Abdullakutty, Jabir

Agarwal, Anubha

Baldridge, Abigail

Davies, Divin

Devarajan, Raji

Gopinath, Rajesh

Huffman, Mark D

Jayagopal, Pathiyil B

Joseph, Johny

Joseph, Stigi

Kondal, Dimple

Mohanan, Padinhare P

Natesan, Syam

Prabhakaran, Dorairaj

Unni, Govindan

Vijay, Aishwarya

PubMed

LSHTM Research Online

Journal of the American Heart AssociationJ Am Heart Assoc. 2021;10:e021676. DOI: 10.1161/JAHA.121.021676 1 RESEARCH LETTERPolypill Eligibility for Patients with Heart Failure With Reduced Ejection Fraction in South India: A Secondary Analysis of a Prospective, Interrupted Time Series StudyAishwarya Vijay , MD; Padinhare P. Mohanan, MD, DM; Dimple Kondal, PhD; Abigail Baldridge, MS;  Divin Davies, BA; Raji Devarajan, MS; Govindan Unni, MD, DM; Jabir Abdullakutty, MD, DM; Syam Natesan, MD, DM; Johny Joseph , MD, DM; Pathiyil B. Jayagopal, MD, DM; Stigi Joseph, MD, DM; Rajesh Gopinath, MD, DM; Dorairaj Prabhakaran , MD, DM, MSc; Mark D. Huffman , MD, MPH; Anubha Agarwal , MD, MScThe vanguard heart failure (HF) registry in India demonstrated significantly lower 5- year mortal-ity rates for patients with HF with reduced ejec-tion fraction (HFrEF) discharged on guideline- directed medical therapy (GDMT), revealing an important target for intervention to improve clinical outcomes.1 Hospital- based quality improvement initiatives to increase rates of GDMT at hospital discharge have had limited ef-fect, suggesting additional strategies are needed to improve GDMT rates in patients with HFrEF.2 Polypills for HFrEF have been proposed as an implementation strategy to simplify the current treatment paradigm for undertreated patients with HFrEF.3 However, the po-tential effect of HFrEF polypills on increasing GDMT rates in target populations is unknown. The objective of this secondary analysis of a prospective, interrupted times series study is to describe eligibility for a poten-tial HFrEF polypill in the context of GDMT prescription rates for patients with HFrEF who were discharged from 8 hospitals in South India.The HF QUIK (Heart Failure Quality Improvement in Kerala) study was a prospective, interrupted time se-ries study using longitudinal data from February 2018 to August 2018 that evaluated the effect of a quality im-provement intervention on process of care measures and clinical outcomes in patients hospitalized with acute HF in 8 hospitals in South India.4 Patients were eligible for inclusion if they were (1) adults aged ≥18 years, and (2) met at least 2 criteria for diagnosis of HF as defined by the European Society of Cardiology (clinical symptoms and signs of HF, natriuretic peptide elevation, or echocardiographic evidence of left ven-tricular systolic or diastolic dysfunction). The HF QUIK quality improvement intervention consisted of check-lists, audit and feedback reports with site- specific per-formance measures, and patient education materials. The control period consisted of usual care according to local hospital practice. Participants were allocated to the control (February 2018 to May 2018) or inter-vention period (May 2018 to August 2018) based on hospital admission date. The study protocol was re-viewed by and received ethics board approval from Duke University (Durham, NC), Centre for Chronic Disease Control (New Delhi, Delhi, India), Cardiological Society of India- Kerala Chapter (Kochi, Kerala, India), and Indian Health Ministry Screening Committee (New Delhi, Delhi, India) in November 2017. Because data were used at the local hospitals for the purpose of quality improvement, sites were granted a waiver of informed consent under the Common Rule. The data Correspondence to: Anubha Agarwal MD, MSc, Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611. E- mail: anubha.agarwal@northwestern.eduFor Sources of Funding and Disclosures, see page 3.© 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution- NonCommercial- NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non- commercial and no modifications or adaptations are made. JAHA is available at: www.ahajournals.org/journal/jahaKey Words: guideline- directed medical therapy ■ heart failure with reduced ejection fraction ■ India ■ polypillDownloaded from http://ahajournals.org by on December 7, 2021J Am Heart Assoc. 