Heart Failure Polypill at a Safety Net Hospital

Developing a Heart Failure Polypill to Improve Outcomes at a Safety Net Hospital: A Pilot Crossover Randomized Controlled Trial

A novel four-drug regimen for heart failure with reduced ejection fraction (HFrEF) extends patients' life expectancy by an average of 6 years compared to traditional therapies, in addition to improving quality of life. Unfortunately, uptake of this complex multi-drug regimen has been low, especially among underserved communities with barriers to medication adherence. Although combination tablets have transformed access to care for conditions such as HIV and tuberculosis, no combination pill is available for HFrEF.

In the proposed study, the investigators will utilize inexpensive over-encapsulation techniques to develop a novel combination pill ("polypill") for patients with HFrEF. In Aim 1, the investigators will conduct stakeholder interviews with patients, providers, and pharmacists to inform the design of a HFrEF polypill. In Aim 2, the investigators will conduct a pilot, single-center, crossover randomized clinical trial to investigate whether, compared to usual care, a HFrEF polypill increases medication adherence among 20-40 adults with HFrEF. Given the high daily pill burden among patients with HIV and HFrEF, the investigators aim to recruit a subgroup of patients with HIV (~10-20 participants) in addition to a subgroup of patients without HIV (~10-20 participants).

Study Overview

• Status: Completed
• Conditions: HIV Infections; Heart Failure With Reduced Ejection Fraction
• Intervention / Treatment: Drug: Control Rx; Drug: Heart failure polypill

Detailed Description

Hypothesis: Compared with usual care, a HFrEF polypill implementation strategy will increase adherence to GDMT 4 weeks and reduce total daily pill burden among patients with HFrEF.

Rationale:HFrEF among PWH is associated with a high pill burden, which adversely impacts adherence. Over-encapsulation is an inexpensive and replicable method to co-package several tablets into a single capsule at the level of the pharmacy. However, the role of over-encapsulation to reduce pill burden among adults with HIV and HFrEF is unknown.

Design: Pilot phase II open-label randomized trial with a 2x2 crossover design (AB/BA)

Intervention: The intervention will be pharmacy-level over-encapsulation of once-daily heart failure medications (beta-blocker, SGLT2 inhibitor, spironolactone, and ACE/ARB/ARNI) into a single capsule. For some patients, other once-daily cardiovascular medications, such as a diuretic, may be included if capsule size allows (otherwise, these medications will continued to be filled separate to the polypill, as individual tablets). If the patient uses a twice-daily ARNI medication, the morning dose may be included in the polypill and the PM dose will continue to be dispensed separately. The investigators will partner with Daniel's Pharmacy, a local community pharmacy with proficiency in over-encapsulation and over 20 years' experience working with ZSFG to deliver adherence interventions.

Polypill Description: For patients in the polypill arm, heart failure medications will be filled as usual, but rather than dispensing each medication separately, the pharmacy technician will hand-pack all once-daily heart failure medications into a small plastic capsule. The doses will be individualized to the patient based on their physician's prescription. Thus, the polypill will be a late-stage implementation intervention to reduce pill burden, without restricting dose possibilities or interfering with medication titration.

Visit Schedule and Randomization: Patients will first attend an intake visit (week T-1), where eligibility will be reviewed, informed consent will be obtained, baseline patient questionnaires will be collected, and additional GDMT agents may be prescribed by the study clinician if clinically indicated and there are no contraindications. At the first trial visit (week 0), baseline labs will be collected and additional GDMT agents may prescribed if clinically indicated, with the goal of all participants being prescribed guideline-directed quad therapy for HFrEF prior to randomization if there are no contraindications.

During the first trial visit (week 0), half of participants will be randomized to the AB group (polypill for 4 weeks, then individual tablets for 4 weeks). The other half of participants will be randomized to the BA group (individual tablets for 4 weeks, then polypill for 4 weeks).

After randomization, participants assigned to receive the polypill up-front will be delivered 30-day supplies of the polypill via their preferred delivery method (mail, pick up at a ZSFG clinic, or pick up at Daniel's Pharmacy). Participants assigned to usual care will be mailed or pick up their existing heart failure medications as individual pills. The screening visit and first trial visit may be timed by study clinicians based on when the participant's heart failure medications will be ready for a refill according to insurance.

