Traditional Chinese Medicine Compound (Tongxinluo) and Clinical Outcomes of Patients With Acute Myocardial Infarction: The CTS-AMI Randomized Clinical Trial

Abstract

Importance: Tongxinluo, a traditional Chinese medicine compound, has shown promise in in vitro, animal, and small human studies for myocardial infarction, but has not been rigorously evaluated in large randomized clinical trials.

Objective: To investigate whether Tongxinluo could improve clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI).

Design, setting, and participants: Randomized, double-blind, placebo-controlled clinical trial was conducted among patients with STEMI within 24 hours of symptom onset from 124 hospitals in China. Patients were enrolled from May 2019 to December 2020; the last date of follow-up was December 15, 2021.

Interventions: Patients were randomized 1:1 to receive either Tongxinluo or placebo orally for 12 months (a loading dose of 2.08 g after randomization, followed by the maintenance dose of 1.04 g, 3 times a day), in addition to STEMI guideline-directed treatments.

Main outcomes and measures: The primary end point was 30-day major adverse cardiac and cerebrovascular events (MACCEs), a composite of cardiac death, myocardial reinfarction, emergent coronary revascularization, and stroke. Follow-up for MACCEs occurred every 3 months to 1 year.

Results: Among 3797 patients who were randomized, 3777 (Tongxinluo: 1889 and placebo: 1888; mean age, 61 years; 76.9% male) were included in the primary analysis. Thirty-day MACCEs occurred in 64 patients (3.4%) in the Tongxinluo group vs 99 patients (5.2%) in the control group (relative risk [RR], 0.64 [95% CI, 0.47 to 0.88]; risk difference [RD], -1.8% [95% CI, -3.2% to -0.6%]). Individual components of 30-day MACCEs, including cardiac death (56 [3.0%] vs 80 [4.2%]; RR, 0.70 [95% CI, 0.50 to 0.99]; RD, -1.2% [95% CI, -2.5% to -0.1%]), were also significantly lower in the Tongxinluo group than the placebo group. By 1 year, the Tongxinluo group continued to have lower rates of MACCEs (100 [5.3%] vs 157 [8.3%]; HR, 0.64 [95% CI, 0.49 to 0.82]; RD, -3.0% [95% CI, -4.6% to -1.4%]) and cardiac death (85 [4.5%] vs 116 [6.1%]; HR, 0.73 [95% CI, 0.55 to 0.97]; RD, -1.6% [95% CI, -3.1% to -0.2%]). There were no significant differences in other secondary end points including 30-day stroke; major bleeding at 30 days and 1 year; 1-year all-cause mortality; and in-stent thrombosis (<24 hours; 1-30 days; 1-12 months). More adverse drug reactions occurred in the Tongxinluo group than the placebo group (40 [2.1%] vs 21 [1.1%]; P = .02), mainly driven by gastrointestinal symptoms.

Conclusions and relevance: In patients with STEMI, the Chinese patent medicine Tongxinluo, as an adjunctive therapy in addition to STEMI guideline-directed treatments, significantly improved both 30-day and 1-year clinical outcomes. Further research is needed to determine the mechanism of action of Tongxinluo in STEMI.

Trial registration: ClinicalTrials.gov Identifier: NCT03792035.

Figure 1.. Population Included in the CTS-AMI Study

CTS-AMI indicates China Tongxinluo Study for Myocardial Protection in Patients With Acute Myocardial Infarction; ITT, intention to treat; LBBB, left bundle-branch block; and STEMI, ST-segment elevation myocardial infarction. ^aDue to the emergent circumstances surrounding patient enrollment and randomization amid the COVID-19 pandemic, screening logs were only available in 82 of 124 sites. As a result, the exact number of potentially eligible patients screened were not known, but it was estimated to be around 50 patients per site in sites with complete screening logs.

Figure 2.. Subgroup Analysis for the Primary End Point of 30-Day Major Adverse Cardiac and Cerebrovascular Events

Killip classes are defined in footnote c of Table 1. P2Y12 receptor inhibitors, aspirin, statins, nitrates, β-blockers, angiotensin II receptor blockers (ARBs)/angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor–neprilysin inhibitor (ARNI), diuretics, and spironolactone refer to medication during hospitalization. Because of the small numbers and/or wide CIs, prespecified subgroup analyses were not presented according to previous heart failure, previous myocardial infarction, receiving aspirin, or P2Y12 receptor inhibitors. The benefit of Tongxinluo was similar across all these prespecified subgroups.

Figure 3.. Kaplan-Meier Curves for 1-Year Major Adverse Cardiac and Cerebrovascular Events (MACCEs) and Individual Components of MACCEs

HR indicates hazard ratio.

Figure 4.. Post Hoc Landmark Analysis at 30-Day Point for 1-Year Major Adverse Cardiac and Cerebrovascular Events (MACCEs)

MACCEs are a composite of cardiac death, myocardial reinfarction, emergent coronary revascularization, and stroke. HR indicates hazard ratio.