Cited by 131Statistical Methods in Clinical TrialsMeta-analysis and systematic reviewsStatistical Methods in Epidemiology

The DOI matches its Crossref record; 98 of the 99 references it cites were found in a registry or an index.

Subgroup analyses in therapeutic cardiovascular clinical trials: Are most of them misleading?

Hernández, Adrián V., Boersma, Eric, Murray, Gordon D., Habbema, J. Dik F., Steyerberg, Ewout W.·2006·American Heart Journal

DOI 10.1016/j.ahj.2005.04.020

Open this paper in CoChat — free account

Abstract

Background Treatment decisions in clinical cardiology are directed by results from randomized clinical trials (RCTs). We studied the appropriateness of the use and interpretation of subgroup analysis in current therapeutic cardiovascular RCTs.Methods We reviewed main reports of phase 3 cardiovascular RCTs with at least 100 patients, published in 2002 and 2004, and from major journals (Circulation, J Am Coll Cardiol, Am Heart J, Am J Cardiol, N Engl J Med, Lancet, JAMA, BMJ, Ann Intern Med). Information on subgroups included prespecification, number, interaction test use, significant subgroups found, and emphasis on findings. We examined appropriateness of reporting and differences according to sample size, overall trial result, and CONSORT adoption.Results We selected 63 RCTs, with a median of 496 (range 100-15,245) patients. Thirty-nine RCTs were reported with subgroup analyses and 26 with > 5 subgroups. No trial was specifically powered to detect subgroup effects, and only 14 RCTs were reported with fully prespecified subgroups. Only 11 RCTs were reported with interaction tests. Furthermore, 21 RCTs were reported with claims of significant subgroups and 15 with equal or more emphasis to subgroups than to the overall results. Subgroup analyses in large RCTs (> 500 patients) were reported more often than in small ones (24/30 vs 15/33, P = .005). No differences were found according to overall result (positive/negative) or CONSORT adoption.Conclusions Subgroup analyses in recent cardiovascular RCTs were reported with several shortcomings, including a lack of prespecification and testing of a large number of subgroups without the use of the statistically appropriate test for interaction. Reporting of subgroup analysis needs to be substantially improved because emphasis on these secondary results may mislead treatment decisions.

Integrity signals

Registry

Crossref · 10.1016/j.ahj.2005.04.020

Cites

98 of 98 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Tissue Plasminogen Activator for Acute Ischemic Stroke
(1995) · New England Journal of Medicine · doi:10.1056/nejm199512143332401 · Cited by 11,654
Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S)
OLSSON, A. G., McMurray, J. J. V., Thorgeirsson, G., Spaulding, C. M., Slattery, J., Pyörälà, K., Færgeman, O., Wright, R. S., Berg, K. M., Wilhelmsen, L., et al. (1994) · The Lancet · Cited by 8,467
Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure
The SOLVD Investigators* (1991) · New England Journal of Medicine · doi:10.1056/nejm199108013250501 · Cited by 8,029
Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure
Bristow, M. R., Saxon, L. A., Boehmer, J., Krueger, S., Kass, D. A., De Marco, T., Carson, P., DiCarlo, L., DeMets, D., White, B. G., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa032423 · Cited by 5,812
Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in-Congestive Heart Failure (MERIT-HF)
(1999) · The Lancet · doi:10.1016/s0140-6736(99)04440-2 · Cited by 5,141
Sirolimus-Eluting Stents versus Standard Stents in Patients with Stenosis in a Native Coronary Artery
Moses, J. W., Leon, M. B., Popma, J. J., Fitzgerald, P. J., Holmes, D. R., O’Shaughnessy, C. D., Caputo, R. P., Kereiakes, D. J., Williams, D. O., Teirstein, P. S., et al. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa035071 · Cited by 4,222
The Revised CONSORT Statement for Reporting Randomized Trials: Explanation and Elaboration
Altman, D. G., Schulz, K. F., Moher, D., Egger, M., Davidoff, F., Elbourne, D., Gøtzsche, P. C., Lang, T., & for the CONSORT Group (2001) · Annals of Internal Medicine · doi:10.7326/0003-4819-134-8-200104170-00012 · Cited by 3,835
Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial
Shepherd, J., Blauw, G. J., Murphy, M. B., Bollen, E. L., Buckley, B. M., Cobbe, S. M., Ford, I., Gaw, A., Hyland, M., Jukema, J. W., et al. (2002) · The Lancet · doi:10.1016/s0140-6736(02)11600-x · Cited by 3,378
Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S)
Pedersen, T. R. (2004) · Atherosclerosis Supplements · doi:10.1016/j.atherosclerosissup.2004.08.027 · Cited by 3,098
Early and Sustained Dual Oral Antiplatelet Therapy Following Percutaneous Coronary Intervention
Steinhubl, S. R., Berger, P. B., Mann, J. T., Fry, E. T. A., DeLago, A. J., Wilmer, C. I., Topol, E. J., & for the CREDO Investigators (2002) · JAMA · doi:10.1001/jama.288.19.2411 · Cited by 3,071