At trial follow-up visits at 4 and 8 weeks, participants will be assessed for outcomes and adverse events and will undergo lab monitoring as clinically indicated. Patients will be asked to bring in their pill bottles and/or MediSets or bubble packs. Medication doses may be titrated at these visits if clinically indicated. Participants in the AB and BA arms will have the same follow-up schedule, and can opt to receive refills of their medications by mail, at the pharmacy, or in clinic. Any new starts of guideline-directed heart failure medications that are included in the polypill will be continued as individual pills when the polypill group crosses over to the individual tablet condition, and/or when the trial concludes. All participants will be referred to cardiology clinic, if not already established there, for ongoing management of their heart failure therapies after the trial.

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94110
      • Zuckerberg San Francisco General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

• Adults age 18+ with heart failure (current or prior NYHA stage II-IV)
• Ejection fraction <50% on the most recent echocardiogram or MRI
• Last eGFR > 30
• Able to conveniently obtain medications through one of 3 available mechanisms (mail, pick up at a ZSFG clinic, or pick up at Daniel's pharmacy)
• Working phone number for telephone visits
• In addition to the inclusion criteria above, the investigators will preferentially recruit the following patient groups: people with HIV for a recruitment subgroup; patients who are less connected to cardiology care; people who are on <4 pillars of GDMT, and have difficulty with medication adherence (as evidenced by detectable HIV viral load or refill gaps in Epic); and people who do not use bubble packs and do not have daily medication support staff for med administration.

Exclusion criteria:

