BACKGROUND: Physical activity is pivotal in managing heart failure with reduced ejection fraction, and walking integrated into daily life is an especially suitable form of physical activity. This study aimed to determine whether a 6-month lifestyle walking intervention combining self-monitoring and regular telephone counseling improves functional capacity assessed by the 6-minute walk test (6MWT) in patients with stable heart failure with reduced ejection fraction compared with usual care. METHODS: The WATCHFUL trial (Pedometer-Based Walking Intervention in Patients With Chronic Heart Failure With Reduced Ejection Fraction) was a 6-month multicenter, parallel-group randomized controlled trial recruiting patients with heart failure with reduced ejection fraction from 6 cardiovascular centers in the Czech Republic. Eligible participants were ≥18 years of age, had left ventricular ejection fraction <40%, and had New York Heart Association class II or III symptoms on guidelines-recommended medication. Individuals exceeding 450 meters on the baseline 6MWT were excluded. Patients in the intervention group were equipped with a Garmin vívofit activity tracker and received monthly telephone counseling from research nurses who encouraged them to use behavior change techniques such as self-monitoring, goal-setting, and action planning to increase their daily step count. The patients in the control group continued usual care. The primary outcome was the between-group difference in the distance walked during the 6MWT at 6 months. Secondary outcomes included daily step count and minutes of moderate to vigorous physical activity as measured by the hip-worn Actigraph wGT3X-BT accelerometer, NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity C-reactive protein biomarkers, ejection fraction, anthropometric measures, depression score, self-efficacy, quality of life, and survival risk score. The primary analysis was conducted by intention to treat. RESULTS: Of 218 screened patients, 202 were randomized (mean age, 65 years; 22.8% female; 90.6% New York Heart Association class II; median left ventricular ejection fraction, 32.5%; median 6MWT, 385 meters; average 5071 steps/day; average 10.9 minutes of moderate to vigorous physical activity per day). At 6 months, no between-group differences were detected in the 6MWT (mean 7.4 meters [95% CI, -8.0 to 22.7]; P=0.345, n=186). The intervention group increased their average daily step count by 1420 (95% CI, 749 to 2091) and daily minutes of moderate to vigorous physical activity by 8.2 (95% CI, 3.0 to 13.3) over the control group. No between-group differences were detected for any other secondary outcomes. CONCLUSIONS: Whereas the lifestyle intervention in patients with heart failure with reduced ejection fraction improved daily steps by about 25%, it failed to demonstrate a corresponding improvement in functional capacity. Further research is needed to understand the lack of association between increased physical activity and functional outcomes. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03041610.

1st Department of Internal Medicine Cardioangiology Faculty of Medicine in Hradec Kralove Charles University Prague and University Hospital Hradec Kralove Czech Republic

2nd Department of Medicine Department of Cardiovascular Medicine 1st Faculty of Medicine Charles University Prague and General University Hospital Prague Czech Republic

Department of Cardiology Tomas Bata Regional Hospital Zlin Czech Republic

Department of Internal Medicine 1 Cardiology University Hospital Olomouc Czech Republic

Department of Internal Medicine and Cardiology University Hospital Brno and Faculty of Medicine of Masaryk University Brno Czech Republic

Edumed sro Broumov and Faculty of Medicine in Hradec Kralove Charles University Prague Czech Republic

Faculty of Physical Education and Sport Charles University Prague Czech Republic

Institute of Biostatistics and Analyses Ltd Brno Czech Republic

Komentář v

Circulation. 2024 Jan 16;149(3):189-191. doi: 10.1161/CIRCULATIONAHA.123.067588. PubMed

Zobrazit více v PubMed

Becher PM, Lund LH, Coats AJS, Savarese G. An update on global epidemiology in heart failure. Eur Heart J. 2022;43:3005–3007. doi: 10.1093/eurheartj/ehac248 PubMed

Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, Deswal A, Drazner MH, Dunlay SM, Evers LR, et al. . 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. Circulation. 2022;145:e895–e1032. doi: 10.1161/CIR.0000000000001063 PubMed

McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, Burri H, Butler J, Čelutkienė J, Chioncel O, et al. ; ESC Scientific Document Group. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur J Heart Fail. 2022;24:4–131. doi: 10.1002/ejhf.2333 PubMed

