The NUDGE trial pragmatic trial to enhance cardiovascular medication adherence: study protocol for a randomized controlled trial

Russell E Glasgow, Christopher E Knoepke, David Magid, Gary K Grunwald, Thomas J Glorioso, Joy Waughtal, Joel C Marrs, Sheana Bull, P Michael Ho, Russell E Glasgow, Christopher E Knoepke, David Magid, Gary K Grunwald, Thomas J Glorioso, Joy Waughtal, Joel C Marrs, Sheana Bull, P Michael Ho

Abstract

Background: Nearly half of patients do not take their cardiovascular medications as prescribed, resulting in increased morbidity, mortality, and healthcare costs. Mobile and digital technologies for health promotion and disease self-management offer an opportunity to adapt behavioral "nudges" using ubiquitous mobile phone technology to facilitate medication adherence. The Nudge pragmatic clinical trial uses population-level pharmacy data to deliver nudges via mobile phone text messaging and an artificial intelligent interactive chat bot with the goal of improving medication adherence and patient outcomes in three integrated healthcare delivery systems.

Methods: The Theory of mHealth, the Expanded RE-AIM/PRISM, and the PRECIS-2 frameworks were used for program planning, implementation, and evaluation, along with a focus on dissemination and cost considerations. During the planning phase, the Nudge study team developed and piloted a technology-based nudge message and chat bot of optimized interactive content libraries for a range of diverse patients. Inclusion criteria are very broad and include patients in one of three diverse health systems who take medications to treat hypertension, atrial fibrillation, coronary artery disease, diabetes, or hyperlipidemia. A target of approximately 10,000 participants will be randomized to one of 4 study arms: usual care (no intervention), generic nudge (text reminder), optimized nudge, and optimized nudge plus interactive AI chat bot. The PRECIS-2 tool indicated that the study protocol is very pragmatic, although there is variability across PRECIS-2 dimensions.

Discussion: The primary effectiveness outcome is medication adherence defined by the proportion of days covered (PDC) using pharmacy refill data. Implementation outcomes are assessed using the RE-AIM framework, with a particular focus on reach, consistency of implementation, adaptations, cost, and maintenance/sustainability. The project has limitations including limited power to detect some subgroup effects, medication complications (bleeding), and longer-term outcomes (myocardial infarction). Strengths of the study include the diverse healthcare systems, a feasible and generalizable intervention, transparent reporting using established pragmatic research and implementation science frameworks, strong stakeholder engagement, and planning for dissemination and sustainment.

Trial registration: ClinicalTrials.gov NCT03973931 . Registered on 4 June 2019. The study was funded by the NIH; grant number is 4UH3HL144163-02 issued 4/5/19.

Keywords: Cardiovascular; Dissemination; Implementation; Medication adherence; PRECIS-2; Pragmatic trial; RE-AIM; mHealth.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
SPIRIT checklist outlining the schedule of enrolment, interventions, and assessments
Fig. 2
Fig. 2
CONSORT figure and estimated participation and attrition rates in the Nudge trial
Fig. 3
Fig. 3
PRECIS-2 figure
Fig. 4
Fig. 4
Example of text messages
Fig. 5
Fig. 5
Example of text messaging survey

