Impact of recruitment and retention on all-cause mortality in a large all-comers randomised controlled trial: insights from the GLOBAL LEADERS trial



Recruitment and retention in trials may bias the results and subsequently complicate their interpretation and validity. The aim of this study is to evaluate the impact of recruitment and retention on all-cause mortality in a large all-comers trial.


The recruitment rate in each investigating center of the GLOBAL LEADERS trial was assessed and the 130 centers were subdivided into low and high recruiters according to the median, with all-cause mortality then compared between the two groups. Vital status was obtained from public records in patients with incomplete follow-up.


The trial randomized 15,991 (7.86%) of 203,483 eligible patients with percutaneous coronary intervention during the recruitment period, of whom 15,267 (95.47%) completed follow-up, 23 (0.14%) patients withdrew consent and formally requested to be deleted from the database; 183 (1.14%) withdrew consent but only objected to future data collection; 303 (1.89%) discontinued the study; and 215 (1.34%) were lost to follow-up. Vital status was finally obtained in all but 31 patients (99.81%). Patients from low recruiters had a significantly lower all-cause mortality than high ones (2.26% vs. 3.24%; hazard ratio: 0.69; 95% confidence interval: 0.55–0.87; p = 0.002). There was a significant difference in all-cause mortality among the incomplete follow-up groups (log-rank p < 0.001) with a significantly higher mortality in the 183 patients who withdrew consent than those who completed follow-up (7.38% vs. 2.99%, p = 0.002).


Recruitment and retention significantly impacted all-cause mortality. Search for vital status through public domains is of paramount importance in the interpretation and validity of large clinical trials.

Graphic abstract

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4


  1. 1.

    Hordijk-Trion M, Lenzen M, Wijns W, de Jaegere P, Simoons ML, Scholte op Reimer WJ, Bertrand ME, Mercado N, Boersma E, Investigators E-C (2006) Patients enrolled in coronary intervention trials are not representative of patients in clinical practice: results from the Euro Heart Survey on Coronary Revascularization. Eur Heart J 27(6):671–678.

    Article  PubMed  Google Scholar 

  2. 2.

    Rothwell PM (2005) External validity of randomised controlled trials: “To whom do the results of this trial apply?”. Lancet 365(9453):82–93.

    Article  PubMed  Google Scholar 

  3. 3.

    Windecker S, Serruys PW, Wandel S, Buszman P, Trznadel S, Linke A, Lenk K, Ischinger T, Klauss V, Eberli F, Corti R, Wijns W, Morice MC, di Mario C, Davies S, van Geuns RJ, Eerdmans P, van Es GA, Meier B, Juni P (2008) Biolimus-eluting stent with biodegradable polymer versus sirolimus-eluting stent with durable polymer for coronary revascularisation (LEADERS): a randomised non-inferiority trial. Lancet 372(9644):1163–1173.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    de Boer SP, Lenzen MJ, Oemrawsingh RM, Simsek C, Duckers HJ, van der Giessen WJ, Serruys PW, Boersma E (2011) Evaluating the ‘all-comers’ design: a comparison of participants in two ‘all-comers’ PCI trials with non-participants. Eur Heart J 32(17):2161–2167.

    Article  PubMed  Google Scholar 

  5. 5.

    Franzone A, Heg D, Raber L, Valgimigli M, Piccolo R, Zanchin T, Yamaji K, Stortecky S, Blochlinger S, Hunziker L, Praz F, Juni P, Windecker S, Pilgrim T (2016) External validity of the “all-comers” design: insights from the BIOSCIENCE trial. Clin Res Cardiol 105(9):744–754.

    Article  PubMed  Google Scholar 

  6. 6.

    von Birgelen C, van der Heijden LC, Basalus MW, Kok MM, Sen H, Louwerenburg HW, van Houwelingen KG, Stoel MG, de Man FH, Linssen GC, Tandjung K, Doggen CJ, van der Palen J, Lowik MM (2017) Five-year outcome after implantation of zotarolimus- and everolimus-eluting stents in randomized trial participants and nonenrolled eligible patients: a secondary analysis of a randomized clinical trial. JAMA Cardiol 2(3):268–276.

    Article  Google Scholar 

  7. 7.

    Schulz KF, Grimes DA (2002) Sample size slippages in randomised trials: exclusions and the lost and wayward. Lancet 359(9308):781–785.