Beatty AL, Beckie TM, Dodson J, Goldstein CM, Hughes JW, Kraus WE, Martin SS, Olson TP, Pack QR, Stolp H, et al. . A new era in cardiac rehabilitation delivery: research gaps, questions, strategies, and priorities. Circulation. 2023;147:254–266. doi: 10.1161/CIRCULATIONAHA.122.061046 PubMed PMC

Taylor RS, Dalal HM, McDonagh STJ. The role of cardiac rehabilitation in improving cardiovascular outcomes. Nat Rev Cardiol. 2022;19:180–194. doi: 10.1038/s41569-021-00611-7 PubMed PMC

Shoemaker MJ, Tresh T, Hart J, Wood T. Objective improvement in daily physical activity in heart failure remains elusive. Cardiopulm Phys Ther J. 2018;29:63–80. doi: 10.1097/cpt.0000000000000071

Kitzman DW, Whellan DJ, Duncan P, Pastva AM, Mentz RJ, Reeves GR, Nelson MB, Chen H, Upadhya B, Reed SD, et al. . Physical rehabilitation for older patients hospitalized for heart failure. N Engl J Med. 2021;385:203–216. doi: 10.1056/NEJMoa2026141 PubMed PMC

O’Connor CM, Whellan DJ, Lee KL, Keteyian SJ, Cooper LS, Ellis SJ, Leifer ES, Kraus WE, Kitzman DW, Blumenthal JA, et al. ; HF-ACTION Investigators. Efficacy and safety of exercise training in patients with chronic heart failure: HF-ACTION randomized controlled trial. JAMA. 2009;301:1439–1450. doi: 10.1001/jama.2009.454 PubMed PMC

Pandey A, Keshvani N, Zhong L, Mentz RJ, Piña IL, DeVore AD, Yancy C, Kitzman DW, Fonarow GC. Temporal trends and factors associated with cardiac rehabilitation participation among Medicare beneficiaries with heart failure. JACC Heart Fail. 2021;9:471–481. doi: 10.1016/j.jchf.2021.02.006 PubMed

Piepoli MF, Binno S, Corrà U, Seferovic P, Conraads V, Jaarsma T, Schmid J-P, Filippatos G, Ponikowski PP; Committee on Exercise Physiology & Training of the Heart Failure Association of the ESC. ExtraHF survey: the first European survey on implementation of exercise training in heart failure patients. Eur J Heart Fail. 2015;17:631–638. doi: 10.1002/ejhf.271 PubMed

Nelson RK, Solomon R, Hosmer E, Zuhl M. Cardiac rehabilitation utilization, barriers, and outcomes among patients with heart failure. Heart Fail Rev. 2023;28:1239–1249. doi: 10.1007/s10741-023-10309-2 PubMed

Taylor RS, Dalal HM, Zwisler A-D. Cardiac rehabilitation for heart failure: ‘Cinderella’ or evidence-based pillar of care? Eur Heart J. 2023;44:1511–1518. doi: 10.1093/eurheartj/ehad118 PubMed PMC

Amirova A, Fteropoulli T, Williams P, Haddad M. Efficacy of interventions to increase physical activity for people with heart failure: a meta-analysis. Open Heart. 2021;8:e001687. doi: 10.1136/openhrt-2021-001687 PubMed PMC

Heizmann A-N, Chapelle C, Laporte S, Roche F, Hupin D, Hello CL. Impact of wearable device-based interventions with feedback for increasing daily walking activity and physical capacities in cardiovascular patients: a systematic review and meta-analysis of randomised controlled trials. BMJ Open. 2023;13:e069966. doi: 10.1136/bmjopen-2022-069966 PubMed PMC

Harris T, Kerry SM, Limb ES, Victor CR, Iliffe S, Ussher M, Whincup PH, Ekelund U, Fox-Rushby J, Furness C, et al. . Effect of a primary care walking intervention with and without nurse support on physical activity levels in 45- to 75-year-olds: the Pedometer And Consultation Evaluation (PACE-UP) cluster randomised clinical trial. PLoS Med. 2017;14:e1002210. doi: 10.1371/journal.pmed.1002210 PubMed PMC

