Subgroup analyses with special reference to the effect of antiplatelet agents in acute coronary syndromes

Summary

Controlled trials estimate treatment effects averaged over the reference population of subjects. However, physicians are interested in whether the treatment effect varies across subgroups (effect heterogeneity) in order to target specific subgroups to maximise the benefit of treatment and minimise harm. Therefore, large clinical trials of antiplatelet agents include subgroup analyses that examine whether treatment effects differ between subgroups of subjects identified by baseline characteristics. Reporting subgroup is pervasive and often accompanied by claims of difference of treatment effects between subgroups with potential important implications for clinical practice. However, subgroup-specific analyses of clinical trial data have inherent limitations that reduce their reliability. These include reduced statistical power, failure to specify the subgroups of interest a priori, failure to account for examining large numbers of subgroups, lack of strong rationale for biological response modification, and performing analyses based on variables measured post randomisation or in trials showing no overall difference between treatments. Rules for interpretation of subgroup findings in subgroups have been suggested but are frequently not applied. In this article we draw attention to the pitfalls of subgroup analyses in the context of recent trials of antiplatelet agents.

Keywords

Clinical trials - effect modification - interaction - prasugrel - statistics - subgroup analysis - ticagrelor

• References

• 1 Kent DM, Rothwell PM, Ioannidis JP. et al. Assessing and reporting heterogeneity in treatment effects in clinical trials: a proposal. Trials 2010; 11: 85.
• 2 Altman DG, Matthews JN. Statistics notes. Interaction 1: Heterogeneity of effects. Br Med J 1996; 313: 486.
• 3 Kravitz RL, Duan N, Braslow J. Evidence-based medicine, heterogeneity of treatment effects, and the trouble with averages. Milbank Q 2004; 82: 661-687.
• 4 Groenwold RH, Donders AR, van der Heijden GJ. et al. Confounding of subgroup analyses in randomized data. Arch Intern Med 2009; 169: 1532-1534.
• 5 Cui L, Hung HM, Wang SJ. et al. Issues related to subgroup analysis in clinical trials. J Biopharm Stat 2002; 12: 347-358.
• 6 Hernandez AV, Boersma E, Murray GD. et al. Subgroup analyses in therapeutic cardiovascular clinical trials: are most of them misleading?. Am Heart J 2006; 151: 257-264.
• 7 Oxman AD. Subgroup analyses. Br Med J 2012; 344: e2022.
• 8 Yusuf S, Wittes J, Probstfield J. et al. Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials. J Am Med Assoc 1991; 266: 93-98.
• 9 Pocock SJ, Hughes MD, Lee RJ. Statistical problems in the reporting of clinical trials. A survey of three medical journals. N Engl J Med 1987; 317: 426-432.
• 10 Assmann SF, Pocock SJ, Enos LE. et al. Subgroup analysis and other (mis)uses of baseline data in clinical trials. Lancet 2000; 355: 1064-1069.
• 11 Bulpitt CJ. Subgroup analysis. Lancet 1988; 02: 31-34.
• 12 Rothwell PM. Treating individuals 2. Subgroup analysis in randomised controlled trials: importance, indications, and interpretation. Lancet 2005; 365: 176-186.
• 13 Tukey JW. Some thoughts on clinical trials, especially problems of multiplicity. Science 1977; 198: 679-684.
• 14 Wang R, Lagakos SW, Ware JH. et al. Statistics in medicine--reporting of subgroup analyses in clinical trials. N Engl J Med 2007; 357: 2189-2194.
• 15 Lagakos SW. The challenge of subgroup analyses--reporting without distorting. N Engl J Med 2006; 354: 1667-1669.
• 16 Adams Jr KF. Post hoc subgroup analysis and the truth of a clinical trial. Am Heart J 1998; 136: 753-758.
• 17 Pocock SJ, Assmann SE, Enos LE. et al. Subgroup analysis, covariate adjustment and baseline comparisons in clinical trial reporting: current practice and problems. Stat Med 2002; 21: 2917-2930.
• 18 Sleight P. Debate: Subgroup analyses in clinical trials: fun to look at - but don't believe them!. Curr Control Trials Cardiovasc Med 2000; 01: 25-27.
