Characteristics and threshold setting of non-inferiority trials for cardiovascular therapeutic medical devices: a systematic review_Chinese Journal of Evidence-Based Medicine

Authors：

FENG Kun ^1,2 , GUO Qiong ^2,3 , ZHONG Wentao ⁴ , LIU Yue ⁴ , LIU Yuqi ⁴ , LENG Roufei ⁴ , XU Yihan ^1,2 , GU Xianlin ^1,2 , LONG Youlin ² ,  DU Liang ^1,2,3,5 ,  LI Zhengchi ^5,6 ,  HUANG Jin ²

1. Chinese Evidence-Based Medicine Center, West China Hospital of Sichuan University, Chengdu 610041, P. R. China;
2. Medical Device Regulatory Research and Evaluation Center, West China Hospital of Sichuan University, Chengdu 610041, P. R. China;
3. West China Publishers, West China Hospital of Sichuan University, Chengdu 610041, P. R. China;
4. West China School of Public Health, Sichuan University, Chengdu 610041, P. R. China;
5. Center for Education of Medical Humanities, West China Hospital of Sichuan University, Chengdu 610041, P. R. China;
6. Institute of Hospital Management, West China Hospital of Sichuan University, Chengdu 610041, P. R. China;

Corresponding author：

DU Liang, Email: duliang0606@vip.sina.com; LI Zhengchi, Email: 603172078@qq.com; HUANG Jin, Email: michael_huangjin@163.com

Keywords：

Therapeutic medical devices; Cardiovascular medical devices; Non-inferiority trial; Non-inferiority threshold; Systematic review

DOI：

10.7507/1672-2531.202312134

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Abstract Full text Figures/Tables Video References Cited by

Objective To systematically review the non-inferiority trials in the cardiovascular domain that utilize medical devices as interventions, and investigate its characteristics and threshold settings. Methods The PubMed, Embase, and CENTRAL databases were electronically searched to collect non-inferiority trials in the cardiovascular field involving medical devices from inception to July 26, 2023. Two reviewers independently screened literature and extracted data. The reported information included basic characteristics, features of non-inferiority trials, and threshold-setting features of the included studies. Data analysis was performed using Excel 2020 and R 4.2.1 software. Results A total of 214 studies were included, with 167 studies (78.0%) focusing on interventions related to coronary artery stents. The trials predominantly utilized a two-arm design (92.9%), with a prevalent use of non-inferiority absolute thresholds (96.7%) as the criteria for non-inferiority determination. In 150 studies (70.1%), non-inferiority thresholds were established based on estimated control group effect values, while 33 studies (15.4%) did not report the source of these values. The non-inferiority trial endpoint outcomes exhibited diversity, and there were substantial differences in threshold settings. The three most studied qualitative indicators were target lesion failure rates (2.1%-8.6%), target vessel failure rates (2.5%-19.6%), and major adverse cardiovascular events rates (2.1%-10.0%). Late lumen loss (0.1-0.4 mm) emerged as the most frequently studied quantitative indicator. After converting absolute non-inferiority thresholds for all indicators into relative thresholds, the range was 1.20-3.67. Conclusion Significant variations in non-inferiority threshold settings are observed for identical endpoint outcomes across included studies, highlighting a lack of reporting on the rationale behind threshold settings.

Citation： FENG Kun, GUO Qiong, ZHONG Wentao, LIU Yue, LIU Yuqi, LENG Roufei, XU Yihan, GU Xianlin, LONG Youlin, DU Liang, LI Zhengchi, HUANG Jin. Characteristics and threshold setting of non-inferiority trials for cardiovascular therapeutic medical devices: a systematic review. Chinese Journal of Evidence-Based Medicine, 2024, 24(3): 288-294. doi: 10.7507/1672-2531.202312134 Copy

1.	《中国心血管健康与疾病报告2022》要点解读. 中国心血管杂志, 2023, 28(4): 297-312.
2.	沈雳, 李晨光, 吴轶喆, 等. 《中国心血管医疗器械产业创新白皮书(2021)》概要. 中国介入心脏病学杂志, 2022, 30(4): 251-258.
3.	中国心血管健康与疾病报告编写组. 中国心血管健康与疾病报告2022概要. 中国循环杂志, 2023, 38(6): 583-612.
4.	李盼, 冯静, 许博轩, 等. 冠状动脉血管支架的研究现状. 医疗卫生装备, 2023, 44(6): 92-100.
5.	周齐, 严鸿伊, 张艳丽, 等. 非劣效性设计临床试验. 中国卒中杂志, 2023, 18(6): 636-644.
6.	张新佶, 贺江南, 任建玲, 等. 阳性药对照临床试验中非劣效性检验的统计分析方法及相关问题. 数理统计与管理, 2010, 29(2): 372-379.
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11.	Ellert-Gregersen J, Jensen LO, Jakobsen L, et al. Polymer-free biolimus-coated stents versus ultrathin-strut biodegradable polymer sirolimus-eluting stents: two-year outcomes of the randomised SORT OUT IX trial. EuroIntervention, 2022, 18(2): e124-e131.
12.	Piaggio G, Elbourne DR, Pocock SJ, et al. Reporting of noninferiority and equivalence randomized trials: extension of the CONSORT 2010 statement. JAMA, 2012, 308(24): 2594-2604.
13.	Leung JT, Barnes SL, Lo ST, et al. Non-inferiority trials in cardiology: what clinicians need to know. Heart, 2020, 106(2): 99-104.
14.	Rehal S, Morris TP, Fielding K, et al. Non-inferiority trials: are they inferior. A systematic review of reporting in major medical journals. BMJ Open, 2016, 6(10): e012594.
15.	Pong S, Urner M, Fowler RA, et al. Testing for non-inferior mortality: a systematic review of non-inferiority margin sizes and trial characteristics. BMJ Open, 2021, 11(4): e044480.
16.	Althunian TA, de Boer A, Klungel OH, et al. Methods of defining the non-inferiority margin in randomized, double-blind controlled trials: a systematic review. Trials, 2017, 18(1): 107.
17.	Donken R, de Melker HE, Rots NY, et al. Comparing vaccines: a systematic review of the use of the non-inferiority margin in vaccine trials. Vaccine, 2015, 33(12): 1426-1432.
18.	李新旭, 周军, 高丽丽, 等. 非劣效临床试验的总结与思考. 中国新药杂志, 2020, 29(13): 1469-1477.
19.	FDA. Non-inferiority clinical trials to establish effectiveness-guidance for industry. 2016.
20.	Simonato M, Ben-Yehuda O, Vincent F, et al. Consequences of inaccurate assumptions in coronary stent noninferiority trials: a systematic review and meta-analysis. JAMA Cardiol, 2022, 7(3): 320-327.
21.	陈靖. 非劣效验证中基于率差和率比的界值确定方法的比较. 广州: 南方医科大学, 2012.
22.	刘朋. 药物洗脱支架在经皮冠状动脉介入治疗中的应用现状. 外科研究与新技术, 2021, 10(3): 209-213.
23.	Ofori S, Cafaro T, Devereaux PJ, et al. Noninferiority margins exceed superiority effect estimates for mortality in cardiovascular trials in high-impact journals. J Clin Epidemiol, 2023, 161: 20-27.