Bearne LM, Volkmer B, Peacock J, Sekhon M, Fisher G, Holmes MNG, Douiri A, Amirova A, Farran D, Quirke-McFarlane S, et al. . Effect of a home-based, walking exercise behavior change intervention vs usual care on walking in adults with peripheral artery disease. JAMA. 2022;327:1344–1355. doi: 10.1001/jama.2022.3391 PubMed PMC

Vetrovsky T, Borowiec A, Juřík R, Wahlich C, Śmigielski W, Steffl M, Tufano JJ, Drygas W, Stastny P, Harris T, et al. . Do physical activity interventions combining self-monitoring with other components provide an additional benefit compared with self-monitoring alone? A systematic review and meta-analysis. Br J Sports Med. 2022;56:1366–1374. doi: 10.1136/bjsports-2021-105198 PubMed PMC

Hodkinson A, Kontopantelis E, Adeniji C, van Marwijk H, McMillian B, Bower P, Panagioti M. Interventions using wearable physical activity trackers among adults with cardiometabolic conditions. JAMA Netw Open. 2021;4:e2116382. doi: 10.1001/jamanetworkopen.2021.16382 PubMed PMC

Chaudhry UAR, Wahlich C, Fortescue R, Cook DG, Knightly R, Harris T. The effects of step-count monitoring interventions on physical activity: systematic review and meta-analysis of community-based randomised controlled trials in adults. Int J Behav Nutr Phys Act. 2020;17:129. doi: 10.1186/s12966-020-01020-8 PubMed PMC

Dibben GO, Dalal HM, Taylor RS, Doherty P, Tang LH, Hillsdon M. Cardiac rehabilitation and physical activity: systematic review and meta-analysis. Heart. 2018;104:1394–1402. doi: 10.1136/heartjnl-2017-312832 PubMed PMC

Laranjo L, Ding D, Heleno B, Kocaballi B, Quiroz JC, Tong HL, Chahwan B, Neves AL, Gabarron E, Dao KP, et al. . Do smartphone applications and activity trackers increase physical activity in adults? Systematic review, meta-analysis and metaregression. Br J Sports Med. 2021;55:422–432. doi: 10.1136/bjsports-2020-102892 PubMed

Oliveira JS, Sherrington C, Zheng ERY, Franco MR, Tiedemann A. Effect of interventions using physical activity trackers on physical activity in people aged 60 years and over: a systematic review and meta-analysis. Brit J Sport Med. 2019;54:1188–1194. doi: 10.1136/bjsports-2018-100324 PubMed

Franssen WMA, Franssen GHLM, Spaas J, Solmi F, Eijnde BO. Can consumer wearable activity tracker-based interventions improve physical activity and cardiometabolic health in patients with chronic diseases? A systematic review and meta-analysis of randomised controlled trials. Int J Behav Nutr Phys Act. 2020;17:57. doi: 10.1186/s12966-020-00955-2 PubMed PMC

Ligibel JA, Meyerhardt J, Pierce JP, Najita J, Shockro L, Campbell N, Newman VA, Barbier L, Hacker E, Wood M, et al. . Impact of a telephone-based physical activity intervention upon exercise behaviors and fitness in cancer survivors enrolled in a cooperative group setting. Breast Cancer Res Treat. 2012;132:205–213. doi: 10.1007/s10549-011-1882-7 PubMed PMC

Lee LL, Mulvaney CA, Wong YKY, Chan ES, Watson MC, Lin HH. Walking for hypertension. Cochrane Database Syst Rev. 2021;2021:CD008823. doi: 10.1002/14651858.CD008823.pub2 PubMed PMC

Thomas RJ, Beatty AL, Beckie TM, Brewer LC, Brown TM, Forman DE, Franklin BA, Keteyian SJ, Kitzman DW, Regensteiner JG, et al. . Home-based cardiac rehabilitation: a scientific statement from the American Association of Cardiovascular and Pulmonary Rehabilitation, the American Heart Association, and the American College of Cardiology. Circulation. 2019;140:e69–e89. doi: 10.1161/CIR.0000000000000663 PubMed