2021;10:e021676. DOI: 10.1161/JAHA.121.021676 2Vijay et al HFrEF Polypill Eligibility in South Indiathat support the findings of this study are available from the corresponding author upon reasonable request.Participants with HFrEF with left ventricular ejection fraction <40% were included in this secondary analy-sis. The primary outcome was prescription of GDMT defined as an angiotensin- converting enzyme inhibitor or angiotensin receptor blocker or angiotensin recep-tor neprilysin inhibitor, along with a beta blocker and aldosterone antagonist, measured separately and as a combined outcome. Additional outcomes included prescription of loop and thiazide diuretic. Participants were eligible for a HFrEF polypill containing GDMT in-cluding angiotensin- converting enzyme inhibitor or angiotensin receptor blocker or angiotensin receptor neprilysin inhibitor, beta blocker, and aldosterone an-tagonist at hospital discharge if left ventricular ejection fraction <40%, heart rate ≥50 beats/min, serum cre-atinine ≤2.5 mg/dL in men and ≤2 mg/dL in women, and serum potassium <5 mEq/L. Creatinine thresholds were based on guideline- recommended thresholds for aldosterone antagonists. Categorical variables were reported as counts with percentages, and we per-formed a complete case analysis due to low rate of missing data. The difference in proportions between medication at admission and discharge for control and intervention periods was calculated using chi- square test. We used R software (version 4.0.3, R Foundation, Vienna, Austria) for statistical analyses.We included 937 participants with HFrEF (n=494 control period, n=443 intervention period). The Table illustrates prescription of medications for HF at admis-sion (reflecting medications participants were on before admission) and at hospital discharge by control and intervention periods. Prescription rates of angiotensin- converting enzyme inhibitor or angiotensin receptor blocker or angiotensin receptor neprilysin inhibitor, beta blocker, and aldosterone antagonists were low on hospital admission and increased at hospital dis-charge. The rate of loop diuretic prescription increased at discharge. The prescription of GDMT increased from 5.5% to 28.8% in the control period and from 4.5% to 42.3% in the intervention period. More than 80% of participants were eligible for a HFrEF polypill at hospital discharge during both control (n/N=364/494) and intervention (n/N=336/443) periods, with similar rates among female and male participants.In the HF QUIK study population, more than 80% of patients were eligible for a HFrEF polypill at dis-charge. Although the HF QUIK quality improvement intervention increased rates of GDMT at hospital Table. Medication Prescription and HFrEF Polypill Eligibility of HF QUIK Participants by Control and Intervention PeriodsControl period*   N=494P valueIntervention period*  N=443P valueAdmission*  N=494Discharge*   N=441Admission*  N=443Discharge*  N=404Medication prescriptionACE- I or ARB or ARNi123 (24.9%) 208 (47.2%) <0.01 104 (23.5%) 211 (52.2%) <0.01Beta- blocker 152 (30.8%) 333 (75.5%) <0.01 159 (35.9%) 332 (82.2%) <0.01Aldosterone antagonist94 (19.0%) 286 (64.9%) <0.01 61 (13.8%) 305 (75.5%) <0.01Loop diuretic 197 (39.9%) 409 (92.7%) <0.01 177 (40.0%) 396 (98.0%) <0.01Thiazide diuretic 8 (1.6%) 9 (2.0%) 0.63 6 (1.4%) 8 (2.0%) 0.48GDMT† 27 (5.5%) 127 (28.8%) <0.01 20 (4.5%) 171 (42.3%) <0.01HFrEF polypill eligibility at discharge‡Control period: discharge  N=441 (F: 164, M: 277)Intervention period: discharge  N=404 (F: 127, M: 277)Total§ 364 (82.5%) 336 (83.2%) 0.81#Female|| 133 (81.1%) 0.54** 100 (78.7%) 0.11**Male|| 231 (83.4%) 236 (85.2%)ACE- I indicates angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNi, angiotensin receptor neprilysin inhibitor; GMDT, guideline- directed medical therapy; and HFrEF, heart failure with reduced ejection fraction.*Among participants with LVEF <40%.†Defined as ACE- I or ARB or ARNi+beta- blocker+aldosterone antagonist.‡Eligible participants meet the following criteria: LVEF <40%, heart rate ≥50 beats/min, serum creatinine ≤2.5 mg/dL in men and ≤2 mg/dL in women, serum potassium <5 mEq/L.§Percentages indicate proportion out of total discharged participants in control (n=441) and intervention (n=404) periods.||Percentages indicate proportion of females and males participants eligible for a HFrEF polypill among total females and males participants at hospital discharge in the control and intervention periods.#P- value indicates difference between HFrEF polypill eligibility during control period and intervention periods.**P- value indicates difference between female and male participants eligible for a HFrEF polypill at hospital discharge in the control and intervention periods.Downloaded from http://ahajournals.org by on December 7, 2021J Am Heart Assoc. 