Heterogeneity of Treatment Effects for Intensive Blood Pressure Therapy by Individual Components of FRS: An Unsupervised Data-Driven Subgroup Analysis in SPRINT and ACCORD

Yaqian Wu; Jianling Bai; Mingzhi Zhang; Fang Shao; Honggang Yi; Dongfang You; Yang Zhao

doi:10.3389/fcvm.2022.778756

Heterogeneity of Treatment Effects for Intensive Blood Pressure Therapy by Individual Components of FRS: An Unsupervised Data-Driven Subgroup Analysis in SPRINT and ACCORD

Front Cardiovasc Med. 2022 Feb 3:9:778756. doi: 10.3389/fcvm.2022.778756. eCollection 2022.

Authors

Yaqian Wu¹, Jianling Bai^{1

2}, Mingzhi Zhang¹, Fang Shao¹, Honggang Yi¹, Dongfang You¹, Yang Zhao^{1

2

3

4

5}

Affiliations

¹ Department of Biostatistics, Nanjing Medical University, Nanjing, China.
² Key Laboratory of Medical Big Data Research and Application, Nanjing Medical University, Nanjing, China.
³ Jiangsu Provincial Key Laboratory of Biomarkers of Cancer Prevention and Control, Nanjing Medical University, Nanjing, China.
⁴ Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
⁵ Key Laboratory of Modern Toxicology, Nanjing Medical University, Nanjing, China.

Abstract

Background: Few studies have answered the guiding significance of individual components of the Framingham risk score (FRS) to the risk of cardiovascular disease (CVD) after antihypertensive treatment. This study on the systolic blood pressure intervention trial (SPRINT) and the Action to Control Cardiovascular Risk in Diabetes blood pressure trial (ACCORD-BP) aimed to reveal previously undetected association patterns between individual components of the FRS and heterogeneity of treatment effects (HTEs) of intensive blood pressure control.

Methods: A self-organizing map (SOM) methodology was applied to identify CVD-risk-specific subgroups in the SPRINT (n = 8,773), and the trained SOM was utilized directly in 4,495 patients from the ACCORD. The primary endpoints were myocardial infarction (MI), non-myocardial infarction acute coronary syndrome (non-MI ACS), stroke, heart failure (HF), death from CVD causes, and a primary composite cardiovascular outcome. Cox proportional hazards models were then used to explore the potential heterogeneous response to intensive SBP control.

Results: We identified four SOM-based subgroups with distinct individual components of FRS profiles and the CVD risk. For individuals with type 2 diabetes mellitus (T2DM) in the ACCORD or without diabetes in the SPRINT, subgroup I characterized by male with the lowest concentrations for total cholesterol (TC) and high-density lipoprotein (HDL) cholesterol measures, experienced the highest risk for major CVD. Conversely, subgroup III characterized by a female with the highest values for these measures represented as the lowest CVD risk. Furthermore, subgroup II, with the highest systolic blood pressure (SBP) and no antihypertensive agent use at baseline, had a significantly greater frequency of non-MI ACS under intensive BP control, the number needed to harm (NNH) was 84.24 to cause 1 non-MI ACS [absolute risk reduction (ARR) = -1.19%; 95% CI: -2.08, -0.29%] in the SPRINT [hazard ratio (HR) = 3.62; 95% CI: 1.33, 9.81; P = 0.012], and the NNH of was 43.19 to cause 1 non-MI ACS (ARR = -2.32%; 95% CI: -4.63, 0.00%) in the ACCORD (HR = 1.81; 95% CI: 1.01-3.25; P = 0.046). Finally, subgroup IV characterized by mostly younger patients with antihypertensive medication use and smoking history represented the lowest risk for stroke, HF, and relatively low risk for death from CVD causes and primary composite CVD outcome in SPRINT, however, except stroke, a low risk for others were not observed in ACCORD.

Conclusion: Similar findings in patients with hypertensive with T2DM or without diabetes by multivariate subgrouping suggested that the individual components of the FRS could enrich or improve CVD risk assessment. Further research was required to clarify the potential mechanism.

Keywords: ACCORD; SPRINT; cardiovascular diseases; framingham risk score; heterogeneous treatment effects; self-organizing map.