Heart Failure Clinical Trial
Heart Failure Polypill at a Safety Net Hospital
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 40 adults with HFrEF. Given the high daily pill burden among patients both with HIV and HFrEF, the investigators aim to recruit an HIV+ subgroup (~20 participants) and an HIV- subgroup (~20 participants).
Hypothesis: Compared with usual care, a HFrEF polypill implementation strategy will increase adherence to guideline-directed medical therapy (GDMT) at 4 and 8 weeks and reduce total daily pill burden among patients with HFrEF, with no increase in serious adverse events.
Rationale: HFrEF among PWH is associated with a high pill burden, which adversely impacts adherence. Over-encapsulation is an inexpensive and replicable method to combine tablets into a single capsule. 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) Participants: Participants will be assessed for eligibility at outpatient cardiology visits at Zuckerberg San Francisco General Hospital (ZSFG), leveraging the Epic-based health information technology system to identify potentially eligible participants. Participants will be eligible if they are ≥ 18 years old and carry a diagnosis of heart failure, with echocardiographic or MRI evidence of reduced ejection fraction (≤45%). We will recruit HIV positive and HIV negative patient subgroups. Patients will be excluded if they have contraindications to any of the components of GDMT (for example, pregnancy, medication allergy, or history of hyperkalemia). After obtaining informed consent at an initial screening visit, eligible participants will be randomized to the AB group or BA group using a random number generator via REDcap.
Intervention: The intervention will be pharmacy-level over-encapsulation of once-daily heart failure medications (beta blocker, SGLT2 inhibitor, and mineralocorticoid receptor antagonist) into a single capsule. For some patients, a diuretic and once-daily ACE inhibitor or angiotensin receptor blocker may also be included if capsule size allows. Any twice-daily HFrEF medications, such as sacubitril/valsartan, will be omitted from the polypill and will continue to be filled individually. the investigators will partner with a community pharmacy with proficiency in over-encapsulation and over 20 years' experience working with ZSFG to deliver adherence interventions.
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 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.
Prior to randomization, participants who are not already prescribed a beta blocker, SGLT2 inhibitor (SGLT2i), and mineralocorticoid receptor antagonist (MRA) will be initiated on these medications at starting doses if no contraindications exist. Half of the participants will then be randomized to the AB group (polypill for 2 months, then usual care for 2 months). The other half of participants will be randomized to the BA group (usual care for 2 months, then polypill for 2 months). 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 the pharmacy). Participants assigned to usual care will be mailed or pick up their existing heart failure medications as individual pills.
At trial follow-up visits at 4, 8, 12, and 16 weeks, participants will be assessed for outcomes and adverse events and will undergo lab monitoring. 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 or in clinic. Participants will receive gift certificates for each visit, with an additional gift certificate if blood draws are needed. Bus tokens or other transportation vouchers will also be provided. At the conclusion of the study, the investigators will perform semi-structured exit interviews with participants, clinicians, and pharmacists. The investigators will use prepared interview guides, and will offer gift cards for participation in a 30-60 minute exit interview. Investigators will elicit stakeholders' experiences with the polypill, barriers encountered, preferences for trade-offs between pill size and number of pills, perceptions about taking polypills vs. the individual components, and experience working with the pharmacy for medication delivery.
Outcomes: The primary outcome will be adherence to overall and individual components of GDMT at 4, 8, 12, and 16 weeks, as measured by pill count. Specifically, investigators will calculate the adherence ratio (number of pills missing divided by the number of days between the 2 visits). Secondary outcomes will include adherence ratio to other medications, self-report of GDMT adherence using the MMAS-8 questionnaire, treatment satisfaction using the Treatment Satisfaction Questionnaire for Medication, and documented episodes of treatment-related adverse effects (e.g. allergy, hyperkalemia, bradycardia). Investigators will also capture feasibility metrics in conjunction with the study's pharmacy partner, including production time and costs for polypill packaging. As a pilot trial, this study will not be powered for clinical outcomes, but key exploratory outcomes will include HFrEF admissions and change in health-related quality of life measured by the Kansas City Cardiomyopathy Questionnaire. The exit interviews will be transcribed, coded, and analyzed using the Consolidated Framework for Implementation Research (CFIR) for evaluation of an implementation project.
Data management, sample size, and statistical analyses: In the FOCUS trial of an over-encapsulated polypill for hypertension, patients randomized to a polypill were 24% more likely to be adherent compared to those receiving separate pills (50.8% adherence in polypill group vs. 41% adherence in usual care, p = 0.019; OR, 1.24; 95% CI, 1.06-1.47). Considering a power of 80% and alpha of 5%, using a two-treatment crossover trial design, a minimum sample size of 20 participants total (10 per arm) will be necessary to identify a 20% absolute change in adherence ratio among patients prescribed the polypill vs. usual care, assuming a standard deviation of 30% in the change in adherence ratio over time. Assuming that up to 50% of patients will not complete the run-in period, it is estimated that 40 patients (20 per arm) should be recruited. A sample size of 20 participants in each arm is comparable to other pilot studies of cardiovascular polypills.45 Demographic data for participants will be described in each group and compared using a Student's T-test (continuous variables) or Fisher's exact test (categorical variables). Investigators will use mixed model multilevel linear regression analyses to determine the effect of a polypill vs. usual care on GDMT adherence. Analyses will be performed according to an intention-to-treat principle, using Stata, version 17. The threshold for statistical significance will be P < 0.05.
Age > 18 years old
Previously diagnosed with heart failure with reduced ejection fraction ( <40% by echocardiogram or cardiac MRI)
With or without a prior diagnosis of HIV (HIV+ and HIV- subgroups)
Able to conveniently obtain medications through one of 3 available mechanisms (mail, pick up at a ZSFG clinic, or pick up at our pharmacy partner)
Patients who are not fluent in English. These patients are excluded from this small pilot trial for feasibility reasons (i.e. access to medical interpreters)
Patients who have dementia or lack capacity
Patients who are incarcerated
Patients who cannot provide informed consent
Patients with contraindications to any of the components of GDMT (for example, pregnancy or breastfeeding, medication allergy, CKD with eGFR < 30, or history of hyperkalemia)
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San Francisco California, 94110, United States More Info
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