References

    1. Jackevicius CA, Mamdani M, Tu JV. Adherence with statin therapy in elderly patients with and without acute coronary syndromes. JAMA. 2002;288(4):462–467. doi: 10.1001/jama.288.4.462.
    1. Jackevicius CA, Li PV, Tu J. Prevalence, predictors, and outcomes of primary nonadherence after acute myocardial infarction. Circulation. 2008;117(8):1028–1036. doi: 10.1161/CIRCULATIONAHA.107.706820.
    1. Ho PM, Spertus JA, Masoudi FA, Reid KJ, Peterson ED, Magid DJ, Krumholz HM, Rumsfeld JS. Impact of medication therapy discontinuation on mortality after myocardial infarction. Arch Intern Med. 2006;166(17):1842–1847. doi: 10.1001/archinte.166.17.1842.
    1. Rasmussen JN, Chong A, Alter DA. Relationship between adherence to evidence-based pharmacotherapy and long-term mortality after acute myocardial infarction. JAMA. 2007;297(2):177–186. doi: 10.1001/jama.297.2.177.
    1. Spertus JA, Kettlelkamp R, Vance C, Decker C, Jones P, Rumsfeld JS, et al. Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement: results from the PREMIER registry. Circulation. 2006;113(24):2803–2809. doi: 10.1161/CIRCULATIONAHA.106.618066.
    1. Brown MT, Bussell JK. Medication adherence: WHO cares? Mayo Clin Proc. 2011;86(4):304–314. doi: 10.4065/mcp.2010.0575.
    1. Wei L, Wang J, Thompson P, Wong S, Struthers AD, Macdonald TM. Adherence to statin treatment and readmission of patients after myocardial infarction: a six year follow up study. Heart. 2002;88(3):229–22933. doi: 10.1136/heart.88.3.229.
    1. Wei L, Flynn R, Murray GD, MacDonald TM. Use and adherence to beta-blockers for secondary prevention of myocardial infarction: who is not getting the treatment? Pharmacoepidemiol Drug Saf. 2004;13(11):761–766. doi: 10.1002/pds.963.
    1. Pearson SA, Lu CY, Ross-Degnan D, Soumerai SB. Interventions designed to improve the quality and efficiency of medication use in managed care: a critical review of the literature – 2001–2007. BMC Health Serv Res. 2008;8(1):75. doi: 10.1186/1472-6963-8-75.
    1. Volpp KG, Loewenstein G, Troxel AB, Doshi J, Price M, Laskin M, Kimmel SE. A test of financial incentives to improve warfarin adherence. BMC Health Serv Res. 2008;8(1):272. doi: 10.1186/1472-6963-8-272.
    1. Murray MD, Young J, Hoke S, Tu W, Weiner M, Morrow D, Stroupe KT, Wu J, Clark D, Smith F, Gradus-Pizlo I, Weinberger M, Brater DC. Pharmacist intervention to improve medication adherence in heart failure: a randomized trial. Ann Intern Med. 2007;146(10):714–725. doi: 10.7326/0003-4819-146-10-200705150-00005.
    1. Lee JK, Grace KA, Taylor AJ. Effect of a pharmacy care program on medication adherence and persistence, blood pressure, and low-density lipoprotein cholesterol: a randomized controlled Trial. JAMA. 2006;296(21):2563–2571. doi: 10.1001/jama.296.21.joc60162.
    1. Peterson PN, Campagna EJ, Maravi MA, Allen LF, Bull SP, Steiner JM, et al. Acculturation and outcomes among patients with heart failure. Circ Heart Fail. 2012;5(2):160–166. doi: 10.1161/CIRCHEARTFAILURE.111.963561.
    1. Jalal ZS, Smith F, Taylor D, Finlay K, Patel H, Antoniou S. Impact of pharmacy care upon adherence to cardiovascular medicines: a feasibility pilot controlled trial. Eur J Hosp Pharm. 2016;23(5):250–256. doi: 10.1136/ejhpharm-2015-000790.
    1. Hoyt GM. Nudge: improving decisions about health, wealth, and happiness. International Review of Economics Education. 2009;8(1):158–159. doi: 10.1016/S1477-3880(15)30073-6.
    1. Hirsh BJ, Smilowitz NR, Rosenson RS, Fuster V, Sperling LS. Utilization of and adherence to guideline-recommended lipid-lowering therapy after acute coronary syndrome. J Am Coll Cardiol. 2015;66(2):184–189. doi: 10.1016/j.jacc.2015.05.030.