• Patients who are not fluent in English (due to constraints of the small pilot trial)
• Patients who are incarcerated
• Patients who cannot provide informed consent
• Patients with a ventricular assist device (VAD) or patients with an MI, unstable angina, stroke, or TIA within 12 weeks prior to enrollment
• Women who are pregnant, breastfeeding or of childbearing potential and are not using and do not plan to continue using medically acceptable form of contraception throughout the study (pharmacological or barrier methods).
• Concomitant medical condition which in the opinion of the study team could interfere with the safe conduct of the study including outcome assessment.
• Participation in a concurrent interventional medical investigation or pharmacologic clinical trial. Patients in observational, natural history or epidemiological studies not involving an intervention are eligible.
• Participant's responsible physician believes it is not appropriate for participant to take part in the study.
• Unable to complete study procedures and/or plan to move out of the study area in the next 2 months.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GDMT delivered in a heart failure polypill; The polypill intervention will be pharmacy-level over-encapsulation of heart failure medications (beta-blocker, SGLT2 inhibitor, mineralocorticoid receptor antagonist, and ACE/ARB/ARNI) into a single capsule. For patients on twice-daily sacubitril/valsartan, one dose will be included in the polypill and the second dose will be dispensed separately. The investigators will partner with a local community pharmacy with proficiency in over-encapsulation. For patients in the polypill arm, heart failure medications will be filled as usual, but rather than dispensing each medication separately, the pharmacy technician will hand-pack all once-daily heart failure medications into a small vegan capsule.	Drug: Heart failure polypill; Copackaging of heart failure medications (beta blocker, SGLT2i, MRA, and ACE/ARB/ARNI) in an overencapsulated polypill. Individual tablets will be hand-packed into a single capsule at the level of the pharmacy. Specific medications and doses will be individualized to the participant.
Active Comparator: GDMT delivered as individual tablets; As described above, participants who are not already prescribed a beta blocker, SGLT2i, ACE/ARB/ARNI, and MRA will be initiated on these medications prior to randomization if no contraindications exist. Participants randomized to usual care will receive their heart failure medications as individual pills. They will have the option to receive medications by mail, clinic pick-up, or pharmacy pick-up.	Drug: Control Rx; GDMT delivered as individual tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measured Adherence to GDMT by Pill Count	The primary outcome will be overall adherence to GDMT, as determined by pill count. We will first calculate the % adherence ratio for each prescribed class of GDMT (# pills missing / # pills supposed to be missing). The adherence ratio for each prescribed class of GDMT will then be averaged to derive the overall adherence ratio to GDMT. Pill count may be performed in-office or over videoconferencing.	The outcome will be measured 1) following a month of polypill use, and 2) following a month of individual tablet use.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Morisky Medication Adherence-8 (MMAS-8) Questionnaire	The MMAS-8 scale consists of 8 items. Each of the first 7 items has 2 possible responses (yes/no), while the 8th item is answered with a 5-point Likert scale. The possible total medication adherence score ranges between 0 and 8, and the higher the score, the better the adherence level. A total score < 6 is considered low adherence, while a total score of ≥ 6 but < 8 indicates moderate adherence, and a score of 8 indicates high adherence.	The outcome will be measured 1) following a month of polypill use, and 2) following a month of individual tablet use.
Treatment Satisfaction Using the Treatment Satisfaction Questionnaire for Medication (TSQM 9)	TSQM scores range from 0 to 100, with higher scores indicating greater treatment satisfaction.	The outcome will be measured 1) following a month of polypill use, and 2) following a month of individual tablet use.
Heart Failure Admission Rate	As a pilot trial, our study will not be powered for clinical outcomes, but key exploratory outcomes will include HFrEF admissions.	The outcome will be measured 1) following a month of polypill use, and 2) following a month of individual tablet use.
Kansas City Cardiomyopathy Questionnaire (KCCQ) 12	Exploratory clinical outcomes will include change in health-related quality of life as measured by the Kansas City Cardiomyopathy Questionnaire. KCCQ scores range from 0 to 100, with higher scores indicating higher quality of life.	The outcome will be measured 1) following a month of polypill use, and 2) following a month of individual tablet use.
Adherence Ratio to Individual Components of GDMT by Pill Count	The investigators will calculate the adherence ratio for each individual component of GDMT (beta blocker, MRA, SGLT2i, and ACE/ARB/ARNI). This will be calculated as the (# pills missing) / (# pills supposed to be missing based on time elapsed between visits). This will allow us to investigate whether there is differential adherence to some categories of GDMT (for example, lower adherence to beta-blockers).	The outcome will be measured 1) following a month of polypill use, and 2) following a month of individual tablet use.
Blood Pressure (mmHg)	Systolic Blood pressure at baseline and study follow-up	The outcome will be measured 1) following a month of polypill use, and 2) following a month of individual tablet use.
Heart Rate	Heart rate (beats per minute)	The outcome will be measured 1) following a month of polypill use, and 2) following a month of individual tablet use.
Weight	Weight at baseline and study follow-up	The outcome will be measured 1) following a month of polypill use, and 2) following a month of individual tablet use.
NT-ProBNP	Lab test	The outcome will be measured 1) following a month of polypill use, and 2) following a month of individual tablet use.
Adverse Events	The investigators will document adverse events throughout the study period, for example, hyperkalemia, dizziness, or other medication-related side effects. The investigators will ask participants about adverse events at in-person visits (0, 4, and 8 weeks) and at telephone calls at approximately 2 and 6 weeks.	0, 2, 4, 6, and 8 weeks
Total Daily Pill Burden of the Patient	This will be calculated based on the patient's active medication list.	The outcome will be measured 1) following a month of polypill use, and 2) following a month of individual tablet use.
Number of GDMT Pillars Prescribed	The number of GDMT pillars prescribed to the patient (BB, MRA, SGLT2i, and either ACEi, ARB, or ARNI) will be calculated at baseline and week 4.	The outcome will be measured 1) at the start of the polypill intervention, and 2) at the start of the individual tablet intervention.
HFrEF Polypill Patient Satisfaction Exit Survey	A Likert scale-style exit survey will be administered asking participants to compare their experience with the HFrEF polypill vs. individual tablets. 4 questions will comprise an Acceptability of Intervention Measure (AIM): 1) the polypill met my approval; 2) the polypill was appealing to me; 3) I liked the polypill; and 4) I welcomed the polypill as a treatment option for my heart failure. Each question includes a 5-point Likert scale, from 1 (strongly disagree) to 5 (strongly agree). Participants' responses to the 4 AIM questions will be averaged to comprise an AIM summary score.	After study completion
Number of Participants Completing a Qualitative Exit Interview	Participation in a semi-structured exit interview using a RE-AIM framework (Reach, Effectiveness, Adoption, Implementation, Maintenance)	After study completion (between 8 and 12 weeks)
Implementation Outcome: Time Required to Manufacture the HFrEF Polypill at Our Community Pharmacy Partner	Time required to prepare a 30-day supply of HFrEF polypill	Assessed at week 0 or week 4
Implementation Outcome: Cost of HFrEF Polypill Manufacturing at Our Community Pharmacy Partner	Cost of manufacturing a 30-day supply of HFrEF polypill	Assessed at week 0 or week 4
Number of Days Off of GDMT	Number of days off GDMT due to a clinical event (e.g. hospitalization) or due to logistical / pharmacy issues	Assessed at weeks 4 and 8

