Application and challenge of composite endpoints in clinical research_Chinese Journal of Evidence-Based Medicine

Authors：

WANG Xinyi ^1,2,3 , LONG Youlin ³ , FANG Ke ⁴ , YANG Jianlan ⁴ , LI Yao ⁴ , JIANG Zixuan ⁴ , ZHANG Na ² , WANG Xinyao ² , WAN Xingli ⁵ , GUO Qiong ⁶ , HUANG Jin ³ ,  LI Zhengchi ⁷ ,  DU Liang ^2,3

1. General Practice Medical Center, West China Hospital, Sichuan University, Chengdu 610041, P. R. China;
2. Chinese Evidence-based Medicine Center, West China Hospital, Sichuan University, Chengdu 610041, P. R. China;
3. Medical Device Regulatory Research and Evaluation Center, West China Hospital, Sichuan University, Chengdu 610041, P. R. China;
4. West China School of Public Health, Sichuan University, Chengdu 610041, P. R. China;
5. Nursing Department, West China Second University Hospital, Sichuan University/ Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu 610041, P. R. China;
6. West China Medical Publishers, West China Hospital, Sichuan University, Chengdu 610041, P. R. China;
7. CPC Committee Office, West China Hospital, Sichuan University, Chengdu 610041, P. R. China;

Corresponding author：

LI Zhengchi, Email: 603172078@qq.com; DU Liang, Email: duliang0606@vip.sina.com

Keywords：

Composite endpoints; Clinical trial; Advantage; Challenge

DOI：

10.7507/1672-2531.202311094

Video：

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The widespread application of composite endpoints in clinical research has afforded researchers a more comprehensive perspective, enabling a deeper understanding of intricate medical issues. Simultaneously, it effectively enhances the efficiency and efficacy of studies, thereby reducing the overall economic costs of research. A profound comprehension of the strengths and limitations of composite endpoints is crucial for their correct application and the accurate interpretation of results. This paper aims to introduce the recent advancements in the application of composite endpoints in clinical trials, discussing their advantages and limitations, and providing practical recommendations for their use. The intention is to offer guidance to researchers in understanding and managing composite endpoints effectively.

Citation： WANG Xinyi, LONG Youlin, FANG Ke, YANG Jianlan, LI Yao, JIANG Zixuan, ZHANG Na, WANG Xinyao, WAN Xingli, GUO Qiong, HUANG Jin, LI Zhengchi, DU Liang. Application and challenge of composite endpoints in clinical research. Chinese Journal of Evidence-Based Medicine, 2023, 23(12): 1465-1471. doi: 10.7507/1672-2531.202311094 Copy

