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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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.	《中國心血管健康與疾病報告2022》要點解讀. 中國心血管雜志, 2023, 28(4): 297-312.
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4.	李盼, 馮靜, 許博軒, 等. 冠狀動脈血管支架的研究現狀. 醫療衛生裝備, 2023, 44(6): 92-100.
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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.
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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, 周軍, 高麗麗, 等. 非劣效臨床試驗的總結與思考. 中國新藥雜志, 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.	陳靖. 非劣效驗證中基于率差和率比的界值確定方法的比較. 廣州: 南方醫科大學, 2012.
22.	劉朋. 藥物洗脫支架在經皮冠狀動脈介入治療中的應用現狀. 外科研究與新技術, 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. 《中國心血管健康與疾病報告2022》要點解讀. 中國心血管雜志, 2023, 28(4): 297-312.
2. 沈靂, 李晨光, 吳軼喆, 等. 《中國心血管醫療器械產業創新白皮書(2021)》概要. 中國介入心臟病學雜志, 2022, 30(4): 251-258.
3. 中國心血管健康與疾病報告編寫組. 中國心血管健康與疾病報告2022概要. 中國循環雜志, 2023, 38(6): 583-612.
4. 李盼, 馮靜, 許博軒, 等. 冠狀動脈血管支架的研究現狀. 醫療衛生裝備, 2023, 44(6): 92-100.
5. 周齊, 嚴鴻伊, 張艷麗, 等. 非劣效性設計臨床試驗. 中國卒中雜志, 2023, 18(6): 636-644.
6. 張新佶, 賀江南, 任建玲, 等. 陽性藥對照臨床試驗中非劣效性檢驗的統計分析方法及相關問題. 數理統計與管理, 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, 周軍, 高麗麗, 等. 非劣效臨床試驗的總結與思考. 中國新藥雜志, 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. 陳靖. 非劣效驗證中基于率差和率比的界值確定方法的比較. 廣州: 南方醫科大學, 2012.
22. 劉朋. 藥物洗脫支架在經皮冠狀動脈介入治療中的應用現狀. 外科研究與新技術, 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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