Objective: Measurement timing is a fundamental yet frequently overlooked component of outcome specification in core outcome set (COS) development. In cardiovascular disease (CVD) trials, long-term endpoints such as major adverse cardiac events (MACE) are often underreported owing to impractical follow-up durations, and existing COS rarely provide standardized measurement timepoints, leading to substantial inter-study heterogeneity and compromised evidence synthesis. This study aims to develop an evidence- and consensus-based framework for recommended timepoints for long-term outcome measurement in CVD, thereby refining future COS updates and offering actionable guidance for trialists.
Methods: This mixed-methods study comprises three sequential phases. Phase I involves a systematic search of the COMET database to identify all published CVD-related COS studies, and to extract their recommended long-term outcome domains and specified measurement timepoints. Phase II comprises a comprehensive systematic search of randomized controlled trials (RCTs) published between January 2023 and September 2025 across PubMed, Embase, and the Cochrane Library, to collect empirical data on actual measurement timepoints, event rates, and statistical significance across various CVD subtypes; descriptive analyses and consistency assessments against Phase I recommendations will be performed. Phase III consists of an international online survey targeting corresponding authors of the included RCTs and COS studies, collecting quantitative importance ratings and qualitative justifications for timepoint selections. Thematic analysis of open-ended responses and descriptive statistics of closed-ended items will be integrated to inform the final recommendations.
Conclusion: By integrating existing COS recommendations, real-world RCT evidence, and multidisciplinary expert consensus, this study will fill a critical methodological gap in COS timing standardization. The resulting framework is expected to enhance the comparability and clinical applicability of CVD trial evidence, support systematic reviewers and guideline developers, and provide a replicable methodological template for standardizing outcome measurement timepoints in other chronic disease areas.
Tianqi Zuo(Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China)
Yuhan Feng(The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, China)
Yinghui Jin(Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China)
Jinbo Zhai(Tianjin University of Traditional Chinese Medicine, Tianjin, China)
Shuangqiu Wang(Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China)
Lulu Shi(Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China)
Xiaoying Zhong(Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China)
Qianqian Xu(Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, China)
Hongcai Shang(Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China)?principal investigator?
Ruijin Qiu(Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China)?supervisor?
Disease Category: Heart & circulation
Disease Name: Cardiovascular Disease
Age Range: 18 - 120
Sex: Either
Nature of Intervention: Any
- Clinical experts
- Methodologists
- Researchers
- COS for clinical trials or clinical research
- COS methods research
- Recommendations for outcome measures (measurement/how)
- Literature review
- Survey
- Systematic review
This mixed-methods study comprises three sequential phases. Phase I involves a systematic search of the COMET database to identify all published CVD-related COS studies, and to extract their recommended long-term outcome domains and specified measurement timepoints. Phase II comprises a comprehensive systematic search of randomized controlled trials (RCTs) published between January 2023 and September 2025 across PubMed, Embase, and the Cochrane Library, to collect empirical data on actual measurement timepoints, event rates, and statistical significance across various CVD subtypes; descriptive analyses and consistency assessments against Phase I recommendations will be performed. Phase III consists of an international online survey targeting corresponding authors of the included RCTs and COS studies, collecting quantitative importance ratings and qualitative justifications for timepoint selections. Thematic analysis of open-ended responses and descriptive statistics of closed-ended items will be integrated to inform the final recommendations.