1.	McCoy CE. Understanding the use of composite endpoints in clinical trials. West J Emerg Med, 2018, 19(4): 631-634.
2.	Guyatt GH, Rennie D. Users' guides to the medical literature. JAMA, 1993, 270(17): 2096-2097.
3.	Luborsky L, Mintz J, Auerbach A, et al. Predicting the outcome of psychotherapy. Findings of the Penn Psychotherapy Project. Arch Gen Psychiatry, 1980, 37(4): 471-481.
4.	Racenberg J, Intaglietta M, Messmer K. Effect of the vasoactive drug buflomedil in arterial occlusive disease. Fortschr Med, 1982, 100(41): 1926-1930.
5.	Simpson DD, Savage LJ. Client types in different drug abuse treatments: comparisons of follow-up outcomes. Am J Drug Alcohol Abuse, 1981, 8(4): 401-418.
6.	Hater JJ, Singh BK, Simpson DD. Influence of family and religion on long-term outcomes among opioid addicts. Adv Alcohol Subst Abuse, 1984, 4(1): 29-40.
7.	Ross G, Lipper E, Auld PA. Early predictors of neurodevelopmental outcome of very low-birthweight infants at three years. Dev Med Child Neurol, 1986, 28(2): 171-179.
8.	Hallstrom AP, Litwin PE, Weaver WD. A method of assigning scores to the components of a composite outcome: an example from the MITI trial. Control Clin Trials, 1992, 13(2): 148-155.
9.	Braunwald E, Cannon CP, Mccabe CH. Use of composite endpoints in thrombolysis trials of acute myocardial infarction. Am J Cardiol, 1993, 72(19): 3G-12G.
10.	Montori VM, Permanyer-Miralda G, Ferreira-González I, et al. Validity of composite end points in clinical trials. BMJ, 2005, 330(7491): 594-596.
11.	彭菊聪, 孙甜甜, 李伦, 等. 复合终点. 中国循证儿科杂志, 2012, 7(4): 305-307.
12.	Phillips A, Haudiquet V. ICH E9 guideline 'statistical principles for clinical trials': a case study. Stat Med, 2003, 22(1): 1-11.
13.	Terheyden JH, Schmitz-Valckenberg S, Crabb DP, et al. Use of composite end points in early and intermediate age-related macular degeneration clinical trials: state-of-the-art and future directions. Ophthalmologica, 2021, 244(5): 387-395.
14.	Shaikh A, Ochani RK, Khan MS, et al. Contribution of individual components to composite end points in contemporary cardiovascular randomized controlled trials. Am Heart J, 2020, 230: 71-81.
15.	Ferreira JP, Kraus BJ, Zwiener I, et al. Cardio/kidney composite end points: a post hoc analysis of the EMPA-REG OUTCOME trial. J Am Heart Assoc, 2021, 10(7): e020053.
16.	Lozano I, Perez de Prado A, Quiros A. Letter: Composite endpoints in clinical trials - simplicity or perfection. EuroIntervention, 2022, 17(13): 1120.
17.	Freemantle N, Calvert M, Wood J, et al. Composite outcomes in randomized trials: greater precision but with greater uncertainty. JAMA, 2003, 289(19): 2554-2559.
18.	Myles PS, Devereaux PJ. Pros and cons of composite endpoints in anesthesia trials. Anesthesiology, 2010, 113(4): 776-778.
19.	Busse WW, Morgan WJ, Taggart V, et al. Asthma outcomes workshop: overview. J Allergy Clin Immunol, 2012, 129(3 Suppl): S1-S8.
20.	D'Haens GR, Fedorak R, Lémann M, et al. Endpoints for clinical trials evaluating disease modification and structural damage in adults with Crohn's disease. Inflamm Bowel Dis, 2009, 15(10): 1599-1604.
21.	Roig MB, Melis GG, Posch M, et al. Adaptive clinical trial designs with blinded selection of binary composite endpoints and sample size reassessment. Biostatistics, 2022, 2022: kxac040.
