Globally, stroke is the third most common cause of mortality (10.7% of total deaths) and stands fourth in disability-adjusted life years (DALYs) lost (5.6% of total DALYs) (GBD 2021 Diseases and Injuries Collaborators, 2024; GBD 2021 Stroke Risk Factor Collaborators et al., 2024). In China, stroke imposes a notably high disease burden. According to the latest Global Burden of Disease estimates, 3.94 million new stroke cases were recorded nationwide in 2019, including 2.87 million new Ischemic Stroke (IS) events, and 1.03 million patients died from IS (Wang et al., 2022). Despite guideline-based optimal treatment and secondary prevention strategies, the 1-year stroke recurrence rate remains 9.6%–17.7% (Chinese Society of Neurology, and Chinese Stroke Society, 2022; Pan et al., 2021). In clinical practice across China, traditional Chinese medicine (TCM) is commonly used as an adjunctive therapy for acute ischemic stroke (AIS), largely due to its potential multi-target and multi-pathway effects.

Danhong injection (DHI) is composed of Salvia miltiorrhiza (Danshen) and Carthamus tinctorius (Honghua), promoting blood circulation, resolving blood stasis, and relaxing meridians. As one of the most commonly used Chinese botanical drug injections in China, DHI is approved for the treatment of ischemic cardiovascular and cerebrovascular diseases (Fu et al., 2018). DHI exhibits multiple pharmacological effects, including inhibiting oxidative stress and inflammation, anticoagulation, lowering lipids, preventing apoptosis, inducing vasodilation, and promoting angiogenesis (Feng et al., 2019). In animal experiments, DHI alleviated neuronal injury in the ischemic penumbra of rats after cerebral ischemia/reperfusion (CI/R) (Zeng et al., 2021). In IS model rats, DHI reduced infarct volume and enhanced neurological recovery by promoting neurogenesis (Li et al., 2023). Moreover, a meta-analysis involving 67 randomized controlled trials (RCTs) indicated that combining DHI with biomedicine significantly enhanced neurological outcomes, self-care capacity, and blood lipid profiles in IS patients (Ma et al., 2022).

Nevertheless, previous clinical research was constrained by relatively small sample sizes and tended to focus on specific endpoints, resulting in insufficient evidence regarding the overall efficacy of DHI as an adjunct therapy in AIS. To our knowledge, no large-scale real-world study has comprehensively evaluated the clinical effectiveness of adjunctive DHI therapy in routine biomedicine-based AIS management. Hence, this real-world, multicenter study set out to evaluate the impact of combining DHI with standard treatment on neurological function and other clinical outcomes in AIS patients, ultimately supplying stronger clinical evidence for DHI’s use as an adjunct therapy.

To our knowledge, this is the first real-world, multicenter, retrospective cohort study to evaluate the efficacy of adjunctive DHI therapy in patients with AIS. Of the 3,560 patients with complete data on both primary and secondary outcomes, 2,830 (1,415 in each group) were successfully matched by PSM. These findings suggest that adjunctive DHI therapy not only lowers post-treatment NIHSS scores and increases the proportion of patients achieving NIHSS ≤4 or ≤1, but also reduces mRS scores and raises the proportion of patients with mRS ≤1. Hence, it appears to enhance both neurological function and quality of life. Notably, no effect of DHI on IHC was observed in AIS patients.

DHI is prepared from Salvia miltiorrhiza (Danshen) and Carthamus tinctorius (Honghua), and is commonly used in Chinese clinical practice to treat ischemic cardiovascular and cerebrovascular diseases due to its blood-activating and stasis-resolving properties. According to the literature, DHI contains multiple active metabolites, including danshensu, salvianolic acids, and hydroxysafflor yellow A (HSYA), which act on diverse molecular targets to improve hemorheology, protect vascular endothelium, and attenuate inflammation and oxidative stress (Feng et al., 2019; Ma et al., 2022). Experimental studies have shown that DHI reduces infarct volume, promotes neurovascular remodeling, and facilitates neurological recovery in IS models (Feng et al., 2019). These effects are thought to be mediated by suppression of the NF-κB and NLRP3 inflammasome pathways (Du et al., 2021; Wang J. et al., 2024), enhancement of antioxidant capacity via the Nrf2/ARE signaling axis (Guo et al., 2014), and regulation of neuronal apoptosis and autophagy through the PI3K/Akt/mTOR and BDNF/CREB pathways (Zhang et al., 2023; Li et al., 2023). Among its bioactive metabolites, danshensu exhibits anti-inflammatory and autophagy-regulating effects (Hu et al., 2022); salvianolic acids inhibit oxidative stress and platelet aggregation (Zhao et al., 2024; Liu et al., 2023); and HSYA exerts neuroprotective actions, potentially by modulating SIRT1-related pathways (Fangma et al., 2021). Collectively, these multi-target mechanisms support the therapeutic potential of DHI in the treatment of AIS.