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility of Recruitment	Number of months taken to recruit 30-40 people to consent to participate in the study	Completion of recruitment within 1 year of initiating recruitment
Feasibility of Adherence to Study Protocols	Successful completion of study related procedures for at least 20 participants (screening, randomization, drug allocation, follow-up procedures, retention, and transition to ongoing care)	Assessed following study completion (approximately 1 year)

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: UCSF CAPS-HIV Innovative Grant; UCSF CFAR-ARI HIV Boost Award; ACC/ABC Merck Research Fellowship Award (support for Dr. DeJong)
• Investigators: Principal Investigator: Priscilla Hsue, MD, University of California, San Francisco; Principal Investigator: Colette DeJong, MD, University of California, San Francisco

Publications and helpful links

General Publications

• Munoz D, Uzoije P, Reynolds C, Miller R, Walkley D, Pappalardo S, Tousey P, Munro H, Gonzales H, Song W, White C, Blot WJ, Wang TJ. Polypill for Cardiovascular Disease Prevention in an Underserved Population. N Engl J Med. 2019 Sep 19;381(12):1114-1123. doi: 10.1056/NEJMoa1815359.
• Pandey A, Keshvani N, Wang TJ. Should Polypills Be Used for Heart Failure With Reduced Ejection Fraction? Circulation. 2022 Jul 26;146(4):276-278. doi: 10.1161/CIRCULATIONAHA.122.059661. Epub 2022 Jul 25. No abstract available.
• Gnanenthiran SR, Agarwal A, Patel A. Frontiers of cardiovascular polypills: From atherosclerosis and beyond. Trends Cardiovasc Med. 2023 Apr;33(3):182-189. doi: 10.1016/j.tcm.2021.12.013. Epub 2021 Dec 30.
• Mastromarino V, Casenghi M, Testa M, Gabriele E, Coluccia R, Rubattu S, Volpe M. Polypharmacy in heart failure patients. Curr Heart Fail Rep. 2014 Jun;11(2):212-9. doi: 10.1007/s11897-014-0186-8.
• Castellano JM, Pocock SJ, Bhatt DL, Quesada AJ, Owen R, Fernandez-Ortiz A, Sanchez PL, Marin Ortuno F, Vazquez Rodriguez JM, Domingo-Fernandez A, Lozano I, Roncaglioni MC, Baviera M, Foresta A, Ojeda-Fernandez L, Colivicchi F, Di Fusco SA, Doehner W, Meyer A, Schiele F, Ecarnot F, Linhart A, Lubanda JC, Barczi G, Merkely B, Ponikowski P, Kasprzak M, Fernandez Alvira JM, Andres V, Bueno H, Collier T, Van de Werf F, Perel P, Rodriguez-Manero M, Alonso Garcia A, Proietti M, Schoos MM, Simon T, Fernandez Ferro J, Lopez N, Beghi E, Bejot Y, Vivas D, Cordero A, Ibanez B, Fuster V; SECURE Investigators. Polypill Strategy in Secondary Cardiovascular Prevention. N Engl J Med. 2022 Sep 15;387(11):967-977. doi: 10.1056/NEJMoa2208275. Epub 2022 Aug 26.
• Mohd Salleh NA, Richardson L, Kerr T, Shoveller J, Montaner J, Kamarulzaman A, Milloy MJ. A Longitudinal Analysis of Daily Pill Burden and Likelihood of Optimal Adherence to Antiretroviral Therapy Among People Living With HIV Who Use Drugs. J Addict Med. 2018 Jul/Aug;12(4):308-314. doi: 10.1097/ADM.0000000000000403.
• Baldridge AS, Huffman MD, Lazar D, Abbas H, Flowers FM, Quintana A, Jackson A, Khan SS, Chopra A, Vu M, Tripathi P, Jacobson T, Sanuade OA, Kandula NR, Persell SD, Paparello JJ, Rosul LL, Mejia J, Lloyd-Jones DM, Chow CK, Ciolino JD. Efficacy and safety of a quadruple ultra-low-dose treatment for hypertension (QUARTET USA): Rationale and design for a randomized controlled trial. Am Heart J. 2022 Dec;254:183-193. doi: 10.1016/j.ahj.2022.09.004. Epub 2022 Sep 15.
