Efficacy and Safety of Shexiang Baoxin Pill (MUSKARDIA) in Patients with Stable Coronary Artery Disease: A Multicenter, Double-Blind, Placebo-Controlled Phase IV Randomized Clinical Trial
Cardiovascular diseases (CVDs) are the leading causes of death globally, accounting for 31.5% of all deaths worldwide and 45% of deaths due to non-communicable diseases. Among CVDs, coronary artery disease (CAD) is a major contributor to morbidity and mortality. Despite the widespread use of optimal medical therapy (OMT), which includes aspirin and statins, many patients with stable CAD continue to experience residual cardiovascular risks. This highlights the need for additional therapeutic strategies to further reduce the risk of major adverse cardiovascular events (MACEs) and improve patient outcomes. Traditional Chinese Medicine (TCM) has been used for centuries in China to treat CAD, and Shexiang Baoxin Pill (MUSKARDIA) is one such TCM formulation that has been in use for over 30 years. However, robust clinical trials evaluating its efficacy and safety are limited. This study aimed to assess the long-term efficacy, safety, and compliance of MUSKARDIA as an add-on therapy to OMT in patients with stable CAD.
Study Design and Methodology
This was a multicenter, double-blind, placebo-controlled, phase IV randomized clinical trial conducted across 97 hospitals in China. The trial enrolled 2674 patients with stable CAD, who were randomized in a 1:1 ratio to receive either MUSKARDIA or placebo for 24 months. Both groups received OMT according to local tertiary hospital protocols. The primary endpoint was the occurrence of a MACE, defined as a composite of cardiovascular death, non-fatal myocardial infarction (MI), or non-fatal stroke. Secondary endpoints included all-cause mortality, non-fatal MI, non-fatal stroke, hospitalization for unstable angina or heart failure, peripheral revascularization, angina stability, and angina frequency. The study also assessed patient compliance and safety, including adverse events (AEs) and serious adverse events (SAEs).
Patient Population and Baseline Characteristics
Patients aged 18 years or older with stable ischemic myocardial symptoms for at least one month were eligible for the study. Key inclusion criteria included a history of acute MI over six months, a history of percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG) over six months, or epicardial coronary stenosis of ≥50% in at least one major branch as indicated by coronary computed tomography (CT) angiography or coronary angiography. Exclusion criteria included patients preparing to receive PCI or CABG, severe CVDs, severe respiratory diseases, uncontrolled diabetes or hypertension, severe liver or kidney disease, and other severe conditions such as malignant tumors or severe anemia.
The mean age of the study population was 63.8 years, with 70.8% being male. The majority of patients (99.7%) were treated with aspirin, and 93.0% were on statin therapy. Baseline characteristics, including medical history, medication use, and angina frequency, were similar between the MUSKARDIA and placebo groups.
Treatment and Follow-Up
Patients entered a 28-day run-in period during which they received standard therapy for stable CAD. After this period, patients were randomized to receive either MUSKARDIA (two pills, three times daily, totaling 135 mg) or placebo (two pills, three times daily, totaling 135 mg). The study medication was administered for 24 consecutive months or until the development of a major adverse event. Patients were followed up at 1, 3, 6, 9, 12, 18, and 24 months. Compliance was defined as the proportion of prescribed medication taken by the patients, and angina stability and frequency were assessed using the Seattle Angina Questionnaire.
Primary and Secondary Outcomes
After 24 months of treatment, the occurrence of MACEs was 1.9% in the MUSKARDIA group compared to 2.6% in the placebo group (odds ratio [OR] = 0.80; 95% confidence interval [CI]: 0.45–1.07; P = 0.2869). This represented a 26.9% reduction in the occurrence of MACEs in the MUSKARDIA group. Although this reduction did not reach statistical significance, the Kaplan-Meier curves showed a trend toward divergence after 18 months of treatment, suggesting a potential benefit of MUSKARDIA over a longer period.
In terms of individual MACE components, there were no significant differences in all-cause mortality (0.37% in the MUSKARDIA group vs. 0.23% in the placebo group), non-fatal MI (0.97% in the MUSKARDIA group vs. 1.51% in the placebo group), or non-fatal stroke (0.67% in the MUSKARDIA group vs. 0.90% in the placebo group). However, MUSKARDIA significantly reduced angina frequency at 18 months (P = 0.0362), with a trend toward improvement in angina stability (P = 0.0458). No significant differences were observed in other secondary endpoints, including hospitalization for unstable angina or heart failure and peripheral revascularization.
Subgroup Analysis
Subgroup analysis revealed that MUSKARDIA was particularly beneficial in females and in patients with a body mass index (BMI) < 24 kg/m². These findings suggest that MUSKARDIA may offer additional cardiovascular protection in specific patient populations, particularly those who may have a higher risk of residual cardiovascular events or who are intolerant to standard therapies.
Safety and Adverse Events
The safety profile of MUSKARDIA was comparable to that of placebo. In the safety set, 17.7% of patients in the MUSKARDIA group experienced at least one AE, compared to 17.4% in the placebo group (P = 0.8785). The total number of AEs was 443 in the MUSKARDIA group and 477 in the placebo group. SAEs occurred in 3.5% of patients in the MUSKARDIA group and 3.1% in the placebo group. Common AEs included unstable angina, atrial fibrillation, acute MI, and stable angina. There were no significant differences in liver or renal function between the two groups, indicating that MUSKARDIA is safe for long-term use in patients with stable CAD.
Discussion
This study represents one of the largest and most comprehensive clinical trials evaluating the efficacy and safety of a TCM formulation in patients with stable CAD. The results demonstrate that MUSKARDIA, as an add-on therapy to OMT, is safe and significantly reduces angina frequency in patients with stable CAD. Although the reduction in MACEs did not reach statistical significance, the trend toward a lower incidence of MACEs in the MUSKARDIA group suggests potential benefits, particularly over a longer treatment period.
The bioactive components of MUSKARDIA, including muscone, ginsenosides, storax, bufadienolides, cinnamic acid, arenobufagin, and borneol, have been shown to exert various cardioprotective effects. Muscone has been reported to improve cardiac remodeling, while ginsenosides have anti-oxidative, anti-platelet, and lipid-lowering properties. Cinnamic acid is known for its anti-diabetic effects, and borneol has anti-ischemic properties. The combination of these components may contribute to the observed benefits of MUSKARDIA in reducing angina frequency and potentially lowering the risk of MACEs.
The low MACE rate observed in this study (2.3% in the MUSKARDIA group and 3.1% in the placebo group) is lower than that reported in other populations, which may be attributed to the high proportion of patients on optimal therapy at baseline and the high compliance rate during the study. However, the unexpectedly low MACE rate may have underpowered the study to detect a significant difference in the primary endpoint. The trend toward curve divergence after 18 months of treatment suggests that a longer treatment period or a larger sample size may be needed to fully evaluate the benefits of MUSKARDIA.
Conclusion
In conclusion, this study provides evidence that MUSKARDIA, as an add-on therapy to OMT, is safe and effective in reducing angina frequency in patients with stable CAD. The trend toward a reduction in MACEs, although not statistically significant, suggests potential benefits that warrant further investigation. MUSKARDIA may be particularly beneficial in specific patient populations, such as females and those with a lower BMI. These findings support the use of MUSKARDIA as a complementary therapy in the management of stable CAD, particularly for patients who continue to experience residual cardiovascular risks despite optimal medical therapy.
doi.org/10.1097/CM9.0000000000001257
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