Show all 99 references

Sorted by citations

SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials
Chan, A.-W., Tetzlaff, J. M., Gotzsche, P. C., Altman, D. G., Mann, H., Berlin, J. A., Dickersin, K., Hrobjartsson, A., Schulz, K. F., Parulekar, W. R., et al. (2013) · BMJ · doi:10.1136/bmj.e7586 · Cited by 6,251
Consolidated Health Economic Evaluation Reporting Standards (CHEERS)—Explanation and Elaboration: A Report of the ISPOR Health Economic Evaluation Publication Guidelines Good Reporting Practices Task Force
Husereau, D., Drummond, M., Petrou, S., Carswell, C., Moher, D., Greenberg, D., Augustovski, F., Briggs, A. H., Mauskopf, J., & Loder, E. (2013) · Value in Health · doi:10.1016/j.jval.2013.02.002 · Cited by 1,998
Bivalirudin for Patients with Acute Coronary Syndromes
Stone, G. W., McLaurin, B. T., Cox, D. A., Bertrand, M. E., Lincoff, A. M., Moses, J. W., White, H. D., Pocock, S., Ware, J. H., Feit, F., et al. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa062437 · Cited by 1,461
Statistics in Medicine — Reporting of Subgroup Analyses in Clinical Trials
Wang, R., Lagakos, S. W., Ware, J. H., Hunter, D. J., & Drazen, J. M. (2007) · New England Journal of Medicine · doi:10.1056/nejmsr077003 · Cited by 1,445
Regional Variation in Patients and Outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) Trial
Pfeffer, M. A., Claggett, B. L., Assmann, S. F., Boineau, R., Anand, I. S., Clausell, N., Desai, A. S., Díaz, R., Fleg, J. L., Gordeev, I. G., et al. (2014) · Circulation · doi:10.1161/circulationaha.114.013255 · Cited by 1,083
Consolidated Health Economic Evaluation Reporting Standards (CHEERS) 2022 Explanation and Elaboration: A Report of the ISPOR CHEERS II Good Practices Task Force
Husereau, D., Drummond, M., Augustovski, F., de Bekker-Grob, E., Briggs, A. H., Carswell, C., Caulley, L., Chaiyakunapruk, N., Greenberg, D., Loder, E., et al. (2022) · Value in Health · doi:10.1016/j.jval.2021.10.008 · Cited by 847
Development of the instrument to assess the credibility of effect modification analyses (ICEMAN) in randomized controlled trials and meta-analyses
Schandelmaier, S., Briel, M., Varadhan, R., Schmid, C. H., Devasenapathy, N., Hayward, R. A., Gagnier, J., Borenstein, M., van der Heijden, G. J. M. G., Dahabreh, I. J., et al. (2020) · Canadian Medical Association Journal · doi:10.1503/cmaj.200077 · Cited by 749
Comparison of an Everolimus-Eluting Stent and a Paclitaxel-Eluting Stent in Patients With Coronary Artery Disease
Stone, G. W. (2008) · JAMA · doi:10.1001/jama.299.16.1903 · Cited by 580
Assessing and reporting heterogeneity in treatment effects in clinical trials: a proposal
Kent, D. M., Rothwell, P. M., Ioannidis, J. P., Altman, D. G., & Hayward, R. A. (2010) · Trials · doi:10.1186/1745-6215-11-85 · Cited by 504
Personalized evidence based medicine: predictive approaches to heterogeneous treatment effects
Kent, D. M., Steyerberg, E. W., & Klaveren, D. V. (2018) · BMJ · doi:10.1136/bmj.k4245 · Cited by 518
Self-citation
The Predictive Approaches to Treatment effect Heterogeneity (PATH) statement
Kent, D. M., Paulus, J. K., van Klaveren, D., D'Agostino, R., Goodman, S., Hayward, R., Ioannidis, J. P. A., Patrick-Lake, B., Morton, S., Pencina, M., et al. (2020) · Annals of Internal Medicine · doi:10.7326/m18-3667 · Cited by 469
Self-citation
Credibility of claims of subgroup effects in randomised controlled trials: systematic review
Sun, X., Briel, M., Busse, J. W., You, J. J., Akl, E. A., Mejza, F., Bała, M. M., Bassler, D., Mertz, D., Diaz-Granados, N., et al. (2012) · BMJ · doi:10.1136/bmj.e1553 · Cited by 397
Examining the Evidence: A Systematic Review of the Inclusion and Analysis of Older Adults in Randomized Controlled Trials
Zulman, D. M., Sussman, J. B., Chen, X., Cigolle, C. T., Blaum, C. S., & Hayward, R. A. (2011) · Journal of General Internal Medicine · doi:10.1007/s11606-010-1629-x · Cited by 405
Bivalirudin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a subgroup analysis from the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial
Stone, G. W., White, H. D., Ohman, E. M., Bertrand, M. E., Lincoff, A. M., McLaurin, B. T., Cox, D. A., Pocock, S., Ware, J. H., Feit, F., et al. (2007) · The Lancet · doi:10.1016/s0140-6736(07)60450-4 · Cited by 388
Routine Upstream Initiation vs Deferred Selective Use of Glycoprotein IIb/IIIa Inhibitors in Acute Coronary Syndromes
Stone, G. W., Bertrand, M. E., Moses, J. W., Ohman, E. M., Lincoff, A. M., Ware, J. H., Pocock, S., McLaurin, B. T., Cox, D. A., Jafar, M. Z., et al. (2007) · JAMA · doi:10.1001/jama.297.6.591 · Cited by 297
