Improving Care for Heart Failure With Reduced Ejection Fraction—A Potential Polypill-Based Strategy | Cardiology | JAMA | JAMA Network
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November 19, 2020

Improving Care for Heart Failure With Reduced Ejection Fraction—A Potential Polypill-Based Strategy

Author Affiliations
  • 1Division of Cardiology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
  • 2Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
  • 3George Institute for Global Health, University of New South Wales, Sydney, Australia
JAMA. Published online November 19, 2020. doi:10.1001/jama.2020.21395

Heart failure (HF) is a leading global public health problem with more than 26 million prevalent cases around the world.1 The disease burden associated with HF has increasingly shifted from high-income countries to low- and middle-income countries due to population growth, aging, and increasing prevalence of HF risk factors.

Patients with HF with reduced ejection fraction (HFrEF) from low- and middle-income countries experience a higher 1-year mortality rate than those in high-income countries (20% vs 18%, respectively; adjusted hazard ratio [HR], 1.58 [95% CI, 1.41-1.78]) despite being almost 1 decade younger.2 Guideline-directed medical therapy (GDMT) consisting of β-blockers, renin angiotensin system blockers with neprilysin inhibitors, and mineralocorticoid receptor antagonists substantially reduces mortality among patients with HFrEF by an estimated 63% vs placebo (19.5% vs 50.0% mortality rate at 5 years) based on a network meta-analysis of 57 randomized trials.3 These medicines are among the most cost-effective interventions and are thus included as the “highest priority” interventions recommended by the Disease Control Priorities Project.4 Evidence has demonstrated a further 2.3% absolute risk reduction in all-cause mortality at 18 months from sodium-glucose cotransporter 2 (SGLT2) inhibitors (11.6% vs 13.9% for placebo; HR, 0.83 [95% CI, 0.71-0.97]), likely adding another drug class to the recommended regimens.5 Global inequalities in GDMT and HFrEF mortality may widen as use of SGLT2 inhibitors increases in high-income countries.

Implementation strategies are needed to derive benefits from GDMT for patients with HFrEF, yet most existing strategies have limited effects on treatment adherence. To improve GDMT uptake, HF management needs to be simplified by shifting the treatment strategy for undertreated patients with HFrEF from multidrug therapy with sequential initiation and titration to a pragmatic implementation strategy. One possible approach may involve development and use of HFrEF polypills consisting of a β-blocker, a renin angiotensin receptor blocker, a mineralocorticoid receptor antagonist, and an SGLT2 inhibitor. This Viewpoint describes existing implementation strategies; provides supporting evidence for HFrEF polypills as a new implementation strategy; proposes a research roadmap to design, implement, and evaluate HFrEF polypills; and explores multilevel implementation strategies to facilitate broader reach, effectiveness, adoption, implementation, and maintenance of HFrEF polypills.

Implementation Strategies

The Expert Recommendations for Implementing Change (ERIC) study6 highlighted the importance of identifying, developing, and testing implementation strategies to bridge clinical guideline and practice gaps. Using a concept mapping approach that includes multidimensional scaling and hierarchical clustering to aggregate common strategies, the ERIC investigators identified 73 discrete implementation strategies that were categorized in 9 thematic clusters (eFigure in the Supplement). The result was a widely used conceptual map in implementation science research that can be applied to any condition, including HF. Whether this approach is effective remains uncertain.

The existing implementation strategies from the conceptual map that have been applied toward improving GDMT rates in HFrEF include: evaluative and iterative strategies (eg, audit and feedback mechanisms), strategies to support clinicians (eg, automated GDMT reminders), strategies to develop relationships among various groups (eg, clinicians and case managers), and strategies to engage patients (eg, postdischarge telephone calls). Despite widespread study and implementation, these quality improvement efforts in isolation have not demonstrated a consistent effect on process of care measures (eg, discharge GDMT rates, clinical outcomes) in high-income countries, suggesting a need for additional strategies among patients with HFrEF.7

Polypill as a Pragmatic Implementation Strategy

A HFrEF polypill–based strategy could use fixed-dose combinations of GDMT with the goal of increasing medication adherence to improve outcomes in patients with HFrEF. This pragmatic implementation strategy was not captured in the ERIC conceptual map yet could potentially be an effective, safe, and efficient approach to improve clinical outcomes and population health. Polypills are a standard approach in the treatment of other conditions, such as HIV and hypertension, because high-quality evidence demonstrates increased adherence with taking a single pill. Individuals with lower baseline adherence have greater relative and absolute improvements with this approach vs individuals with higher baseline adherence. The first adequately powered randomized trial included 6838 participants and found a polypill-based strategy for atherosclerotic cardiovascular disease prevention demonstrated a 2.9% absolute reduction in major cardiovascular events over 5 years with this approach (8.8% vs 5.9% for those not taking polypill; adjusted HR, 0.66 [95% CI, 0.55-0.80]).8 Polypills for patients with HFrEF could represent an extension of this implementation strategy from prior polypill applications. Establishing the safety of HFrEF polypills will be a critical step in the research roadmap.