22.	Goldberg R, Gore JM, Barton B, et al. Individual and composite study endpoints: separating the wheat from the chaff. Am J Med, 2014, 127(5): 379-384.
23.	Leon MB, Teirstein PS, Moses JW, et al. Localized intracoronary gamma-radiation therapy to inhibit the recurrence of restenosis after stenting. N Engl J Med, 2001, 344(4): 250-256.
24.	Ferreira-González I, Busse JW, Heels-Ansdell D, et al. Problems with use of composite end points in cardiovascular trials: systematic review of randomised controlled trials. BMJ, 2007, 334(7597): 786.
25.	Jacobsen FM, Kvorning Ternov K, Nolsøe AB, et al. Interpretation of composite endpoints in urology: an analysis of citation quality. Scand J Urol, 2022, 56(3): 206-212.
26.	Waksman R, Ajani AE, White RL, et al. Intravascular gamma radiation for in-stent restenosis in saphenous-vein bypass grafts. N Engl J Med, 2002, 346(16): 1194-1199.
27.	Khan MS, Bakris GL, Packer M, et al. Kidney function assessment and endpoint ascertainment in clinical trials. Eur Heart J, 2022, 43(14): 1379-1400.
28.	Cordoba G, Schwartz L, Woloshin S, et al. Definition, reporting, and interpretation of composite outcomes in clinical trials: systematic review. BMJ, 2010, 341: c3920.
29.	Marx N, McGuire DK, Perkovic V, et al. Composite primary end points in cardiovascular outcomes trials involving type 2 diabetes patients: should unstable angina be included in the primary end point. Diabetes Care, 2017, 40(9): 1144-1151.
30.	McMenamin ME, Barrett JK, Berglind A, et al. Sample size estimation using a latent variable model for mixed outcome co-primary, multiple primary and composite endpoints. Stat Med, 2022, 41(13): 2303-2316.
31.	Dash K, Goodacre S, Sutton L. Composite outcomes in clinical prediction modeling: are we trying to predict apples and oranges. Ann Emerg Med, 2022, 80(1): 12-19.
32.	Ferreira-González I, Permanyer-Miralda G, Busse JW, et al. Methodologic discussions for using and interpreting composite endpoints are limited, but still identify major concerns. J Clin Epidemiol, 2007, 60(7): 651-657.
33.	Ozga AK, Rauch G. Weighted composite time to event endpoints with recurrent events: comparison of three analytical approaches. BMC Med Res Methodol, 2022, 22(1): 38.
34.	张义涵. 复发和终末事件的复合终点研究. 上海: 华东师范大学, 2022.
35.	Cortés Martínez J, Geskus RB, Kim K, et al. Using the geometric average hazard ratio in sample size calculation for time-to-event data with composite endpoints. BMC Med Res Methodol, 2021, 21(1): 99.
36.	Marsal JR, Urreta-Barallobre I, Ubeda-Carrillo M, et al. Sample size requirement in trials that use the composite endpoint major adverse cardiovascular events (MACE): new insights. Trials, 2022, 23(1): 1037.
37.	Packer M. Development and evolution of a hierarchical clinical composite end point for the evaluation of drugs and devices for acute and chronic heart failure: a 20-year perspective. Circulation, 2016, 134(21): 1664-1678.
38.	郭正梅, 姚晨, 阎小妍. 临床试验复合终点评价指标的构建方法概述. 中国新药杂志, 2013, 22(23): 2789-2796, 2830.
39.	Braunwald E, Cannon CP, McCabe CH. An approach to evaluating thrombolytic therapy in acute myocardial infarction. The 'unsatisfactory outcome' end point. Circulation, 1992, 86(2): 683-687.