Building on these advantages, these studies have explored the efficacy of DHI in patients with AIS and angina. They found that DHI improved neurological function and self-care ability in AIS patients in a dose-dependent manner (Du et al., 2018; Ma et al., 2022). In angina patients, add-on DHI therapy reduced the frequency of anginal episodes, alleviated myocardial ischemic symptoms, and improved TCM syndromes (Liu et al., 2021; Chen et al., 2022). These reports further indicated that adjunct DHI therapy did not introduce additional safety risks. However, their conclusions relied mainly on relatively small sample sizes, limiting the ability to fully characterize DHI’s effectiveness in real-world practice.

The results of our study align with outcomes reported in other adjunctive therapy trials. For example, the TISS trial indicated that adding Tongxinluo markedly increased the proportion of AIS patients attaining a 90-day NIHSS score of 0–1 or a reduction of ≥4 points (Dong et al., 2024). In the TASTE trial, Edaravone Dexborneol lowered the NIHSS score by an additional 0.4 points compared with Edaravone alone in the acute phase (Xu et al., 2021). The BAST trial showed that at 90 days, butylphthalide reduced the NIHSS score by about one point more than the control group (Wang et al., 2023). Using a large-scale, multicenter, real-world cohort, our study similarly confirmed the beneficial effects of DHI on NIHSS and mRS scores, supporting its role in adjunctive AIS treatment. However, whether these short-term improvements in neurological function and disability reduction translate into better long-term outcomes remains unclear and will require extended follow-up and large-scale RCTs.

This study used a multicenter, retrospective, real-world cohort design, providing data closer to clinical practice, including treatment pathways, concomitant medications, and disease heterogeneity, than conventional RCTs. It thereby offers greater external validity for applying botanical drug–based therapy in AIS (Tan et al., 2022). In contrast to prior RCTs or preclinical reports, this multicenter analysis provides pragmatic and clinically relevant evidence on DHI use in real-world AIS patients across diverse hospital settings. Nonetheless, real-world observational studies may still be influenced by unaccounted confounding factors (Psaty et al., 1999). To mitigate potential confounding, we conducted crude analysis, PSM, sIPTW, and multivariable regression. Subgroup and sensitivity analyses were then performed to verify the robustness and consistency of our findings. No effect of adjunct DHI therapy on IHC was identified, possibly because patients who develop such complications often present with advanced age, severe stroke, or multi-organ dysfunction.

As this was a retrospective study, active monitoring of medication-related adverse events (AEs) was not performed. Nonetheless, large-scale pharmacovigilance studies in China have reported a low incidence of DHI-related adverse drug reactions (ADRs), approximately 3.5‰, primarily type A reactions (e.g., sweating, dizziness, headache, flushing), which typically resolved after drug withdrawal (Liu et al., 2021; Chen et al., 2022). Notably, no cases of anaphylactic shock or allergic respiratory distress were reported. Moreover, RCTs have reported no significant difference in AEs incidence between DHI-treated and control groups (Li et al., 2015; Ge et al., 2022). DHI has also shown good compatibility and safety when administered with common intravenous solvents (Wang A. et al., 2024). These findings collectively support the favorable safety profile of DHI in both clinical trials and routine practice.

This large-scale, multicenter study closely reflects real-world TCM clinical settings, offering a model for examining adjunctive AIS therapy. Although high-quality evidence supporting TCM interventions in AIS remains limited, TCM’s multi-component and multi-target properties suggest broader clinical utility. By evaluating DHI’s impact on neurological function and disability in AIS patients, our results confirm that adjunct DHI therapy can improve clinical outcomes.

Nonetheless, our study has certain limitations. First, although we used multiple approaches to address confounding, unmeasured factors (e.g., prior medication use) may still bias the results, and E-value analysis only provides supplementary insights. Second, excluding AIS patients hospitalized for longer than 21 days reduced the representation of severely ill patients requiring extended hospitalization. Third, our findings were limited to short-term clinical outcomes (discharge NIHSS and mRS scores), as follow-up imaging, biomarker, and other relevant data were not consistently available across centers, making it infeasible to assess radiographic or mechanistic responses. Fourth, all eight participating centers were affiliated with TCM institutions, potentially limiting generalizability. Fifth, as a retrospective observational study without randomization or blinding, there may be a risk of residual bias, though we applied multiple statistical strategies to enhance internal validity and transparency. In light of these limitations, our results should be interpreted with caution. Looking ahead, well-designed multicenter RCTs are needed to validate the efficacy of adjunctive DHI therapy and to provide stronger evidence for its clinical application in AIS.

In conclusion, adjunctive DHI therapy can lower NIHSS and mRS scores in AIS patients, thereby enhancing clinical outcomes. These findings support the use of DHI as an adjunctive treatment for AIS. However, larger-scale, multicenter RCTs are still needed to further validate its efficacy and safety in routine biomedicine-based practice.