HFrEF Polypill Research Roadmap

Rigorous clinical research is needed to evaluate HFrEF polypills by incorporating lessons learned from polypill development for primary and secondary atherosclerotic cardiovascular disease prevention. First, formative mixed-methods research involving diverse participants will be needed to evaluate readiness, appropriateness, acceptability, and adaptation of a HFrEF polypill–based approach. For example, patients most likely to benefit from HFrEF polypills are likely to be inadequately treated, have low baseline adherence to polypill component drugs, and live in areas where frequent follow-up visits for sequential initiation and titration of medications may be impractical, such as in rural settings.

Second, bioequivalence, pharmacokinetic, and pharmacodynamic testing will be critical steps in establishing preliminary efficacy and safety of HFrEF polypills. Even though data from contemporary HF trials have demonstrated the safety of combination therapy, the manufacturing of fixed-dose combinations can lead to unexpected issues related to drug stability and degradation kinetics. For the early, smaller studies, polypills could be manufactured using low-cost, overencapsulation methods whereby individual component drugs are inserted in 1 capsule. Larger trials would benefit from experienced manufacturing companies developing polypills by combining active pharmaceutical ingredients in highly controlled production settings.

Third, implementation science research is needed to understand (1) initiation of HFrEF polypills in patients with de novo HFrEF, (2) step up or substitution of HFrEF polypills in patients undertreated with conventional pharmacotherapy, and (3) titration algorithms. A key step is developing titration algorithms with multiple polypill doses to prioritize clinical and laboratory safety and tolerability by initiating a quarter-dose or half-dose HFrEF polypill and titrating to a full-dose HFrEF polypill via a stepped-care approach.

Fourth, randomized trials evaluating whether HFrEF polypills vs usual care may improve clinical outcomes should include evaluation of efficacy with implementation a priori to explore contextual factors that may influence HFrEF polypill initiation and adherence, as well as differences in outcomes across age, sex, racial/ethnic, and geographic subgroups. These trials will need to be designed to demonstrate the benefits of individual polypill components to overcome regulatory hurdles, receive marketing approval, and be available and accepted by physicians and patients. Cost-effectiveness analyses within trials and modeled economic evaluations will help guide scaling investment in HFrEF polypills.

Multilevel Implementation Strategies

Even though HFrEF polypills theoretically have promise, they will not solve the GDMT treatment gap without additional and complementary approaches. If the efficacy and safety of HFrEF polypills are established in clinical trials, multilevel implementation strategies targeting various barriers will be needed to facilitate broader and equitable reach, effectiveness, adoption, implementation, and therapy maintenance. At the health system level, the polypill approach could be integrated into existing or complementary implementation strategies. Partnerships among academic partners, pharmaceutical companies, and governments will be necessary to catalyze investments in and financing of HFrEF polypills to ensure equitable availability and access. The Global Fund partnership invests more than $4 billion per year to diagnose and treat AIDS, tuberculosis, and malaria, and these investments have contributed to an estimated more than 38 million lives saved since 2002.9 Similar investments have not been made for cardiovascular diseases despite favorable estimates of returns on potential lives saved.

Polypills for HFrEF have potential limitations, such as increased risk for adverse events, including some that would be expected from increased medicine exposure. Importantly, lower doses should mitigate this risk and each drug component has been demonstrated to have an independent benefit in reducing morbidity and mortality. Polypills for HFrEF would have fewer titration options, and this approach might reduce decision fatigue associated with the clinical inertia that prevents adding or titrating GDMT in clinical practice. Polypills for HFrEF could help more with medication initiation vs medication adherence and may be transformative for patients with low baseline adherence because of any reason.


A simplified HF management strategy is needed by shifting the current treatment approach for undertreated patients with HFrEF to a pragmatic polypill–based strategy that could help close the gap in HFrEF inequities globally. High-quality research will be needed to evaluate this approach and understand safety, efficacy, titration algorithms, and implementation science outcomes in targeted populations that may benefit from HFrEF polypills.

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Article Information

Corresponding Author: Anubha Agarwal, MD, MSc, Northwestern University Feinberg School of Medicine, 676 N St Clair St, Arkes Family Pavilion, Ste 600, Chicago, IL 60611 (

Published Online: November 19, 2020. doi:10.1001/jama.2020.21395

Conflict of Interest Disclosures: Drs Agarwal and Huffman reported they are planning to submit patents for heart failure polypills, including for heart failure with reduced ejection fraction. Dr Huffman reported receiving funding from the World Heart Federation to serve as its senior program advisor for the Emerging Leaders program, which is supported by Boehringer Ingelheim and Novartis with previous support from BUPA and AstraZeneca; receiving support from the American Heart Association, Verily, AstraZeneca, and the American Medical Association; and that the George Institute for Global Health via George Health Enterprises receives investment funds to develop fixed-dose combination products containing aspirin, statin, and blood pressure–lowering drugs. No other disclosures were reported.

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Global Fund. Global Fund Overview. Accessed November 17, 2020.
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    1 Comment for this article
    Polypil in HFrEF
    Vladimir Baksheev, MD, PhD | FSBI Cvkg named A.A. Vishnevskii
    Simplifications are not always reliable, but in the case of patients with chronic disease, polypills are justified and may be successful.