    1. Cialdini RB, Demaine LJ, Sagarin BJ, Barrett DW, Rhoads K, Winter PL. Managing social norms for persuasive impact. Soc Influ. 2006;1(1):3–15. doi: 10.1080/15534510500181459.
    1. Car J, Gurol-Urganci I, de Jongh T, Vodopivec-Jamsek V, Atun R. Mobile phone messaging reminders for attendance at healthcare appointments. The Cochrane database of systematic reviews. 2012;7:CD007458.
    1. De Jongh T, Gurol-Urganci I, Vodopivec-Jamsek V, Car J, Atun R. Mobile phone messaging for facilitating self-management of long-term illnesses. The Cochrane database of systematic reviews. 2012;12(12):CD007459.
    1. Vodopivecjamsek V, de Jongh T, Gurolurganci I, Atun R, Car J. Mobile phone messaging for preventive health care. Cochrane Consumers and Communication Group. 2012;12(12):CD007457.
    1. Loudon K, Treweek S, Sullivan F, Donnan P, Thorpe KE, Zwarenstein M. The PRECIS-2 tool: designing trials that are fit for purpose. Br Med J. 2015;350(may08 1):h2147. doi: 10.1136/bmj.h2147.
    1. Glasgow RE, Huebschmann AG, Brownson RC. Expanding the CONSORT figure: increasing transparency in reporting on external validity. Am J Prev Med. 2018;55(3):422–430. doi: 10.1016/j.amepre.2018.04.044.
    1. Johnson KE, Neta G, Dember LM, Coronado GD, Suls J, Chambers DA, Rundell S, Smith DH, Liu B, Taplin S, Stoney CM, Farrell MM, Glasgow RE. Use of PRECIS ratings in the National Institutes of Health (NIH) Health Care Systems Research Collaboratory. Trials. 2016;17(32):32. doi: 10.1186/s13063-016-1158-y.
    1. Chambers DA. Sharpening our focus on designing for dissemination: lessons from the SPRINT program and potential next steps for the field. Translational behavioral medicine. 2019;XX;XX-XX. doi: 10.1093/tbm/ibz102
    1. Knoepke CE, Ingle MP, Matlock DD, Brownson RC, Glasgow RE. Dissemination and stakeholder engagement practices among dissemination & implementation scientists: results from an online survey. PLoS One 2019;14(11): e0216971. doi:10.1371/journal.pone.0216971
    1. Brownson RC, Jacobs JA, Tabak RG, Hoehner CM, Stamatakis KA. Designing for dissemination among public health researchers: findings from a national survey in the United States. Am J Public Health. 2013;103(9):1693–1699. doi: 10.2105/AJPH.2012.301165.
    1. Feldstein AC, Glasgow RE. A practical, robust implementation and sustainability model (PRISM) for integrating research findings into practice. Jt Comm J Qual Patient Saf. 2008;34(4):228–243. doi: 10.1016/s1553-7250(08)34030-6.
    1. Rogers EM. Diffusion of innovations 5th edition: Free Press; 2003.
    1. Wagner E. The chronic care model. 2008.
    1. Berwick DM. Disseminating innovations in healthcare. JAMA. 2003;289(15):1969–1975. doi: 10.1001/jama.289.15.1969.
    1. Glasgow RE, Harden SM, Gaglio B, Rabin B, Smith ML, Porter GC, Ory MG, Estabrooks PA. RE-AIM planning and evaluation framework: adapting to new science and practice with a 20-year review. Front Public Health. 2019;7:64. doi: 10.3389/fpubh.2019.00064.
    1. Rabin BA, Mccreight M, Battaglia C, Ayele R, Burke RE, Hess PL, et al. Systematic, multimethod assessment of adaptations across four diverse health systems interventions. Front Public Health. 2018;6:102. doi: 10.3389/fpubh.2018.00102.
    1. Buuren SV, Groothuis-Oudshoorn K, Gerarda M. Mice: multivariate imputation by chained equations in R. J Stat Softw. 2011;45(3):urn:issn:1548–7660.
    1. Zou GY. Assessment of risks by predicting counterfactuals. Stat Med. 2009;28(30):3761–3781. doi: 10.1002/sim.3751.