Trial and Error
Kaul, S., & Diamond, G. A. (2010) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2009.06.065 · Cited by 270
Antithrombotic Strategies in Patients With Acute Coronary Syndromes Undergoing Early Invasive Management
Stone, G. W., Ware, J. H., Bertrand, M. E., Lincoff, A. M., Moses, J. W., Ohman, E. M., White, H. D., Feit, F., Colombo, A., McLaurin, B. T., et al. (2007) · JAMA · doi:10.1001/jama.298.21.2497 · Cited by 236
Randomized Comparison of Everolimus- and Paclitaxel-Eluting Stents
Stone, G. W., Rizvi, A., Sudhir, K., Newman, W. N., Applegate, R. J., Cannon, L., Maddux, J. T., Cutlip, D. E., Simonton, C. A., Sood, P., et al. (2011) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2011.02.022 · Cited by 229
Evidence for the Selective Reporting of Analyses and Discrepancies in Clinical Trials: A Systematic Review of Cohort Studies of Clinical Trials
Dwan, K., Altman, D. G., Clarke, M., Gamble, C., Higgins, J. P. T., Sterne, J. A. C., Williamson, P. R., & Kirkham, J. J. (2014) · PLoS Medicine · doi:10.1371/journal.pmed.1001666 · Cited by 187
The Predictive Approaches to Treatment effect Heterogeneity (PATH) Statement: Explanation and Elaboration
Kent, D. M., Klaveren, D. V., Paulus, J. K., D’Agostino, R. B., Goodman, S. N., Hayward, R. A., Ioannidis, J. P. A., Patrick‐Lake, B., Morton, S. C., Pencina, M. J., et al. (2019) · Annals of Internal Medicine · doi:10.7326/m18-3668 · Cited by 183
Self-citation
Detecting moderator effects using subgroup analyses
Wang, R., & Ware, J. H. (2013) · Prevention Science · doi:10.1007/s11121-011-0221-x · Cited by 165
A tutorial on methodological studies: the what, when, how and why
Mbuagbaw, L. C. E., Lawson, D. O., Puljak, L., Allison, D. B., & Thabane, L. (2020) · BMC Medical Research Methodology · doi:10.1186/s12874-020-01107-7 · Cited by 181
Damned if you do, damned if you don't: subgroup analysis and equity
Petticrew, M. P., Tugwell, P., Kristjansson, E., Oliver, S. R., Ueffing, E., & Welch, V. A. (2011) · Journal of Epidemiology & Community Health · doi:10.1136/jech.2010.121095 · Cited by 159
Evaluation of Evidence of Statistical Support and Corroboration of Subgroup Claims in Randomized Clinical Trials
Wallach, J. D., Sullivan, P. G., Trepanowski, J. F., Sainani, K. L., Steyerberg, E. W., & Ioannidis, J. P. A. (2017) · JAMA Internal Medicine · doi:10.1001/jamainternmed.2016.9125 · Cited by 148
Self-citation
Understanding of interaction (subgroup) analysis in clinical trials
Brankovic, M., Kardys, I., Steyerberg, E. W., Lemeshow, S., Markovic, M., Rizopoulos, D., & Boersma, E. (2019) · European Journal of Clinical Investigation · doi:10.1111/eci.13145 · Cited by 130
Self-citation
Evidence-Based Medicine, Systematic Reviews, and Guidelines in Interventional Pain Management: Part 4: Observational Studies
Manchikanti, L. (2009) · Pain Physician · doi:10.36076/ppj.2009/12/73 · Cited by 117
Dealing with heterogeneity of treatment effects: is the literature up to the challenge?
Gabler, N. B., Duan, N., Liao, D., Elmore, J. G., Ganiats, T. G., & Kravitz, R. L. (2009) · Trials · doi:10.1186/1745-6215-10-43 · Cited by 114
The proposed ‘concordance-statistic for benefit’ provided a useful metric when modeling heterogeneous treatment effects
Klaveren, D. V., Steyerberg, E. W., Serruys, P. W. J. C., & Kent, D. M. (2017) · Journal of Clinical Epidemiology · doi:10.1016/j.jclinepi.2017.10.021 · Cited by 111
Self-citation
Perspective: Limiting Dependence on Nonrandomized Studies and Improving Randomized Trials in Human Nutrition Research: Why and How
Trepanowski, J. F., & Ioannidis, J. P. A. (2018) · Advances in Nutrition · doi:10.1093/advances/nmy014 · Cited by 107
Subgroup analyses in randomised controlled trials: cohort study on trial protocols and journal publications
Kasenda, B., Schandelmaier, S., Sun, X., von Elm, E. B., You, J., Blümle, A., Tomonaga, Y., Saccilotto, R. T., Amstutz, A., Bengough, T., et al. (2014) · BMJ · doi:10.1136/bmj.g4539 · Cited by 103
Reading First Impact Study Final Report
Gamse, B., Jacob, R. T., Horst, M. A., Boulay, B. A., Associates, A., Unlu, F., Bozzi, L., Caswell, L., Rodger, C., Carter, W., et al. (2009) · Cited by 100
The influence of study characteristics on reporting of subgroup analyses in randomised controlled trials: systematic review
Sun, X., Briel, M., Busse, J. W., You, J. J., Akl, E. A., Mejza, F., Bała, M. M., Bassler, D., Mertz, D., Diaz-Granados, N., et al. (2011) · BMJ · doi:10.1136/bmj.d1569 · Cited by 103