2021;10:e021676. DOI: 10.1161/JAHA.121.021676 3Vijay et al HFrEF Polypill Eligibility in South Indiadischarge from 28.8% in the control period to 42.3% in the intervention period, routine administration of a HFrEF polypill could increase this rate and improve adherence by 44% (95% CI, 26%– 65%) in a popu-lation that remains undertreated despite targeted quality improvement interventions.4,5 Availability of multiple HFrEF polypill doses could prioritize safety and tolerability with low- dose initiation and subse-quent titration to higher- dose polypills. An import-ant limitation of this analysis is that laboratory values used to determine polypill eligibility at discharge were obtained at time of hospital admission, although renal function frequently changes during hospitalization in many patients with HF. Efficacy, safety, and effec-tiveness of HFrEF polypills initiated at discharge and titrated in outpatient settings will need to be estab-lished in rigorous randomized trials.3 This analysis demonstrates high potential rates of HFrEF polypill eligibility and suggests a simplified polypill- based management strategy could be transformative for closing the treatment gap in HFrEF inequities in India and globally.ARTICLE INFORMATIONReceived April 13, 2021; accepted August 16, 2021.AffiliationsDepartment of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (A.V., M.D.H., A.A.); WestFort Hi- Tech Hospital, Thrissur, Kerala, India (P.P.M., D.D.); Centre for Chronic Disease Control, New Delhi, Delhi, India (D.K., R.D., D.P.); Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (A.B., M.D.H.); Jubilee Mission Medical College and Hospital, Thrissur, Kerala, India (G.U.); Lisie Hospital, Kochi, Kerala, India (J.A.); Kollam District Hospital, Kollam, Kerala, India (S.N.); Caritas Hospital, Kottayam, Kerala, India (J.J.); Lakshmi Hospital, Palakkad, Kerala, India (P.B.J.); Little Flower Hospital and Research Centre, Angamaly, Kerala, India (S.J.) ; Amala Institute of Medical Sciences, Thrissur, Kerala, India (R.G.); The Public Health Foundation of India, Gurugram, Haryana, India (D.P.); and The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia (M.D.H.).Sources of FundingA.A. is currently supported by the Post- Graduate Fellowship in Global Health at the Institute for Global Health, Northwestern University. A.A. received fund-ing from the Fogarty International Center of the National Institutes of Health, Duke Global Health Institute, and Duke Hubert- Yeargan Center for Global Health for this research. Research reported in this publication was supported by the Fogarty International Center and National Institute of Mental Health, of the National Institutes of Health under Award Number D43TW010543. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors are independent from the funders.DisclosuresIn the past 3 years, M.D.H. received funding from the World Heart Federation to serve as its senior program advisor for the Emerging Leaders program, which has been supported by Boehringer Ingelheim, Novartis, Bupa, and AstraZeneca. M.D.H. also received support from the American Heart Association, Verily, AstraZeneca, and American Medical Association for work unrelated to this research. The George Institute for Global Health’s wholly owned enterprise, George Health Enterprises, has received invest-ment funds to develop fixed- dose combination products containing aspirin, statin, and blood pressure lowering drugs. M.D.H. and A.A. plan to submit patents for heart failure polypills, including for heart failure with reduced ejec-tion fraction. The remaining authors have no disclosures to report.REFERENCES 1. Harikrishnan S, Jeemon P, Ganapathi S, Agarwal A, Viswanathan S, Sreedharan M, Vijayaraghavan G, Bahuleyan CG, Biju R, Nair T, et al. Five- year mortality and readmission rates in patients with heart failure in India: results from the Trivandrum heart failure registry. Int J Cardiol. 2021;326:139– 143. doi: 10.1016/j.ijcard.2020.10.012 2. Agarwal A, Bahiru E, Yoo SGK, Berendsen MA, Harikrishnan S, Hernandez AF, Prabhakaran D, Huffman MD. Hospital- based quality improvement interventions for patients with heart failure: a systematic review. Heart. 2019;105:431– 438. doi: 10.1136/heart jnl- 2018- 314129 3. Agarwal A, Yancy CW, Huffman MD. Improving care for heart failure with reduced ejection fraction— a potential polypill- based strategy. JAMA. 2020;324:2259– 2260. doi: 10.1001/jama.2020.21395 4. Agarwal A, Mohanan PP, Kondal D, Baldridge A, Davies D, Devarajan R, Unni G, Abdullakutty J, Natesan S, Joseph J, et al. Effect of a quality improvement intervention for acute heart failure in south India: an inter-rupted time series study. Int J Cardiol. 2021;329:123– 129. doi: 10.1016/j.ijcard.2020.12.048 5. 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;3:CD009868. doi: 10.1002/14651 858.CD009 868.pub3Downloaded from http://ahajournals.org by on December 7, 2021

Polypill Eligibility for Patients with Heart Failure With Reduced Ejection Fraction in South India: A Secondary Analysis of a Prospective, Interrupted Time Series Study.

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Polypill Eligibility for Patients with Heart Failure With Reduced Ejection Fraction in South India: A Secondary Analysis of a Prospective, Interrupted Time Series Study.

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