40.	Freemantle N, Calvert M. Composite and surrogate outcomes in randomised controlled trials. BMJ, 2007, 334(7597): 756-757.
41.	Armstrong PW, Westerhout CM, Van de Werf F, et al. Refining clinical trial composite outcomes: an application to the assessment of the safety and efficacy of a new thrombolytic-3 (ASSENT-3) trial. Am Heart J, 2011, 161(5): 848-854.
42.	Udogwu UN, Howe A, Frey K, et al. A patient-centered composite endpoint weighting technique for orthopaedic trauma research. BMC Med Res Methodol, 2019, 19(1): 242.
43.	Nabipoor M, Westerhout CM, Rathwell S, et al. The empirical estimate of the survival and variance using a weighted composite endpoint. BMC Med Res Methodol, 2023, 23(1): 35.
44.	Sun X, Ding J, Sun L. A semiparametric additive rates model for the weighted composite endpoint of recurrent and terminal events. Lifetime Data Anal, 2020, 26(3): 471-492.
45.	Baraniuk S, Seay R, Sinha AK, et al. Comparison of the global statistical test and composite outcome for secondary analyses of multiple coronary heart disease outcomes. Prog Cardiovasc Dis, 2012, 54(4): 357-361.
46.	Pocock SJ, Ariti CA, Collier TJ, et al. The win ratio: a new approach to the analysis of composite endpoints in clinical trials based on clinical priorities. Eur Heart J, 2012, 33(2): 176-182.
47.	Hara H, van Klaveren D, Kogame N, et al. Statistical methods for composite endpoints. EuroIntervention, 2021, 16(18): e1484-e1495.
48.	Peng L. The use of the win odds in the design of non-inferiority clinical trials. J Biopharm Stat, 2020, 30(5): 941-946.
49.	Redfors B, Gregson J, Crowley A, et al. The win ratio approach for composite endpoints: practical guidance based on previous experience. Eur Heart J, 2020, 41(46): 4391-4399.
50.	Hara H, Onuma Y, Serruys PW. Reply: Composite endpoints in clinical trials - simplicity or perfection. EuroIntervention, 2022, 17(13): 1121-1122.
51.	Yu RX, Ganju J. Sample size formula for a win ratio endpoint. Stat Med, 2022, 41(6): 950-963.
52.	Ferreira JP, Jhund PS, Duarte K, et al. Use of the win ratio in cardiovascular trials. JACC Heart Fail, 2020, 8(6): 441-450.
53.	Mao L, Wang T. A class of proportional win-fractions regression models for composite outcomes. Biometrics, 2021, 77(4): 1265-1275.
54.	闫俊红, 杨紫荆, 侯雅文, 等. 基于赢率分析临床复合终点的统计方法. 中国卫生统计, 2019, 36(4): 497-501.
55.	Kristensen AMD, Pareek M, Kragholm KH, et al. Unstable angina as a component of primary composite endpoints in clinical cardiovascular trials: pros and cons. Cardiology, 2022, 147(3): 235-247.
56.	Armstrong PW, Westerhout CM. Composite end points in clinical research: a time for reappraisal. Circulation, 2017, 135(23): 2299-2307.
57.	Pham TM, White IR, Kahan BC, et al. A comparison of methods for analyzing a binary composite endpoint with partially observed components in randomized controlled trials. Stat Med, 2021, 40(29): 6634-6650.
58.	Lubsen J, Kirwan BA. Combined endpoints: can we use them. Stat Med, 2002, 21(19): 2959-2970.
59.	Wang B, Zhou D, Zhang J, et al. Statistical power considerations in the use of win ratio in cardiovascular outcome trials. Contemp Clin Trials, 2023, 124: 107040.