The REFLECT Statement: Reporting guidelines for randomized controlled trials in livestock and food safety: Explanation and Elaboration
Sargeant, J. M., O’connor, A. M., Gardner, I. A., Dickson, J. S., Torrence, M. E., Dohoo, C. M. P. I. R., Lefebvre, S. L., Morley, P. S., Ramirez, A., & Snedeker, K. (2010) · Journal of Food Protection · doi:10.4315/0362-028x-73.3.579 · Cited by 97
The REFLECT Statement: Reporting Guidelines for Randomized Controlled Trials in Livestock and Food Safety: Explanation and Elaboration
Sargeant, J. M., O'Connor, A. M. C., Gardner, I. A., Dickson, J. S., Torrence, M. E., participants, C. M., Dohoo, I. R., Lefebvre, S. L., Morley, P. S., Ramirez, A., et al. (2010) · Zoonoses and Public Health · doi:10.1111/j.1863-2378.2009.01312.x · Cited by 99
Subgroup analyses in confirmatory clinical trials: time to be specific about their purposes
Tanniou, J., van der Tweel, I., Teerenstra, S., & Roes, K. C. B. (2016) · BMC Medical Research Methodology · doi:10.1186/s12874-016-0122-6 · Cited by 90
Sex based subgroup differences in randomized controlled trials: empirical evidence from Cochrane meta-analyses
Wallach, J. D., Sullivan, P. G., Trepanowski, J. F., Steyerberg, E. W., & Ioannidis, J. P. A. (2016) · BMJ · doi:10.1136/bmj.i5826 · Cited by 89
Self-citation
Randomized trials published in higher vs. lower impact journals differ in design, conduct, and analysis
Bała, M. M., Akl, E. A., Sun, X., Bassler, D., Mertz, D., Mejza, F., Vandvik, P. O., Málaga, G., Johnston, B. C., Dahm, P., et al. (2013) · Journal of Clinical Epidemiology · doi:10.1016/j.jclinepi.2012.10.005 · Cited by 84
Impact of Chronic Kidney Disease on Early (30-Day) and Late (1-Year) Outcomes of Patients With Acute Coronary Syndromes Treated With Alternative Antithrombotic Treatment Strategies
Mehran, R., Nikolsky, E., Lansky, A. J., Kirtane, A. J., Kim, Y., Feit, F., Manoukian, S. V., Moses, J. W., Ebrahimi, R., Ohman, E. M., et al. (2009) · JACC: Cardiovascular Interventions · doi:10.1016/j.jcin.2009.05.018 · Cited by 77
Baseline Matters: The Importance of Covariation for Baseline Severity in the Analysis of Clinical Trials
Nunes, E. V., Pavlicová, M., Hu, M., Campbell, A. N. C., Miele, G. M., Hien, D. A., & Klein, D. F. (2011) · The American Journal of Drug and Alcohol Abuse · doi:10.3109/00952990.2011.596980 · Cited by 64
Subgroup Analysis of Trials Is Rarely Easy (SATIRE): a study protocol for a systematic review to characterize the analysis, reporting, and claim of subgroup effects in randomized trials
Sun, X., Briel, M., Busse, J. W., Akl, E. A., You, J. J., Mejza, F., Bała, M. M., Diaz-Granados, N., Bassler, D., Mertz, D., et al. (2009) · Trials · doi:10.1186/1745-6215-10-101 · Cited by 59
Publicación de ensayos clínicos en revistas científicas: consideraciones editoriales
Alfonso, F., Segovia, J., Heras, M., & Bermejo, J. (2006) · Revista Española de Cardiología · doi:10.1157/13095794 · Cited by 56
Publication of Clinical Trials in Scientific Journals: Editorial Issves
Alfonso, F., Segovia, J., Heras, M., & Bermejo, J. (2006) · Revista Española de Cardiología (English Edition) · doi:10.1016/s1885-5857(07)60074-7 · Cited by 52
Estimates of absolute treatment benefit for individual patients required careful modeling of statistical interactions
Klaveren, D. V., Vergouwe, Y., Farooq, V., Serruys, P. W. J. C., & Steyerberg, E. W. (2015) · Journal of Clinical Epidemiology · doi:10.1016/j.jclinepi.2015.02.012 · Cited by 51
Self-citation
Subgroup Analyses in Reporting of Phase III Clinical Trials in Solid Tumors
Zhang, S., Liang, F., Li, W., & Hu, X. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2014.59.8862 · Cited by 48
Secondary use of randomized controlled trials to evaluate drug safety: a review of methodological considerations
Hammad, T. A., Pinheiro, S. P., & Neyarapally, G. A. (2011) · Clinical Trials · doi:10.1177/1740774511419165 · Cited by 47
Factors Associated with Conflicting Findings on Acupuncture for Tension-Type Headache: Qualitative and Quantitative Analyses
Hao, X., Xue, C. C., Dong, L., & Zheng, Z. (2012) · The Journal of Alternative and Complementary Medicine · doi:10.1089/acm.2011.0914 · Cited by 45
Outcome based subgroup analysis: a neglected concern
Hirji, K. F., & Fagerland, M. W. (2009) · Trials · doi:10.1186/1745-6215-10-33 · Cited by 41
“With a marked potential to yield unreliable assessments of the existence, direction and extent of treatment differences for a specific category of patients, the clinical message emanating from SGA is generally poorly justified, and may also foster unneeded research [1-13].”