• 19 DeMets DL, Califf RM. Lessons learned from recent cardiovascular clinical trials: Part I. Circulation 2002; 106: 746-751.
• 20 Peto R. Current misconception 3: that subgroup-specific trial mortality results often provide a good basis for individualising patient care. Br J Cancer 2011; 104: 1057-1058.
• 21 Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet 1988; 02: 349-360.
• 22 Wedel H, Demets D, Deedwania P. et al. Challenges of subgroup analyses in multinational clinical trials: experiences from the MERIT-HF trial. Am Heart J 2001; 142: 502-511.
• 23 Montalescot G, Wiviott SD, Braunwald E. et al. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet 2009; 373: 723-731.
• 24 Cuzick J. Forest plots and the interpretation of subgroups. Lancet 2005; 365: 1308.
• 25 Pocock S, Travison T, Wruck L. Figures in clinical trial reports: current practice & scope for improvement. Trials 2007; 08: 36.
• 26 Lewis S, Clarke M. Forest plots: trying to see the wood and the trees. Br Med J 2001; 322: 1479-1480.
• 27 Parker AB, Naylor CD. Subgroups, treatment effects, and baseline risks: some lessons from major cardiovascular trials. Am Heart J 2000; 139: 952-961.
• 28 Wallentin L, Becker RC, Budaj A. et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361: 1045-1057.
• 29 Poulson RS, Gadbury GL, Allison DB. Treatment Heterogeneity and Individual Qualitative Interaction. Am Stat 2012; 66: 16-24.
• 30 Greenfield S, Kravitz R, Duan N. et al. Heterogeneity of treatment effects: implications for guidelines, payment, and quality assessment. Am J Med 2007; 120: S3-9.
• 31 Sormani MP, Bruzzi P. Reporting of subgroup analyses from clinical trials. Lancet Neurol 2012; 11: 747 author reply -748
• 32 Altman D, Schulz K, Moher D. The revised CONSORT statement for reporting randomized trials: explanation and elaboration. Ann Inter Med 2001; 134: 663-694.
• 33 Fletcher J. Subgroup analyses: how to avoid being misled. Br Med J 2007; 335: 96-97.
• 34 Altman DG, Bland JM. Interaction revisited: the difference between two estimates. Br Med J 2003; 326: 219.
• 35 Califf RM, DeMets DL. Principles from clinical trials relevant to clinical practice: Part I. Circulation 2002; 106: 1015-1021.
• 36 Montori V, Jaeschke R, Schunemann H. Users' guide to detecting misleading claims in clinical research reports. Br Med J 2004; 329: 1093-1096.
• 37 Sun X, Briel M, Busse JW. et al. Credibility of claims of subgroup effects in randomised controlled trials: systematic review. Br Med J 2012; 344: e1553.
• 38 Gail M, Simon R. Testing for qualitative interactions between treatment effects and patient subsets. Biometrics 1985; 41: 361-372.
• 39 Sun X, Briel M, Walter SD. et al. Is a subgroup effect believable? Updating criteria to evaluate the credibility of subgroup analyses. Br Med J 2010; 340: c117.
• 40 Senn S, Harrell F. On wisdom after the event. J Clin Epidemiol 1997; 50: 749-751.
• 41 Wiviott SD, Braunwald E, McCabe CH. et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001-2015.
• 42 Brookes S, Whitley E, Peters T. et al. Subgroup analyses in randomised controlled trials: quantifying the risks of false-positives and false-negatives. Health Technol Assess 2001; 05: 56.
• 43 Pocock S, Hughes M, Lee R. Statistical problems in the reporting of clinical trials. A survey of three medical journals. N Engl J Med 1987; 317: 426-432.
• 44 Brookes ST, Whitely E, Egger M. et al. Subgroup analyses in randomized trials: risks of subgroup-specific analyses; power and sample size for the interaction test. J Clin Epidemiol 2004; 57: 229-236.
• 45 Wiviott SD, Braunwald E, Angiolillo DJ. et al. Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-Thrombolysis in Myocardial Infarction 38. Circulation 2008; 118: 1626-1636.