    1. Dmitrienko A, Tamhane AC, Wiens BL. General multistage gatekeeping procedures. Biom J. 2008;50(5):667–677. doi: 10.1002/bimj.200710464.
    1. Sjölander A, Dahlqwist E, Zetterqvist J. A note on the noncollapsibility of rate differences and rate ratios. Epidemiology. 2016;27(3):356–359. doi:10.1097/EDE.0000000000000433.PMID: 26680297
    1. Stirman SW, Baumann AA, Miller CJ. The Frame: an expanded framework for reporting adaptations and modifications to evidence-based interventions. Implement Sci. 2019;14(1):58–68. doi: 10.1186/s13012-019-0898-y.
    1. Palinkas L, Zatzick D. Rapid Assessment Procedure Informed Clinical Ethnography (RAPICE) in pragmatic clinical trials of mental health services implementation: methods and applied case study. 2019;46(2):255–70. 10.1007/s10488-018-0909-3.
    1. Chambers DA, Norton WE. The Adaptome: advancing the science of intervention adaptation. Am J Prev Med. 2016;51(4):S124–S131. doi: 10.1016/j.amepre.2016.05.011.
    1. Palinkas LA, Aarons G, et al. Mixed methods designs in implementation research. Admin Pol Ment Health. 2011;38(1):44–53. doi: 10.1007/s10488-010-0314-z.
    1. Cohen EL, Head KJ, McGladrey MJ, Hoover AG, Vaderpool RC, Bridger C, Carman A, Crosby RA, Darling E, Tucker-McLaughlin M, Winterbauer N. Designing for dissemination: lessons in message design from “1-2-3 Pap”. Health Commun. 2015;30(2):196–207. doi: 10.1080/10410236.2014.974130.
    1. US Department of Veteran Affairs. QUERI – Quality Enhancement Research initiative. 2018. .
    1. National Institutes of Health. NIH Collaboratory living textbook of pragmatic clinical trials.2020. .
    1. Jolles MP, Lengnick-Hall R, Mittman BS. Core functions and forms of complex health interventions: a patient-centered medical home illustration. 2019;34(6):1032–8. 10.1007/s11606-018-4818-7.
    1. Bull S, Ezeanochie N. From Foucault to Freire through Facebook: toward an integrated theory of mHealth. Health Ed & Beh. 2016;43(4):399–411. doi: 10.1177/1090198115605310.
    1. Bull S, Devine S, Schmiege SJ, Pickard L, Campbell J, Shlay JC. Text messaging, teen outreach program, and sexual health behavior: a cluster randomized trial. Am J Public Health. 2016;106(S1):S117–S124. doi: 10.2105/AJPH.2016.303363.
    1. Thompson JS, Matlock DD, McIlvennan CK, Jenkins AR, Allen LA. Development of a decision aid for patients with advanced heart failure considering a destination therapy left ventricular assist device. JACC: Heart Fail. 2015;3(12):965–976. doi: 10.1016/j.jchf.2015.09.007.
    1. Gaglio B, Glasgow RE, Bull SS. Do patient preferences for health information vary by health literacy or numeracy? A qualitative assessment. J Health Commun. 2012;17(Suppl 3):109–121. doi: 10.1080/10810730.2012.712616.
    1. Riley WT, Glasgow RE, Etheredge L, Abernethy AP. Rapid, responsive, relevant (R3) research: a call for a rapid learning health research enterprise. Clin Transl Med. 2013;2(1):10. doi: 10.1186/2001-1326-2-10.
    1. Demeyin WA, Frost J, Ukoumunne OC, Briscoe S, Britten N. N of 1 trials and the optimal individualisation of drug treatments: a systematic review protocol. Syst Rev. 2017;6(1):90. doi: 10.1186/s13643-017-0479-6.
    1. Curro FA, Robbins DA, Naftolin F, Grill AC, Vena D, Terracio L. Person-centric clinical trials: defining the N-of-1 clinical trial utilizing a practice-based translational network. Clin Investigation. 2015;5(2):145–159. doi: 10.4155/cli.14.126.
    1. Agency for Healthcare Research and Quality. Design and implementation of N-of-1 trials: a user’s guide - research report - final | AHRQ Effective Health Care Program. 2017.

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