Background
The Problem of Subgroup Analyses: An Example from a Trial on Ruptured Intracranial Aneurysms
Naggara, O. N., Raymond, J., Guilbert, F., & Altman, D. G. (2011) · American Journal of Neuroradiology · doi:10.3174/ajnr.a2442 · Cited by 42
No improvement in the reporting of clinical trial subgroup effects in high-impact general medical journals
Gabler, N. B., Duan, N., Raneses, E., Suttner, L. H., Ciarametaro, M., Cooney, E. L., Dubois, R. W., Halpern, S. D., & Kravitz, R. L. (2016) · Trials · doi:10.1186/s13063-016-1447-5 · Cited by 40
Impact of Diabetes Mellitus on the Safety and Effectiveness of Bivalirudin in Patients With Acute Myocardial Infarction Undergoing Primary Angioplasty
Witzenbichler, B., Mehran, R., Guagliumi, G., Dudek, D., Huber, K., Kornowski, R., Stuckey, T., Fahy, M. P., Parise, H., & Stone, G. W. (2011) · JACC: Cardiovascular Interventions · doi:10.1016/j.jcin.2011.04.008 · Cited by 35
Primer: the fallacy of subgroup analysis
Guillemin, F. (2007) · Nature Clinical Practice Rheumatology · doi:10.1038/ncprheum0528 · Cited by 34
Randomized comparison of everolimus- and paclitaxel-eluting stents: pooled analysis of the 2-year clinical follow-up from the SPIRIT II and III trials
Onuma, Y., Serruys, P. W. J. C., Kukreja, N., Veldhof, S., Doostzadeh, J., Cao, S., Stone, G. W., & on behalf of the SPIRIT II and III Investigators (2010) · European Heart Journal · doi:10.1093/eurheartj/ehp599 · Cited by 32
Confronting diversity in the production of clinical evidence goes beyond merely including under-represented groups in clinical trials
Stronks, K., Wieringa, N. F., & Hardon, A. P. (2013) · Trials · doi:10.1186/1745-6215-14-177 · Cited by 31
Positionspapier der DGK zur Wirksamkeit und Sicherheit von Medikamente freisetzenden Koronarstents (DES)
Silber, S., Borggrefe, M., Böhm, M., Hoffmeister, H.-M., Dietz, R., Ertl, G., & Heusch, G. (2007) · Der Kardiologe · doi:10.1007/s12181-007-0012-6 · Cited by 30
A systematic survey identified 36 criteria for assessing effect modification claims in randomized trials or meta-analyses
Schandelmaier, S., Chang, Y., Devasenapathy, N., Devji, T., Kwong, J. S. W., Colunga‐Lozano, L. E., Lee, Y., Agarwal, A., Bhatnagar, N., Ewald, H., et al. (2019) · Journal of Clinical Epidemiology · doi:10.1016/j.jclinepi.2019.05.014 · Cited by 24
Evaluation of Heterogeneity in Pharmacotherapy Trials for Drug Dependence: A Bayesian Approach
Green, C. E., Moeller, F. G., Schmitz, J. M., Lucke, J. F., Lane, S. D., Swann, A. C., Lasky, R. E., & Carbonari, J. P. (2009) · The American Journal of Drug and Alcohol Abuse · doi:10.1080/00952990802647503 · Cited by 24
Assessing Heterogeneity of Treatment Effects: Are Authors Misinterpreting Their Results?
y García, E. F., Nguyen, H., Duan, N., Gabler, N. B., & Kravitz, R. L. (2009) · Health Services Research · doi:10.1111/j.1475-6773.2009.01064.x · Cited by 24
Treatment effect modification due to comorbidity: Individual participant data meta-analyses of 120 randomised controlled trials
Hanlon, P., Butterly, E. W., Shah, A. S. V., Hannigan, L. J., Lewsey, J., Mair, F. S., Kent, D. M., Guthrie, B., Wild, S. H., Welton, N. J., et al. (2023) · PLoS Medicine · doi:10.1371/journal.pmed.1004176 · Cited by 24
A New and Rapid Scoring System to Assess the Scientific Evidence from Clinical Trials
Silber, S. (2006) · Journal of Interventional Cardiology · doi:10.1111/j.1540-8183.2006.00205.x · Cited by 22
Best practice for analysis of shared clinical trial data
Hollis, S., Fletcher, C., Lynn, F., Urban, H.-J., Branson, J., Burger, H.-U., Smith, C. T., Sydes, M. R., & Gerlinger, C. (2016) · BMC Medical Research Methodology · doi:10.1186/s12874-016-0170-y · Cited by 22
A systematic review of subgroup analyses in randomised clinical trials in cardiovascular disease
Brand, K., Hapfelmeier, A., & Haller, B. (2021) · Clinical Trials · doi:10.1177/1740774520984866 · Cited by 19
Overcoming combination fatigue: Addressing high-dimensional effect measure modification and interaction in clinical, biomedical, and epidemiologic research using multilevel analysis of individual heterogeneity and discriminatory accuracy (MAIHDA)
Evans, C. R. (2023) · Social Science & Medicine · doi:10.1016/j.socscimed.2023.116493 · Cited by 22
Guidance from key organisations on exploring, confirming and interpreting subgroup effects of medical treatments: a scoping review
Wijn, S. R. W., Rovers, M. M., Le, L. H., Belias, M., Hoogland, J., IntHout, J., Debray, T. P. A., & Reitsma, J. B. (2019) · BMJ Open · doi:10.1136/bmjopen-2018-028751 · Cited by 16