Vetrovsky T, Siranec M, Parenica J, Griva M, Stastny J, Precek J, Pelouch R, Bunc V, Linhart A, Belohlavek J. Effect of a 6-month pedometer-based walking intervention on functional capacity in patients with chronic heart failure with reduced (HFrEF) and with preserved (HFpEF) ejection fraction: study protocol for two multicenter randomized controlled trials. J Transl Med. 2017;15:153. doi: 10.1186/s12967-017-1257-x PubMed PMC

Vetrovsky T, Siranec M, Frybova T, Gant I, Semerad M, Miklikova M, Bunc V, Vesely J, Stastny J, Griva M, et al. . Statistical analysis plan for a randomized controlled trial examining pedometer-based walking intervention in patients with heart failure with reduced ejection fraction: the WATCHFUL trial. Trials. 2023;24:539. doi: 10.1186/s13063-023-07516-5 PubMed PMC

Shoemaker MJ, Curtis AB, Vangsnes E, Dickinson MG. Triangulating clinically meaningful change in the six-minute walk test in individuals with chronic heart failure: a systematic review. Cardiopulm Phys Ther J. 2012;23:5–15. PubMed PMC

Akhtar KH, Johnston S, Zhao YD, Amil F, Ford L, Lindenfeld J, Dasari TW. Meta-analysis analyzing the effect of therapies on 6-minute walk distance in heart failure with reduced ejection fraction. Am J Cardiol. 2022;178:72–79. doi: 10.1016/j.amjcard.2022.05.023 PubMed

Piotrowicz E, Pencina MJ, Opolski G, Zaręba W, Banach M, Kowalik I, Orzechowski P, Szalewska D, Pluta S, Główczyńska R, et al. . Effects of a 9-week hybrid comprehensive telerehabilitation program on long-term outcomes in patients with heart failure. JAMA Cardiol. 2020;5:300–308. doi: 10.1001/jamacardio.2019.5006 PubMed PMC

Vetrovsky T, Siranec M, Marencakova J, Tufano JJ, Capek V, Bunc V, Belohlavek J. Validity of six consumer-level activity monitors for measuring steps in patients with chronic heart failure. PLoS One. 2019;14:e0222569. doi: 10.1371/journal.pone.0222569 PubMed PMC

Tudor-Locke C, Craig CL, Aoyagi Y, Bell RC, Croteau KA, Bourdeaudhuij ID, Ewald B, Gardner AW, Hatano Y, Lutes LD, et al. . How many steps/day are enough? For older adults and special populations. Int J Behav Nutr Phys Act. 2011;8:80. doi: 10.1186/1479-5868-8-80 PubMed PMC

Bull FC, Al-Ansari SS, Biddle S, Borodulin K, Buman MP, Cardon G, Carty C, Chaput J-P, Chastin S, Chou R, et al. . World Health Organization 2020 guidelines on physical activity and sedentary behaviour. Br J Sports Med. 2020;54:1451–1462. doi: 10.1136/bjsports-2020-102955 PubMed PMC

Huisman S, Maes S, Gucht VJD, Chatrou M, Haak HR. Low goal ownership predicts drop-out from a weight intervention study in overweight patients with type 2 diabetes. Int J Behav Med. 2010;17:176–181. doi: 10.1007/s12529-009-9071-3 PubMed PMC

Klompstra L, Kyriakou M, Lambrinou E, Piepoli MF, Coats AJS, Cohen-Solal A, Cornelis J, Gellen B, Marques-Sule E, Niederseer D, et al. . Measuring physical activity with activity monitors in patients with heart failure: from literature to practice A position paper from the Committee on Exercise Physiology and Training of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2021;23:83–91. doi: 10.1002/ejhf.2035 PubMed PMC

Choi L, Liu Z, Matthews CE, Buchowski MS. Validation of accelerometer wear and nonwear time classification algorithm. Med Sci Sports Exerc. 2011;43:357–364. doi: 10.1249/MSS.0b013e3181ed61a3 PubMed PMC

Vetrovsky T, Clark CCT, Bisi MC, Siranec M, Linhart A, Tufano JJ, Duncan MJ, Belohlavek J. Advances in accelerometry for cardiovascular patients: a systematic review with practical recommendations. Esc Heart Fail. 2020;7:2021–2031. doi: 10.1002/ehf2.12781 PubMed PMC