1. McCoy CE. Understanding the use of composite endpoints in clinical trials. West J Emerg Med, 2018, 19(4): 631-634.
2. Guyatt GH, Rennie D. Users' guides to the medical literature. JAMA, 1993, 270(17): 2096-2097.
3. Luborsky L, Mintz J, Auerbach A, et al. Predicting the outcome of psychotherapy. Findings of the Penn Psychotherapy Project. Arch Gen Psychiatry, 1980, 37(4): 471-481.
4. Racenberg J, Intaglietta M, Messmer K. Effect of the vasoactive drug buflomedil in arterial occlusive disease. Fortschr Med, 1982, 100(41): 1926-1930.
5. Simpson DD, Savage LJ. Client types in different drug abuse treatments: comparisons of follow-up outcomes. Am J Drug Alcohol Abuse, 1981, 8(4): 401-418.
6. Hater JJ, Singh BK, Simpson DD. Influence of family and religion on long-term outcomes among opioid addicts. Adv Alcohol Subst Abuse, 1984, 4(1): 29-40.
7. Ross G, Lipper E, Auld PA. Early predictors of neurodevelopmental outcome of very low-birthweight infants at three years. Dev Med Child Neurol, 1986, 28(2): 171-179.
8. Hallstrom AP, Litwin PE, Weaver WD. A method of assigning scores to the components of a composite outcome: an example from the MITI trial. Control Clin Trials, 1992, 13(2): 148-155.
9. Braunwald E, Cannon CP, Mccabe CH. Use of composite endpoints in thrombolysis trials of acute myocardial infarction. Am J Cardiol, 1993, 72(19): 3G-12G.
10. Montori VM, Permanyer-Miralda G, Ferreira-González I, et al. Validity of composite end points in clinical trials. BMJ, 2005, 330(7491): 594-596.
11. 彭菊聪, 孙甜甜, 李伦, 等. 复合终点. 中国循证儿科杂志, 2012, 7(4): 305-307.
12. Phillips A, Haudiquet V. ICH E9 guideline 'statistical principles for clinical trials': a case study. Stat Med, 2003, 22(1): 1-11.
13. Terheyden JH, Schmitz-Valckenberg S, Crabb DP, et al. Use of composite end points in early and intermediate age-related macular degeneration clinical trials: state-of-the-art and future directions. Ophthalmologica, 2021, 244(5): 387-395.
14. Shaikh A, Ochani RK, Khan MS, et al. Contribution of individual components to composite end points in contemporary cardiovascular randomized controlled trials. Am Heart J, 2020, 230: 71-81.
15. Ferreira JP, Kraus BJ, Zwiener I, et al. Cardio/kidney composite end points: a post hoc analysis of the EMPA-REG OUTCOME trial. J Am Heart Assoc, 2021, 10(7): e020053.
16. Lozano I, Perez de Prado A, Quiros A. Letter: Composite endpoints in clinical trials - simplicity or perfection. EuroIntervention, 2022, 17(13): 1120.
17. Freemantle N, Calvert M, Wood J, et al. Composite outcomes in randomized trials: greater precision but with greater uncertainty. JAMA, 2003, 289(19): 2554-2559.
18. Myles PS, Devereaux PJ. Pros and cons of composite endpoints in anesthesia trials. Anesthesiology, 2010, 113(4): 776-778.
19. Busse WW, Morgan WJ, Taggart V, et al. Asthma outcomes workshop: overview. J Allergy Clin Immunol, 2012, 129(3 Suppl): S1-S8.
20. D'Haens GR, Fedorak R, Lémann M, et al. Endpoints for clinical trials evaluating disease modification and structural damage in adults with Crohn's disease. Inflamm Bowel Dis, 2009, 15(10): 1599-1604.
21. Roig MB, Melis GG, Posch M, et al. Adaptive clinical trial designs with blinded selection of binary composite endpoints and sample size reassessment. Biostatistics, 2022, 2022: kxac040.
22. Goldberg R, Gore JM, Barton B, et al. Individual and composite study endpoints: separating the wheat from the chaff. Am J Med, 2014, 127(5): 379-384.
23. Leon MB, Teirstein PS, Moses JW, et al. Localized intracoronary gamma-radiation therapy to inhibit the recurrence of restenosis after stenting. N Engl J Med, 2001, 344(4): 250-256.
24. Ferreira-González I, Busse JW, Heels-Ansdell D, et al. Problems with use of composite end points in cardiovascular trials: systematic review of randomised controlled trials. BMJ, 2007, 334(7597): 786.
25. Jacobsen FM, Kvorning Ternov K, Nolsøe AB, et al. Interpretation of composite endpoints in urology: an analysis of citation quality. Scand J Urol, 2022, 56(3): 206-212.
26. Waksman R, Ajani AE, White RL, et al. Intravascular gamma radiation for in-stent restenosis in saphenous-vein bypass grafts. N Engl J Med, 2002, 346(16): 1194-1199.
27. Khan MS, Bakris GL, Packer M, et al. Kidney function assessment and endpoint ascertainment in clinical trials. Eur Heart J, 2022, 43(14): 1379-1400.
28. Cordoba G, Schwartz L, Woloshin S, et al. Definition, reporting, and interpretation of composite outcomes in clinical trials: systematic review. BMJ, 2010, 341: c3920.
29. Marx N, McGuire DK, Perkovic V, et al. Composite primary end points in cardiovascular outcomes trials involving type 2 diabetes patients: should unstable angina be included in the primary end point. Diabetes Care, 2017, 40(9): 1144-1151.