Vitamin E and the risk of pneumonia: using the I2 statistic to quantify heterogeneity within a controlled trial
Hemilä, H. (2016) · British Journal Of Nutrition · doi:10.1017/s0007114516003408 · Cited by 17
Clinical trials: design, endpoints and interpretation of outcomes
Othus, M. K. D., Zhang, M.-J., & Gale, R. P. (2022) · Bone Marrow Transplantation · doi:10.1038/s41409-021-01542-0 · Cited by 18
Secondary Analysis of Clinical Trials—A Cautionary Note
Marler, J. R. (2012) · Progress in Cardiovascular Diseases · doi:10.1016/j.pcad.2011.09.006 · Cited by 17
A systematic approach to subgroup analyses in a smoking cessation trial
Westover, A. N., Kashner, T. M., Winhusen, T. M., Golden, R. M., Nakonezny, P. A., Adinoff, B. H., & Henley, S. S. (2015) · The American Journal of Drug and Alcohol Abuse · doi:10.3109/00952990.2015.1044605 · Cited by 15
Reporting and Interpretation of Subgroup Analyses in Heart Failure Randomized Controlled Trials
Khan, M. S., Khan, M. A. A., Irfan, S., Siddiqi, T. J., Greene, S. J., Anker, S. D., Sreenivasan, J., Friede, T., Tahhan, A. S., Vaduganathan, M., et al. (2020) · ESC Heart Failure · doi:10.1002/ehf2.13122 · Cited by 13
An assessment of the reporting quality of randomised controlled trials relating to anti-arrhythmic agents (2002–2011)
Camm, C. F., Chen, Y., Sunderland, N. P., Nagendran, M., Maruthappu, M., & Camm, A. J. (2013) · International Journal of Cardiology · doi:10.1016/j.ijcard.2012.12.020 · Cited by 14
Telelactation Services and Breastfeeding by Race and Ethnicity
Uscher‐Pines, L., Kapinos, K. A., Waymouth, M., Howell, K., Alvarado, G., Ray, K. N., Demirci, J. R., Mehrotra, A., Rogers, R. C., James, K. F., et al. (2025) · JAMA Network Open · doi:10.1001/jamanetworkopen.2024.61958 · Cited by 13
Embellissement des données : fraude a minima, incompétence ou un mélange des deux
Séror, R., & Ravaud, P. (2012) · La Presse Médicale · doi:10.1016/j.lpm.2012.05.004 · Cited by 13
Heterogeneous treatment effects of a text messaging smoking cessation intervention among university students
Bendtsen, M. (2020) · PLoS ONE · doi:10.1371/journal.pone.0229637 · Cited by 13
Machine-learning approaches to predict individualized treatment effect using a randomized controlled trial
Hamaya, R., Hara, K., Manson, J. E., Rimm, E. B., Sacks, F. M., Xue, Q., Qi, L., & Cook, N. R. (2025) · European Journal of Epidemiology · doi:10.1007/s10654-024-01185-7 · Cited by 13
Research and scholarly methods: Subgroup analysis
Ding, Q., Wan, S., & Dowling, T. C. (2022) · JACCP JOURNAL OF THE AMERICAN COLLEGE OF CLINICAL PHARMACY · doi:10.1002/jac5.1611 · Cited by 11
Is regadenoson an appropriate stressor for MPI in patients with left bundle branch block or pacemakers?
Thomas, G. S., Kinser, C. R., Kristy, R. M., Xu, J., & Mahmarian, J. J. (2013) · Journal of Nuclear Cardiology · doi:10.1007/s12350-013-9802-3 · Cited by 11
High prevalence of potential biases threatens the interpretation of trials in patients with chronic disease
Vollenweider, D. J., Boyd, C. M., & Puhan, M. A. (2011) · BMC Medicine · doi:10.1186/1741-7015-9-73 · Cited by 11
A Comparison of Subgroup Analyses in Grant Applications and Publications
Boonacker, C. W., Hoes, A. W., van Liere-Visser, K., Schilder, A. G., & Rovers, M. M. (2011) · American Journal of Epidemiology · doi:10.1093/aje/kwr075 · Cited by 10
A systematic review of individual patient data meta-analyses on surgical interventions
Hannink, G., Gooszen, H. G., van Laarhoven, C. J. H. M., & Rovers, M. M. (2013) · Systematic Reviews · doi:10.1186/2046-4053-2-52 · Cited by 11
Metformin — a cardiovascular moderator of DPP4 inhibitors?
Scheen, A. J. (2017) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2017.154 · Cited by 10
Reporting of heterogeneity of treatment effect in cohort studies: a review of the literature
Dahan, M., Scemama, C., Porcher, R., & Biau, D. J. (2018) · BMC Medical Research Methodology · doi:10.1186/s12874-017-0466-6 · Cited by 10
Quantile Treatment Effect of Zinc Lozenges on Common Cold Duration: A Novel Approach to Analyze the Effect of Treatment on Illness Duration
Hemilä, H., Chalker, E., & Tukiainen, J. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.817522 · Cited by 10
Reporting characteristics of non-primary publications of results of randomized trials: a cross-sectional review
Hopewell, S., Collins, P. G. S., Hirst, A., Kirtley, S., Tajar, A., Gerry, S., & Altman, D. G. (2013) · Trials · doi:10.1186/1745-6215-14-240 · Cited by 9