    Article  PubMed  Google Scholar 

  8. 8.

    Akl EA, Briel M, You JJ, Sun X, Johnston BC, Busse JW, Mulla S, Lamontagne F, Bassler D, Vera C, Alshurafa M, Katsios CM, Zhou Q, Cukierman-Yaffe T, Gangji A, Mills EJ, Walter SD, Cook DJ, Schunemann HJ, Altman DG, Guyatt GH (2012) Potential impact on estimated treatment effects of information lost to follow-up in randomised controlled trials (LOST-IT): systematic review. BMJ 344:e2809.

    Article  PubMed  Google Scholar 

  9. 9.

    Little RJ, D’Agostino R, Cohen ML, Dickersin K, Emerson SS, Farrar JT, Frangakis C, Hogan JW, Molenberghs G, Murphy SA, Neaton JD, Rotnitzky A, Scharfstein D, Shih WJ, Siegel JP, Stern H (2012) The prevention and treatment of missing data in clinical trials. N Engl J Med 367(14):1355–1360.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Turner L, Shamseer L, Altman DG, Schulz KF, Moher D (2012) Does use of the CONSORT Statement impact the completeness of reporting of randomised controlled trials published in medical journals? A cochrane review. Syst Rev 1:60.

    Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Krantz MJ, Kaul S (2013) The ATLAS ACS 2-TIMI 51 trial and the burden of missing data: (anti-Xa therapy to lower cardiovascular events in addition to standard therapy in subjects with acute coronary syndrome ACS 2-thrombolysis in myocardial infarction 51). J Am Coll Cardiol 62(9):777–781.

    Article  PubMed  Google Scholar 

  12. 12.

    Schulz KF, Altman DG, Moher D, Group C (2010) CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ 340:c332.

    Article  Google Scholar 

  13. 13.

    Vranckx P, Valgimigli M, Windecker S, Steg PG, Hamm C, Juni P, Garcia-Garcia HM, van Es GA, Serruys PW (2016) Long-term ticagrelor monotherapy versus standard dual antiplatelet therapy followed by aspirin monotherapy in patients undergoing biolimus-eluting stent implantation: rationale and design of the GLOBAL LEADERS trial. EuroIntervention 12(10):1239–1245.

    Article  PubMed  Google Scholar 

  14. 14.

    Vranckx P, Valgimigli M, Juni P, Hamm C, Steg PG, Heg D, van Es GA, McFadden EP, Onuma Y, van Meijeren C, Chichareon P, Benit E, Mollmann H, Janssens L, Ferrario M, Moschovitis A, Zurakowski A, Dominici M, Van Geuns RJ, Huber K, Slagboom T, Serruys PW, Windecker S, Investigators GL (2018) Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent: a multicentre, open-label, randomised superiority trial. Lancet.

    Article  PubMed  Google Scholar 

  15. 15.

    Campbell RT, Willox GP, Jhund PS, Hawkins NM, Huang F, Petrie MC, McMurray JJ (2016) Reporting of lost to follow-up and treatment discontinuation in pharmacotherapy and device trials in chronic heart failure: a systematic review. Circ Heart Fail.

    Article  PubMed  Google Scholar 

  16. 16.

    von Birgelen C, Kok MM, van der Heijden LC, Danse PW, Schotborgh CE, Scholte M, Gin R, Somi S, van Houwelingen KG, Stoel MG, de Man F, Louwerenburg JHW, Hartmann M, Zocca P, Linssen GCM, van der Palen J, Doggen CJM, Lowik MM (2016) Very thin strut biodegradable polymer everolimus-eluting and sirolimus-eluting stents versus durable polymer zotarolimus-eluting stents in allcomers with coronary artery disease (BIO-RESORT): a three-arm, randomised, non-inferiority trial. Lancet 388(10060):2607–2617.

    CAS  Article  Google Scholar 

  17. 17.