30. McMenamin ME, Barrett JK, Berglind A, et al. Sample size estimation using a latent variable model for mixed outcome co-primary, multiple primary and composite endpoints. Stat Med, 2022, 41(13): 2303-2316.
31. Dash K, Goodacre S, Sutton L. Composite outcomes in clinical prediction modeling: are we trying to predict apples and oranges. Ann Emerg Med, 2022, 80(1): 12-19.
32. Ferreira-González I, Permanyer-Miralda G, Busse JW, et al. Methodologic discussions for using and interpreting composite endpoints are limited, but still identify major concerns. J Clin Epidemiol, 2007, 60(7): 651-657.
33. Ozga AK, Rauch G. Weighted composite time to event endpoints with recurrent events: comparison of three analytical approaches. BMC Med Res Methodol, 2022, 22(1): 38.
34. 张义涵. 复发和终末事件的复合终点研究. 上海: 华东师范大学, 2022.
35. Cortés Martínez J, Geskus RB, Kim K, et al. Using the geometric average hazard ratio in sample size calculation for time-to-event data with composite endpoints. BMC Med Res Methodol, 2021, 21(1): 99.
36. Marsal JR, Urreta-Barallobre I, Ubeda-Carrillo M, et al. Sample size requirement in trials that use the composite endpoint major adverse cardiovascular events (MACE): new insights. Trials, 2022, 23(1): 1037.
37. Packer M. Development and evolution of a hierarchical clinical composite end point for the evaluation of drugs and devices for acute and chronic heart failure: a 20-year perspective. Circulation, 2016, 134(21): 1664-1678.
38. 郭正梅, 姚晨, 阎小妍. 临床试验复合终点评价指标的构建方法概述. 中国新药杂志, 2013, 22(23): 2789-2796, 2830.
39. Braunwald E, Cannon CP, McCabe CH. An approach to evaluating thrombolytic therapy in acute myocardial infarction. The 'unsatisfactory outcome' end point. Circulation, 1992, 86(2): 683-687.
40. Freemantle N, Calvert M. Composite and surrogate outcomes in randomised controlled trials. BMJ, 2007, 334(7597): 756-757.
41. Armstrong PW, Westerhout CM, Van de Werf F, et al. Refining clinical trial composite outcomes: an application to the assessment of the safety and efficacy of a new thrombolytic-3 (ASSENT-3) trial. Am Heart J, 2011, 161(5): 848-854.
42. Udogwu UN, Howe A, Frey K, et al. A patient-centered composite endpoint weighting technique for orthopaedic trauma research. BMC Med Res Methodol, 2019, 19(1): 242.
43. Nabipoor M, Westerhout CM, Rathwell S, et al. The empirical estimate of the survival and variance using a weighted composite endpoint. BMC Med Res Methodol, 2023, 23(1): 35.
44. Sun X, Ding J, Sun L. A semiparametric additive rates model for the weighted composite endpoint of recurrent and terminal events. Lifetime Data Anal, 2020, 26(3): 471-492.
45. Baraniuk S, Seay R, Sinha AK, et al. Comparison of the global statistical test and composite outcome for secondary analyses of multiple coronary heart disease outcomes. Prog Cardiovasc Dis, 2012, 54(4): 357-361.
46. Pocock SJ, Ariti CA, Collier TJ, et al. The win ratio: a new approach to the analysis of composite endpoints in clinical trials based on clinical priorities. Eur Heart J, 2012, 33(2): 176-182.
47. Hara H, van Klaveren D, Kogame N, et al. Statistical methods for composite endpoints. EuroIntervention, 2021, 16(18): e1484-e1495.
48. Peng L. The use of the win odds in the design of non-inferiority clinical trials. J Biopharm Stat, 2020, 30(5): 941-946.
49. Redfors B, Gregson J, Crowley A, et al. The win ratio approach for composite endpoints: practical guidance based on previous experience. Eur Heart J, 2020, 41(46): 4391-4399.
50. Hara H, Onuma Y, Serruys PW. Reply: Composite endpoints in clinical trials - simplicity or perfection. EuroIntervention, 2022, 17(13): 1121-1122.
51. Yu RX, Ganju J. Sample size formula for a win ratio endpoint. Stat Med, 2022, 41(6): 950-963.
52. Ferreira JP, Jhund PS, Duarte K, et al. Use of the win ratio in cardiovascular trials. JACC Heart Fail, 2020, 8(6): 441-450.
53. Mao L, Wang T. A class of proportional win-fractions regression models for composite outcomes. Biometrics, 2021, 77(4): 1265-1275.
54. 闫俊红, 杨紫荆, 侯雅文, 等. 基于赢率分析临床复合终点的统计方法. 中国卫生统计, 2019, 36(4): 497-501.
55. Kristensen AMD, Pareek M, Kragholm KH, et al. Unstable angina as a component of primary composite endpoints in clinical cardiovascular trials: pros and cons. Cardiology, 2022, 147(3): 235-247.
56. Armstrong PW, Westerhout CM. Composite end points in clinical research: a time for reappraisal. Circulation, 2017, 135(23): 2299-2307.
57. Pham TM, White IR, Kahan BC, et al. A comparison of methods for analyzing a binary composite endpoint with partially observed components in randomized controlled trials. Stat Med, 2021, 40(29): 6634-6650.
58. Lubsen J, Kirwan BA. Combined endpoints: can we use them. Stat Med, 2002, 21(19): 2959-2970.
59. Wang B, Zhou D, Zhang J, et al. Statistical power considerations in the use of win ratio in cardiovascular outcome trials. Contemp Clin Trials, 2023, 124: 107040.

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