Identifying patient subgroups who benefit most from a treatment: using administrative claims data to uncover treatment heterogeneity
Erder, M. H., Signorovitch, J., Setyawan, J., Yang, H., Parikh, K., Betts, K. A., Xie, J., Hodgkins, P., & Wu, E. Q. (2012) · Journal of Medical Economics · doi:10.3111/13696998.2012.689270 · Cited by 9
Subgroup Analyses of Randomized Clinical Trials in Heart Failure: Facts and Numbers
Vidic, A., Chibnall, J. T., Goparaju, N., & Hauptman, P. J. (2016) · ESC Heart Failure · doi:10.1002/ehf2.12093 · Cited by 9
Serelaxin: insights into its haemodynamic, biochemical, and clinical effects in acute heart failure
Hernández, A. V. (2013) · European Heart Journal · doi:10.1093/eurheartj/eht477 · Cited by 8
Self-citation
Designing Studies for Sex and Gender Analyses: How Research Can Derive Clinically Useful Knowledge for Women's Health
Klap, R. S., & Humphreys, K. N. (2019) · Women s Health Issues · doi:10.1016/j.whi.2019.05.002 · Cited by 7
Random Treatment Assignment Using Mathematical Equipoise for Comparative Effectiveness Trials
Selker, H. P., Ruthazer, R., Terrin, N. C., Griffith, J. L., Concannon, T. W., & Kent, D. M. (2011) · Clinical and Translational Science · doi:10.1111/j.1752-8062.2010.00253.x · Cited by 7
Oral diabetes medication monotherapy and short-term mortality in individuals with type 2 diabetes and coronary artery disease
Raghavan, S., Liu, W. G., Saxon, D. R., Grunwald, G. K., Maddox, T. M., Reusch, J. E. B., Berkowitz, S. A., & Caplan, L. (2018) · BMJ Open Diabetes Research & Care · doi:10.1136/bmjdrc-2018-000516 · Cited by 7
Exploration of the regional effects of colchicine in the LoDoCo2 trial
Budgeon, C. A., Nidorf, S. M., Mosterd, A., Fiolet, A. T. L., Eikelboom, J. W., O’Halloran, S., Joyce, D., Schut, A., Tijssen, J. G. P., Cornel, J. H., et al. (2024) · American Heart Journal · doi:10.1016/j.ahj.2024.09.006 · Cited by 6
Precision Medicine in Critical Illness: Sepsis and Acute Respiratory Distress Syndrome
Rogers, A. J., & Meyer, N. J. (2020) · Respiratory medicine · doi:10.1007/978-3-030-31507-8_18 · Cited by 7
Subgroup Analyses in Nephrology Clinical Trials
Fishbane, S. N., Shah, H. H., Kataria, A., Shirazian, S., & Agarwal, R. (2012) · Clinical Journal of the American Society of Nephrology · doi:10.2215/cjn.04870512 · Cited by 6
Preoperative Chemoradiotherapy for Esophageal Cancer
Power, D. G., O'Sulleabhain, C., & Murphy, T. J. (2012) · New England Journal of Medicine · doi:10.1056/nejmc1207702 · Cited by 6
Evaluation of reported claims of sex-based differences in treatment effects across meta-analyses: a meta-research study
Kastrati, L., Farina, S., Gris, A. V., Raeisi‐Dehkordi, H., Llanaj, E., Quezada‐Pinedo, H. G., Bally, L., Muka, T., & Ioannidis, J. P. A. (2025) · BMJ Evidence-Based Medicine · doi:10.1136/bmjebm-2024-113359 · Cited by 7
Unsupervised clustering approach to assess heterogeneity of treatment effects across patient phenotypes in randomized clinical trials
Bellavia, A., Ran, X., Zimerman, A., Antman, E. M., Giugliano, R. P., Morrow, D. A., & Murphy, S. A. (2024) · Contemporary Clinical Trials · doi:10.1016/j.cct.2024.107778 · Cited by 6
Subgroup analyses with special reference to the effect of antiplatelet agents in acute coronary syndromes
Aronson, D. (2014) · Thrombosis and Haemostasis · doi:10.1160/th13-09-0801 · Cited by 5
Randomized controlled trials versus rough set analysis: two competing approaches for evaluating clinical data
Rzepiński, T. (2014) · Metamedicine · doi:10.1007/s11017-014-9283-7 · Cited by 5
MS clinical trials: what can subgroup analyses teach us?
Rudick, R. A. (2012) · The Lancet Neurology · doi:10.1016/s1474-4422(12)70066-2 · Cited by 5
Clinical Trials of Heart Failure: Is There a Question of Sex?
Sohani, Z. N., Alyass, A., & Pilote, L. (2021) · Canadian Journal of Cardiology · doi:10.1016/j.cjca.2021.07.003 · Cited by 5
Systematic literature review of traits and outcomes reported in randomised controlled trials of asthma with regular dosing of inhaled corticosteroids with short-acting β2-agonist reliever, as-needed ICS/formoterol, or ICS/formoterol maintenance and reliever therapy
Roche, N., Yorgancıoğlu, A., Cruz, Á. A., García, G., Lavoie, K., Abhijith, P. G., Verma, M., Majumdar, A., & Chatterjee, S. (2023) · Respiratory Medicine · doi:10.1016/j.rmed.2023.107478 · Cited by 4
Key Changes in Benefit–Risk Assessment Guidelines and Implications for Data Analysis in Drug Development
Hammad, T. A., & Pinto, C. A. (2016) · Statistics in Biopharmaceutical Research · doi:10.1080/19466315.2016.1201001 · Cited by 4