1. 《中国心血管健康与疾病报告2022》要点解读. 中国心血管杂志, 2023, 28(4): 297-312.
2. 沈雳, 李晨光, 吴轶喆, 等. 《中国心血管医疗器械产业创新白皮书(2021)》概要. 中国介入心脏病学杂志, 2022, 30(4): 251-258.
3. 中国心血管健康与疾病报告编写组. 中国心血管健康与疾病报告2022概要. 中国循环杂志, 2023, 38(6): 583-612.
4. 李盼, 冯静, 许博轩, 等. 冠状动脉血管支架的研究现状. 医疗卫生装备, 2023, 44(6): 92-100.
5. 周齐, 严鸿伊, 张艳丽, 等. 非劣效性设计临床试验. 中国卒中杂志, 2023, 18(6): 636-644.
6. 张新佶, 贺江南, 任建玲, 等. 阳性药对照临床试验中非劣效性检验的统计分析方法及相关问题. 数理统计与管理, 2010, 29(2): 372-379.
7. Hills RK. Non-inferiority trials: No better. No worse? No change? No pain? Br J Haematol, 2017, 176(6): 883-887.
8. Mauri L, D'Agostino RB. Challenges in the design and interpretation of noninferiority trials. N Engl J Med, 2017, 377(14): 1357-1367.
9. Serruys PW, Morice MC, Kappetein AP, et al. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med, 2009, 360(10): 961-972.
10. Park SJ, Kim YH, Park DW, et al. Randomized trial of stents versus bypass surgery for left main coronary artery disease. N Engl J Med, 2011, 364(18): 1718-1727.
11. Ellert-Gregersen J, Jensen LO, Jakobsen L, et al. Polymer-free biolimus-coated stents versus ultrathin-strut biodegradable polymer sirolimus-eluting stents: two-year outcomes of the randomised SORT OUT IX trial. EuroIntervention, 2022, 18(2): e124-e131.
12. Piaggio G, Elbourne DR, Pocock SJ, et al. Reporting of noninferiority and equivalence randomized trials: extension of the CONSORT 2010 statement. JAMA, 2012, 308(24): 2594-2604.
13. Leung JT, Barnes SL, Lo ST, et al. Non-inferiority trials in cardiology: what clinicians need to know. Heart, 2020, 106(2): 99-104.
14. Rehal S, Morris TP, Fielding K, et al. Non-inferiority trials: are they inferior. A systematic review of reporting in major medical journals. BMJ Open, 2016, 6(10): e012594.
15. Pong S, Urner M, Fowler RA, et al. Testing for non-inferior mortality: a systematic review of non-inferiority margin sizes and trial characteristics. BMJ Open, 2021, 11(4): e044480.
16. Althunian TA, de Boer A, Klungel OH, et al. Methods of defining the non-inferiority margin in randomized, double-blind controlled trials: a systematic review. Trials, 2017, 18(1): 107.
17. Donken R, de Melker HE, Rots NY, et al. Comparing vaccines: a systematic review of the use of the non-inferiority margin in vaccine trials. Vaccine, 2015, 33(12): 1426-1432.
18. 李新旭, 周军, 高丽丽, 等. 非劣效临床试验的总结与思考. 中国新药杂志, 2020, 29(13): 1469-1477.
19. FDA. Non-inferiority clinical trials to establish effectiveness-guidance for industry. 2016.
20. Simonato M, Ben-Yehuda O, Vincent F, et al. Consequences of inaccurate assumptions in coronary stent noninferiority trials: a systematic review and meta-analysis. JAMA Cardiol, 2022, 7(3): 320-327.
21. 陈靖. 非劣效验证中基于率差和率比的界值确定方法的比较. 广州: 南方医科大学, 2012.
22. 刘朋. 药物洗脱支架在经皮冠状动脉介入治疗中的应用现状. 外科研究与新技术, 2021, 10(3): 209-213.
23. Ofori S, Cafaro T, Devereaux PJ, et al. Noninferiority margins exceed superiority effect estimates for mortality in cardiovascular trials in high-impact journals. J Clin Epidemiol, 2023, 161: 20-27.

Chinese Journal of Evidence-Based Medicine

Characteristics and threshold setting of non-inferiority trials for cardiovascular therapeutic medical devices: a systematic review

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