• 46 Wiviott SD, White HD, Ohman EM. et al. Prasugrel versus clopidogrel for patients with unstable angina or non-ST-segment elevation myocardial infarction with or without angiography: a secondary, prespecified analysis of the TRILOGY ACS trial. Lancet 2013; 382: 605-613.
• 47 Oxman AD, Guyatt GH. A consumer's guide to subgroup analyses. Ann Intern Med 1992; 116: 78-84.
• 48 Moher D, Hopewell S, Schulz KF. et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. Br Med J 2010; 340: c869.
• 49 Schulz KF, Grimes DA. Multiplicity in randomised trials II: subgroup and interim analyses. Lancet 2005; 365: 1657-1661.
• 50 Schulz KF, Grimes DA. Multiplicity in randomised trials I: endpoints and treatments. Lancet 2005; 365: 1591-1595.
• 51 Lee KL, McNeer JF, Starmer CF. et al. Clinical judgment and statistics. Lessons from a simulated randomized trial in coronary artery disease. Circulation 1980; 61: 508-515.
• 52 Cook DI, Gebski VJ, Keech AC. Subgroup analysis in clinical trials. Med J Aust 2004; 180: 289-291.
• 53 Barrett-Connor E. Looking for the pony in the HERS data. Heart and Estrogen/ progestin Replacement Study. Circulation 2002; 105: 902-903.
• 54 Bhatt DL, Fox KA, Hacke W. et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006; 354: 1706-1717.
• 55 Stallones RA. The use and abuse of subgroup analysis in epidemiological research. Prev Med 1987; 16: 183-194.
• 56 Smith PK, Goodnough LT, Levy JH. et al. Mortality benefit with prasugrel in the TRITON-TIMI 38 coronary artery bypass grafting cohort: risk-adjusted retrospective data analysis. J Am Coll Cardiol 2012; 60: 388-396.
• 57 Cannon CP, Harrington RA, James S. et al. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study. Lancet 2010; 375: 283-293.
• 58 James SK, Roe MT, Cannon CP. et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial. Br Med J 2011; 342: d3527.
• 59 Ferreiro JL, Angiolillo DJ. Diabetes and antiplatelet therapy in acute coronary syndrome. Circulation 2011; 123: 798-813.
• 60 Pfeffer MA, Jarcho JA. The charisma of subgroups and the subgroups of CHARISMA. N Engl J Med 2006; 354: 1744-1746.
• 61 Freemantle N. Interpreting the results of secondary end points and subgroup analyses in clinical trials: should we lock the crazy aunt in the attic?. Br Med J 2001; 322: 989-991.
• 62 Guyatt G, Wyer P, Ioannidis J. When to Believe a Subgroup Analysis. User's Guide to the Medical Literature: A Manual for Evidence-Based Clinical Practice 2008; 571-583.
• 63 Roffi M, Chew DP, Mukherjee D. et al. Platelet glycoprotein IIb/IIIa inhibitors reduce mortality in diabetic patients with non-ST-segment-elevation acute coronary syndromes. Circulation 2001; 104: 2767-2771.
• 64 Mehilli J, Kastrati A, Schuhlen H. et al. Randomized clinical trial of abciximab in diabetic patients undergoing elective percutaneous coronary interventions after treatment with a high loading dose of clopidogrel. Circulation 2004; 110: 3627-3635.
• 65 Kastrati A, Mehilli J, Neumann FJ. et al. Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial. J Am Med Assoc 2006; 295: 1531-1538.
• 66 Mahaffey KW, Wojdyla DM, Carroll K. et al. Ticagrelor compared with clopidogrel by geographic region in the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation 2011; 124: 544-554.
• 67 Ohman EM, Roe MT. Explaining the unexpected: insights from the PLATelet inhibition and clinical Outcomes (PLATO) trial comparing ticagrelor and clopidogrel. Editorial on Serebruany “Viewpoint: Paradoxical excess mortality in the PLATO trial should be independently verified” (Thromb Haemost 2011; 105.5). Thromb Haemost 2011; 105: 763-765.