Authors: Hernández, A. V., Boersma, E., Murray, G. D., Habbema, J. D. F., & Steyerberg, E. W.
Affiliations: Erasmus MC (NL)
University of Edinburgh (GB)
Corresponding author: Hernández, Adrián V.
ORCID: Hernández, Adrián V.
Boersma, Eric
Murray, Gordon D.
Steyerberg, Ewout W.
Venue: American Heart Journal
Publisher: Elsevier BV
Published: 2006-02
Volume: 151
Issue: 2
Pages: 257-264
ISSN: 0002-8703 (ISSN-L)
DOI: 10.1016/j.ahj.2005.04.020
OpenAlex: W1971141955
Cited by: 131
References: 99
Citations by year: 2026: 2 · 2025: 3 · 2024: 8 · 2023: 4 · 2022: 5 · 2021: 2 · 2020: 7 · 2019: 6 · 2018: 4 · 2017: 3 · 2016: 7 · 2015: 3 · 2014: 7 · 2013: 11 · 2012: 13
FWCI: 7.82
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: American Heart Journal (publishedVersion)
PubMed (publishedVersion)
EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
Topics: Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
Social Sciences › Decision Sciences › Statistics, Probability and Uncertainty › Meta-analysis and systematic reviews
Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Epidemiology
Keywords: subgroup analysis, cardiovascular clinical trials, interaction testing, trial reporting quality, CONSORT, sample size, treatment decision-making, publication bias
MeSH terms: Cardiovascular Diseases, Data Interpretation, Statistical, Decision Making, Humans, Randomized Controlled Trials as Topic, Treatment Outcome, Clinical Trials, Phase III as Topic, Sample Size

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Subgroup analyses in therapeutic cardiovascular clinical trials: Are most of them misleading?

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Citations

Cites

Cited by

Related

Metadata

Record

About these checks