide and enalapril (replaced with a polypill containing valsartan if the patient developed a cough).
There was no interaction between polypill benefit and pre-existing cardiovascular disease, so the results are relevant to both primary and secondary prevention, they suggested.
With the focus on hard clinical benefits, the PolyIran findings mark a "remarkable accomplishment" and are "what the polypill field has been looking for," according to James De Lemos, MD, of UT Southwestern Medical Center in Dallas, who was not involved with the study.
Although it can't be concluded that the polypill will be effective in the current U.S. practice environment, it holds promise to deliver cardiovascular prevention therapies to a larger number of patients, he told MedPage Today in an interview.
"What will be interesting will be the debate this generates regarding the application of the polypill for underserved populations in the U.S. and other high-income countries. Are there places where this strategy makes sense? Maybe for individuals with less access or who don't come to the doctor," De Lemos suggested.
He was one of a panel of FDA advisors that in 2014 voted against theoretical approval of a three-drug polypill with an antihypertensive, aspirin, and statin.
PolyIran was part of the larger Golestan Cohort Study of more than 50,000 adults from the Golestan province in Iran. The overarching study was cluster-randomized by participating village.
In PolyIran, both groups got their usual care plus non-pharmacological preventive interventions, such as education about healthy lifestyle.
Study participants were ages 50-75 at enrollment. Roughly half of the cohort was female. Individuals at high risk for bleeding were excluded.
Of the 10% who had pre-existing cardiovascular disease, most were already taking medications for it. Non-study cardiovascular drug medication use was similar between groups.
Median adherence to the polypill was 80.5%. When researchers compared controls to only polypill recipients with high adherence, the reduction in risk appeared especially strong (adjusted HR 0.43, 95% CI 0.33-0.55).
For polypill users, the average 3-mm Hg reduction in systolic blood pressure observed at month 24 disappeared by month 60. On the other hand, a significant 20-mg/dL drop in LDL cholesterol was maintained throughout follow-up.
Medication-related adverse event rates were similarly low between groups: Intracranial hemorrhage was observed in 10 versus 11 patients in polypill and control groups, respectively. Upper GI bleeds occurred in 13 and nine individuals, respectively.
Approximately one in eight individuals discontinued polypill use over follow-up.
Malekzadeh's team acknowledged that the first 2,115 patients recruited for the study received care from an unblinded team, resulting in imbalanced groups. Indeed, the benefit of the polypill was weaker in these individuals treated without concealment (adjusted HR 0.73, 95% CI 0.61-0.86), although it remained significant.
Thus, "the benefits of the polypill strategy in this context might be more modest than reported," according to an editorial by Anushka Patel, MBBS, PhD, of The George Institute for Global Health at the University of New South Wales, Australia, and Mark Huffman, MD, MPH, of Northwestern University Feinberg School of Medicine in Chicago.
"However, the likelihood that the observed difference in the primary outcome was due to chance appears small, especially given that the number of major cardiovascular disease events in the PolyIran trial was more than 2.5 times greater than in previous polypill trials combined," the duo noted.
Other limitations of the study include offering just one fixed-dose combo pill to all participants, who in turn all came from a rural environment, Malekzadeh and colleagues added.
"This study represents a monumental effort by a dedicated research team to understand the potential value of the polypill in combating a major global health problem," Patel and Huffman maintained.
"The widespread availability of low-cost polypills, with the inclusion of aspirin for people with established cardiovascular disease, would probably facilitate global goals to provide effective and efficient access to essential medicines to reduce cardiovascular disease morbidity and mortality, whether through initiation, step-up, or even substitution of individual medicines," they wrote.
To achieve this goal would require overcoming regulatory and system-level barriers and developing effective implementation strategies across diverse settings, according to the editorialists.
The study was supported by the Barakat Foundation, Alborz Darou, and Tehran University of Medical Sciences.
Malekzadeh disclosed no conflicts.
De Lemos reported serving on the data safety monitoring boards and/or steering committees for Regeneron, Amgen, and Esperion.
Patel declared that her institution's social enterprise unit has received investments to develop polypills; and she holds grants from the Australian National Health and Medical Research Council.
Huffman disclosed grants from the World Heart Federation via Boehringer Ingelheim and Novartis; grants from One Brave Idea via the American Heart Association, Verily, and AstraZeneca; grants from the National Heart, Lung, and Blood Institute; and personal fees from the American Medical Association.
Source Reference: Roshandel G, et al "Effectiveness of polypill for primary and secondary prevention of cardiovascular diseases (PolyIran): a pragmatic, cluster-randomised trial" Lancet 2019; DOI: 10.1016/S0140-6736(19)31791-X
Source Reference: Patel AA, Huffman MD "Progressing polypills beyond concepts to outcomes" Lancet 2019; 394(10199): 617-619.
Read the original article on Medpage Today: Polypill Prevents CV Events in Rural Iran