Freedson PS, Melanson E, Sirard J. Calibration of the Computer Science and Applications, Inc accelerometer. Med Sci Sports Exerc. 1998;30:777–781. doi: 10.1097/00005768-199805000-00021 PubMed

Banach M, Lewek J, Surma S, Penson PE, Sahebkar A, Martin SS, Bajraktari G, Henein MY, Reiner Z, Bielecka-Dąbrowa A, et al. . The association between daily step count and all-cause and cardiovascular mortality: a meta-analysis [published online August 9, 2023]. Eur J Prev Cardiol. doi: 10.1093/eurjpc/zwad229 PubMed

Zhou Y, Sun X, Yang G, Ding N, Pan X, Zhong A, Guo T, Peng Z, Chai X. Sex-specific differences in the association between steps per day and all-cause mortality among a cohort of adult patients from the United States with congestive heart failure. Heart Lung. 2023;62:175–179. doi: 10.1016/j.hrtlng.2023.07.009 PubMed

Rowlands A, Davies M, Dempsey P, Edwardson C, Razieh C, Yates T. Wrist-worn accelerometers: recommending ~10 m g as the minimum clinically important difference (MCID) in daily average acceleration for inactive adults. Br J Sport Med. 2021;55:814–815. doi: 10.1136/bjsports-2020-102293 PubMed

Demeyer H, Burtin C, Hornikx M, Camillo CA, Remoortel HV, Langer D, Janssens W, Troosters T. The minimal important difference in physical activity in patients with COPD. PLoS One. 2016;11:e0154587. doi: 10.1371/journal.pone.0154587 PubMed PMC

Gardner AW, Montgomery PS, Wang M, Shen B. Minimal clinically important differences in daily physical activity outcomes following supervised and home-based exercise in peripheral artery disease. Vasc Med. 2022;27:142–149. doi: 10.1177/1358863X211072913 PubMed

Taylor JL, Bonikowske AR, Olson TP. Optimizing outcomes in cardiac rehabilitation: the importance of exercise intensity. Front Cardiovasc Med. 2021;8:734278. doi: 10.3389/fcvm.2021.734278 PubMed PMC

Hansen D, Beckers P, Neunhäuserer D, Bjarnason-Wehrens B, Piepoli MF, Rauch B, Völler H, Corrà U, Garcia-Porrero E, Schmid J-P, et al. . Standardised exercise prescription for patients with chronic coronary syndrome and/or heart failure: a consensus statement from the EXPERT working group. Sports Med. 2023;53:2013–2037. doi: 10.1007/s40279-023-01909-x PubMed

Ellingsen O, Halle M, Conraads V, Støylen A, Dalen H, Delagardelle C, Larsen A-I, Hole T, Mezzani A, Craenenbroeck EMV, et al. . High-intensity interval training in patients with heart failure with reduced ejection fraction. Circulation. 2017;135:839–849. doi: 10.1161/CIRCULATIONAHA.116.022924 PubMed PMC

Bozkurt B, Fonarow GC, Goldberg LR, Guglin M, Josephson RA, Forman DE, Lin G, Lindenfeld J, O’Connor C, Panjrath G, et al. ; ACC’s Heart Failure and Transplant Section and Leadership Council. Cardiac rehabilitation for patients with heart failure: JACC Expert Panel. J Am Coll Cardiol. 2021;77:1454–1469. doi: 10.1016/j.jacc.2021.01.030 PubMed

Blasco-Peris C, Climent-Paya V, Vetrovsky T, García-Álvarez MI, Manresa-Rocamora A, Beltrán-Carrillo VJ, Sarabia JM. Self-reported and accelerometer-assessed physical activity: concurrent validity study in heart failure patients [published online October 16, 2023]. ESC Heart Fail. doi: 10.1002/ehf2.14514 PubMed PMC

Frost AE, Langleben D, Oudiz R, Hill N, Horn E, McLaughlin V, Robbins IM, Shapiro S, Tapson VF, Zwicke D, et al. . The 6-min walk test (6MW) as an efficacy endpoint in pulmonary arterial hypertension clinical trials: demonstration of a ceiling effect. Vascul Pharmacol. 2005;43:36–39. doi: 10.1016/j.vph.2005.03.003 PubMed