• Chow CK, Thakkar J, Bennett A, Hillis G, Burke M, Usherwood T, Vo K, Rogers K, Atkins E, Webster R, Chou M, Dehbi HM, Salam A, Patel A, Neal B, Peiris D, Krum H, Chalmers J, Nelson M, Reid CM, Woodward M, Hilmer S, Thom S, Rodgers A. Quarter-dose quadruple combination therapy for initial treatment of hypertension: placebo-controlled, crossover, randomised trial and systematic review. Lancet. 2017 Mar 11;389(10073):1035-1042. doi: 10.1016/S0140-6736(17)30260-X. Epub 2017 Feb 10.
• Bahiru E, de Cates AN, Farr MR, Jarvis MC, Palla M, Rees K, Ebrahim S, Huffman MD. Fixed-dose combination therapy for the prevention of atherosclerotic cardiovascular diseases. Cochrane Database Syst Rev. 2017 Mar 6;3(3):CD009868. doi: 10.1002/14651858.CD009868.pub3.
• Vijay A, Mohanan PP, Kondal D, Baldridge A, Davies D, Devarajan R, Unni G, Abdullakutty J, Natesan S, Joseph J, Jayagopal PB, Joseph S, Gopinath R, Prabhakaran D, Huffman MD, Agarwal A. Polypill Eligibility for Patients with Heart Failure With Reduced Ejection Fraction in South India: A Secondary Analysis of a Prospective, Interrupted Time Series Study. J Am Heart Assoc. 2021 Oct 19;10(20):e021676. doi: 10.1161/JAHA.121.021676. Epub 2021 Oct 6. No abstract available.
• Castellano JM, Sanz G, Penalvo JL, Bansilal S, Fernandez-Ortiz A, Alvarez L, Guzman L, Linares JC, Garcia F, D'Aniello F, Arnaiz JA, Varea S, Martinez F, Lorenzatti A, Imaz I, Sanchez-Gomez LM, Roncaglioni MC, Baviera M, Smith SC Jr, Taubert K, Pocock S, Brotons C, Farkouh ME, Fuster V. A polypill strategy to improve adherence: results from the FOCUS project. J Am Coll Cardiol. 2014 Nov 18-25;64(20):2071-82. doi: 10.1016/j.jacc.2014.08.021. Epub 2014 Sep 1.
• DeJong C, Durstenfeld MS, Davis JD, Wang CS, Riley ED, Huffman MD, Hickey MD, Shade SB, Chen JC, Kazi DS, Grochowski J, Steward WT, Zier LS, Moreau N, Sandhu AT, Heidenreich PA, Agarwal A, Hsue PY. Delivering guideline-directed medical therapy for heart failure with reduced ejection fraction as an over-encapsulated polypill: rationale and protocol for the COMBO-HF-X pilot crossover randomised clinical trial. BMJ Open. 2025 Mar 21;15(3):e093663. doi: 10.1136/bmjopen-2024-093663.

Study record dates

Study Major Dates

• Study Start (Actual): February 27, 2024
• Primary Completion (Actual): September 17, 2024
• Study Completion (Actual): January 29, 2025

Study Registration Dates

• First Submitted: September 1, 2023
• First Submitted That Met QC Criteria: September 1, 2023
• First Posted (Actual): September 8, 2023

Study Record Updates

• Last Update Posted (Actual): December 31, 2025
• Last Update Submitted That Met QC Criteria: December 10, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Medication adherence; Polypill
• Additional Relevant MeSH Terms: Blood-Borne Infections; Urogenital Diseases; Genital Diseases; Immune System Diseases; Infections; RNA Virus Infections; Virus Diseases; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Behavior; Treatment Adherence and Compliance; Health Behavior; Patient Compliance; Patient Acceptance of Health Care; HIV Infections; Medication Adherence; Cariostatic Agents; Inorganic Chemicals; Biomedical and Dental Materials; Manufactured Materials; Technology, Industry, and Agriculture; Fluorides; Hydrofluoric Acid; Fluorine Compounds; Tin Compounds; Tin Fluorides
• Other Study ID Numbers: 23-39360

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No