Naoxintong capsule as adjunctive therapy in ACS: a hypothesis-generating open-label randomized trial

To evaluate, in an exploratory setting, the safety of adjunctive Naoxintong Capsule (NXT) added to standard secondary prevention in patients with acute coronary syndrome (ACS), and to describe between-group differences in major adverse cardiovascular events (MACE), psychological state, angina-related quality of life, lipid profile, cardiac function, and traditional Chinese medicine (TCM) syndrome measures.

In this open-label, multicenter, exploratory randomized controlled trial, 170 ACS patients were randomized 1:1 to standard secondary prevention alone (control, n = 85) or combined with NXT (n = 85) for 12 months. The primary outcome was 12-month MACE (cardiac death, nonfatal myocardial infarction, urgent revascularization, ischemic stroke), ascertained by treating clinicians without an independent blinded events committee. Secondary outcomes included SAS, SDS, SAQ, lipid profile, echocardiographic parameters, TCM syndrome score, and safety indices. The primary analysis was complete-case; multiplicity was not pre-specified, and all secondary P values are nominal.

Of 170 randomized participants, 152 completed 12-month follow-up (NXT n = 78; control n = 74; attrition 10.6%, balanced between arms). MACE was recorded in 8/78 (10.3%) in the NXT arm vs. 13/74 (17.6%) in control (relative risk 0.58; 95% CI 0.26-1.33; P = 0.19; not statistically significant, 95% CI included the null). A worst-case sensitivity check assigning all NXT-arm losses as events and all control-arm losses as non-events yielded 17.6% vs. 15.3%, indicating that the direction of the point estimate was not robust to missing-outcome assumptions. Nominally larger reductions in the NXT arm were observed for SAS (-8.75 vs. -3.75) and SDS (-10.00 vs. -3.75); nominally larger changes were also observed across SAQ domains, lipid parameters (TC, TG, LDL-C), and echocardiographic indices (LVEF, LVEDD, LVESD), all reported as nominal descriptive findings. Safety laboratory parameters did not differ between groups, and no serious adverse events occurred.

In this open-label exploratory trial, adjunctive NXT was not associated with a statistically significant reduction in MACE, and the direction of the estimate was not robust to missing-data assumptions. Between-group differences in secondary outcomes are hypothesis-generating only, given the open-label design, unblinded event ascertainment, absence of multiplicity adjustment, and complete-case analysis of a rare-event endpoint. Adequately powered, placebo-controlled, double-blind trials with independent blinded event adjudication are needed.

Registered on July 22, 2020, with the registration number ChiCTR2000034871 at the Chinese Clinical Trial Registry.