• 68 Ware JH. The National Emphysema Treatment Trial--how strong is the evidence?. N Engl J Med 2003; 348: 2055-2056.
• 69 Altman DG. Within trial variation--a false trail?. J Clin Epidemiol 1998; 51: 301-303.
• 70 Sun X, Briel M, Busse JW. et al. The influence of study characteristics on reporting of subgroup analyses in randomised controlled trials: systematic review. Br Med J 2011; 342: d1569.
• 71 Counsell CE, Clarke MJ, Slattery J. et al. The miracle of DICE therapy for acute stroke: fact or fictional product of subgroup analysis?. Br Med J 1994; 309: 1677-1681.
• 72 Roe MT, Armstrong PW, Fox KA. et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularisation. N Engl J Med 2012; 367: 1297-1309.
• 73 Gurbel PA, Erlinge D, Ohman EM. et al. Platelet Function During Extended Prasugrel and Clopidogrel Therapy for Patients With ACS Treated Without Revascularisation: The TRILOGY ACS Platelet Function Substudy. J Am Med Assoc 2012; 1-10.
• 74 Aradi D, Komocsi A, Vorobcsuk A. et al. Impact of clopidogrel and potent P2Y 12 -inhibitors on mortality and stroke in patients with acute coronary syndrome or undergoing percutaneous coronary intervention: a systematic review and meta-analysis. Thromb Haemost 2013; 109: 93-101.
• 75 U.S. Department of Health and Human Services. Food and Drug Administration. Guidance for Industry: Collection of Race and Ethnicity Data in Clinical Trials. 2005 Available from: http://www.fda.gov/downloads/Guidances/ucm126396.pdf
• 76 Pocock S, Calvo G, Marrugat J. et al. International differences in treatment effect: do they really exist and why?. Eur Heart J 2013; 34: 1846-1852.
• 77 Wallentin L, James S, Storey RF. et al. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet 2010; 376: 1320-1328.
• 78 Pocock SJ, Lubsen J. More on subgroup analyses in clinical trials. N Engl J Med 2008; 358: 2076.
• 79 Kent DM, Lindenauer PK. Aggregating and disaggregating patients in clinical trials and their subgroup analyses. Ann Intern Med 2010; 153: 51-52.
• 80 Rothwell PM, Mehta Z, Howard SC. et al. Treating individuals 3: from subgroups to individuals: general principles and the example of carotid endarterectomy. Lancet 2005; 365: 256-265.
• 81 Rothwell PM. Can overall results of clinical trials be applied to all patients?. Lancet 1995; 345: 1616-1619.
• 82 Mehta SR, Bassand JP, Chrolavicius S. et al. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med 2010; 363: 930-942.
• 83 James S, Angiolillo DJ, Cornel JH. et al. Ticagrelor vs. clopidogrel in patients with acute coronary syndromes and diabetes: a substudy from the PLATelet inhibition and patient Outcomes (PLATO) trial. Eur Heart J 2010; 31: 3006-3016.
• 84 Bhatt DL, Stone GW, Mahaffey KW. et al. Effect of platelet inhibition with cangrelor during PCI on ischaemic events. N Engl J Med 2013; 368: 1303-1313.
• 85 Morrow DA, Braunwald E, Bonaca MP. et al. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med 2012; 366: 1404-1413.
• 86 Tricoci P, Huang Z, Held C. et al. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N Engl J Med 2012; 366: 20-33.
• 87 Montalescot G, Bolognese L, Dudek D. et al. Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes. N Engl J Med 2013; 369: 999-1010.
• 88 Mehta SR, Yusuf S, Peters RJ. et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358: 527-533.
• 89 Yusuf S, Zhao F, Mehta SR. et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494-502.
• 90 Hernandez A, Boersma E, Murray G. Subgroup analyses in therapeutic cardiovascular clinical trials: are most of them misleading?. Am Heart J 2006; 151: 257-264.
• 91 Sun X, Briel M, Busse JW. et al. 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. Trials 2009; 10: 101.
• 92 Browner WS, Hulley SB. Effect of risk status on treatment criteria. Implications of hypertension trials. Hypertension 1989; 13: I51-56.