    Lip GY, Huber K, Andreotti F, Arnesen H, Airaksinen KJ, Cuisset T, Kirchhof P, Marin F, European Society of Cardiology Working Group on T (2010) Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary intervention/stenting. Thromb Haemost 103(1):13–28.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Hansen ML, Sorensen R, Clausen MT, Fog-Petersen ML, Raunso J, Gadsboll N, Gislason GH, Folke F, Andersen SS, Schramm TK, Abildstrom SZ, Poulsen HE, Kober L, Torp-Pedersen C (2010) Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Arch Intern Med 170(16):1433–1441.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Valgimigli M, Bueno H, Byrne RA, Collet JP, Costa F, Jeppsson A, Juni P, Kastrati A, Kolh P, Mauri L, Montalescot G, Neumann FJ, Petricevic M, Roffi M, Steg PG, Windecker S, Zamorano JL, Levine GN, Group ESCSD, Guidelines ESCCfP, Societies ESCNC (2018) 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the task force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 39(3):213–260.

    Article  PubMed  Google Scholar 

  20. 20.

    Shahzad A, Kemp I, Mars C, Wilson K, Roome C, Cooper R, Andron M, Appleby C, Fisher M, Khand A, Kunadian B, Mills JD, Morris JL, Morrison WL, Munir S, Palmer ND, Perry RA, Ramsdale DR, Velavan P, Stables RH, Investigators H-Pt (2014) Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet 384(9957):1849–1858.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Shaw D (2014) HEAT-PPCI sheds light on consent in pragmatic trials. Lancet 384(9957):1826–1827.

    Article  PubMed  Google Scholar 

  22. 22.

    Guyatt GH, Oxman AD, Vist G, Kunz R, Brozek J, Alonso-Coello P, Montori V, Akl EA, Djulbegovic B, Falck-Ytter Y, Norris SL, Williams JW Jr, Atkins D, Meerpohl J, Schunemann HJ (2011) GRADE guidelines: 4 rating the quality of evidence—study limitations (risk of bias). J Clin Epidemiol 64(4):407–415.

    Article  PubMed  Google Scholar 

Download references


The GLOBAL LEADERS trial was conducted under the support of the unrestricted resource from AstraZeneca, Biosensors, and The Medicines Company.

Author information



Corresponding author

Correspondence to Patrick W. Serruys.

Ethics declarations

Conflict of interest

Dr. Liebetrau reports personal fees from Astra Zeneca, outside the submitted work. Dr. Hamm reports personal fees from AstraZeneca, outside the submitted work. Dr. Steg reports Grants and personal fees from Bayer/Janssen, Grants and personal fees from Merck, Grants and personal fees from Sanofi, Grants and personal fees from Amarin, personal fees from Amgen, personal fees from Bristol Myers Squibb, personal fees from Boehringer-Ingelheim, personal fees from Pfizer, personal fees from Novartis, personal fees from Regeneron, personal fees from Lilly, personal fees from AstraZeneca, Grants and personal fees from Servier, outside the submitted work. Dr. Valgimigli reports Grants and personal fees from Abbott, personal fees from Chiesi, personal fees from Bayer, personal fees from Daiichi Sankyo, personal fees from Amgen, Grants and personal fees from Terumo, personal fees from Alvimedica, Grants from Medicure, Grants and personal fees from Astrazeneca, personal fees from Biosensors, outside the submitted work. Dr. Vranckx has received personal fees from AstraZeneca and the Medicines Company during the conduct of the study and personal fees from Bayer Health Care, Terumo, and Daiichi-Sankyo outside the submitted work. Dr. Windecker reports Grants from Amgen, Grants from Abbott, Grants from Boston Scientific, Grants from Biotronik, Grants from Bayer, Grants from Medtronic, Grants from Edwards Lifesciences, Grants from St Jude, Grants from Terumo, outside the submitted work. Dr. Serruys reports personal fees from Abbott Laboratories, personal fees from Biosensors, personal fees from Medtronic, personal fees from Micel Technologies, personal fees from Sinomedical Sciences Technology, personal fees from Stentys, personal fees from Svelte Medical Systems, personal fees from Philips/Volcano, personal fees from Xeltis, personal fees from StentIt and personal fees from HeartFlow outside the submitted work. All other authors declare no competing interests.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (TIFF 26,369 kb)

Supplementary material 2 (DOCX 607 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Takahashi, K., Kogame, N., Tomaniak, M. et al. Impact of recruitment and retention on all-cause mortality in a large all-comers randomised controlled trial: insights from the GLOBAL LEADERS trial. Clin Res Cardiol 109, 918–929 (2020).

Download citation


  • All-cause mortality
  • All-comers
  • Recruitment
  • Retention
  • Randomised controlled trial