Paluch AE, Bajpai S, Ballin M, Bassett DR, Buford TW, Carnethon MR, Chernofsky A, Dooley EE, Ekelund U, Evenson KR, et al. ; Steps for Health Collaborative. Prospective association of daily steps with cardiovascular disease: a harmonized meta-analysis. Circulation. 2022;147:122–131. doi: 10.1161/CIRCULATIONAHA.122.061288 PubMed PMC

Jordan C, Charman SJ, Batterham AM, Flynn D, Houghton D, Errington L, MacGowan G, Avery L. Habitual physical activity levels of adults with heart failure: systematic review and meta-analysis. Heart. 2023;109:1357–1362. doi: 10.1136/heartjnl-2022-321943 PubMed PMC

Vetrovsky T, Frybova T, Gant I, Semerad M, Cimler R, Bunc V, Siranec M, Miklikova M, Vesely J, Griva M, et al. . The detrimental effect of COVID-19 nationwide quarantine on accelerometer-assessed physical activity of heart failure patients. Esc Heart Fail. 2020;7:2093–2097. doi: 10.1002/ehf2.12916 PubMed PMC

Dalal HM, Taylor RS, Jolly K, Davis RC, Doherty P, Miles J, Lingen RV, Warren FC, Green C, Wingham J, et al. . The effects and costs of home-based rehabilitation for heart failure with reduced ejection fraction: the REACH-HF multicentre randomized controlled trial. Eur J Prev Cardiol. 2018;26:262–272. doi: 10.1177/2047487318806358 PubMed PMC

Jaarsma T, Klompstra L, Gal TB, Avraham BB, Boyne J, Bäck M, Chialà O, Dickstein K, Evangelista L, Hagenow A, et al. . Effects of exergaming on exercise capacity in patients with heart failure: results of an international multicentre randomized controlled trial. Eur J Heart Fail. 2020;23:114–124. doi: 10.1002/ejhf.1754 PubMed

Tegegne TK, Rawstorn JC, Nourse RA, Kibret KT, Ahmed KY, Maddison R. Effects of exercise-based cardiac rehabilitation delivery modes on exercise capacity and health-related quality of life in heart failure: a systematic review and network meta-analysis. Open Heart. 2022;9:e001949. doi: 10.1136/openhrt-2021-001949 PubMed PMC

Long L, Mordi IR, Bridges C, Sagar VA, Davies EJ, Coats AJ, Dalal H, Rees K, Singh SJ, Taylor RS. Exercise-based cardiac rehabilitation for adults with heart failure. Cochrane Database Syst Rev. 2019;2019:CD003331. doi: 10.1002/14651858.CD003331.pub5 PubMed PMC

Bjarnason-Wehrens B, Nebel R, Jensen K, Hackbusch M, Grilli M, Gielen S, Schwaab B, Rauch B; German Society of Cardiovascular Prevention and Rehabilitation (DGPR). Exercise-based cardiac rehabilitation in patients with reduced left ventricular ejection fraction: the Cardiac Rehabilitation Outcome Study in Heart Failure (CROS-HF): a systematic review and meta-analysis. Eur J Prev Cardiol. 2019;27:929–952. doi: 10.1177/2047487319854140 PubMed PMC

Taylor RS, Walker S, Smart NA, Piepoli MF, Warren FC, Ciani O, Whellan D, O’Connor C, Keteyian SJ, Coats A, et al. ; ExTraMATCH II Collaboration. Impact of exercise rehabilitation on exercise capacity and quality-of-life in heart failure individual participant meta-analysis. J Am Coll Cardiol. 2019;73:1430–1443. doi: 10.1016/j.jacc.2018.12.072 PubMed PMC

mHealth intervention delivered in general practice to increase physical activity and reduce sedentary behaviour of patients with prediabetes and type 2 diabetes (ENERGISED): statistical analysis plan

Participatory development of an mHealth intervention delivered in general practice to increase physical activity and reduce sedentary behaviour of patients with prediabetes and type 2 diabetes (ENERGISED)

Zobrazit více v PubMed

ClinicalTrials.gov
NCT03041610