2.1. Experimental design
This is a double-center, triple-blinded, randomized, and optimal efficiency clinical trial. A total of 120 patients with aspirin semi-resistance will be randomized into the experimental group or the control group at the ratio of 1:1, with 60 patients in each group. The experimental group is given enteric-coated aspirin tablets 100 mg/day + Panax Notoginseng Powder (3 g/day, oral administrationafter dissolved), while the control group is given enteric-coated aspirin tablets 100 mg/day + placebo (Panax Notoginseng Powder 0.03 g + malt powder / day, oral administration after dissolved). The whole trial period is 37 days, inclusive of 7 days of baseline observation and 30 days of treatment. Platelet aggregation rate, TXA2, PGI2, and ADP are measured before treatment, at day-14, and day-30 of the treatment.
This study has been approved by the ethics committee of the Shaanxi Traditional Chinese Medicine Hospital ( ethical review No. 08) (http://www.chictr.org.cn/index.aspx) with the registration number of ChiCTR2000037833. Informed consent will be obtained from all subjects. Any alteration of the study protocol or informed consent that may affect the rights and interests of participants or affect the implementation of the study shall be reported to the ethics committee for approval. When any serious adverse events are encountered during the trial, the ethics committee shall timely review and propose a written modification, including full authority to suspend the trial.
2.3.1. Diagnostic criteria for semi-resistance to aspirin. Aspirin resistance is diagnosed as having both the AA-induced platelet aggregation rate ≥ 20% and ADP-induced platelet aggregation rate ≥ 70%, while those who meet one of the criteria are aspirin semi-resistance.
2.3.2. Inclusion criteria.
1. 45 < age < 65 years old, any gender, taking the single antiplatelet drug (aspirin);
2. More than 2 weeks after the onset;
3. Diagnosed as aspirin semi-resistance;
4.The Essen stroke risk score is less than 6;
5. Platelet count is 100-400 × 109/L;
6. No tendency of family or individual to bleeding;
7.No history of the myelodysplastic syndrome; no major surgical operation in the past month;
8.Traditional Chinese medicine with the function of promoting blood circulation and removing blood stasis is no longer used in the observation period;
9. Agree to participate in the clinical trial and complete the written informed consent.
2.3.3. Exclusion criteria.
1. Patients with a transient ischemic attack or cerebral infarction and have double-resistance;
2. Patients with cerebral hemorrhage after cerebral infarction, cerebral arteritis, brain tumor, brain trauma, and brain parasitic disease; patients with rheumatic heart disease, previous myocardial infarction, obvious cardiac insufficiency, abnormal liver and kidney function, active peptic ulcer, and severe gastrointestinal reaction;
3. Non-menopausal women;
4. Patients with various blood disorders, hemorrhagic diseases, or bleeding tendency, platelet count >450×109/L or < 100×109/L, or hemoglobin < 90 g/L;
5. Patients with an allergic constitution or taking other anti-inflammatory and analgesic drugs (NSAIDs);
6. Patients with disabilities (blindness, deafness, mute, mental retardation, mental disorder, and physical disability caused by other reasons) defined by law.
7. Patients who are suspected or do have a history of alcohol and drug abuse, or who, according to the judgment of the researchers, have other conditions that may reduce the possibility of enrollment or complicate their enrollment;
8. Those who are actively participating in other clinical trials or have participated in other clinical trials involving drugs within 3 months.
1. Violation of inclusion criteria and clinical trial protocol or compliance withexclusion criteria.
2. No treatment for 30 consecutive days, poor compliance, or loss of follow-up.
3. Serious side effects or adverse reactions.
4. Replacement of treatment that may affect the results of the study without the permission of investigators.
5.Withdrawal of consent by the party concerned or the legal representative.
2.4.Location of study implementation and patient recruitment
This study will be implemented in the Shaanxi Traditional Chinese Medicine Hospital and Xi'an Hospital of Traditional Chinese Medicine. Patients will be recruited via outpatient, inpatient, official hospital WeChat account, official hospital website, posters, and leaflets.
All patients successfully recruited will be randomized into either the experimental group or the control group according to the ratio of 1:1, with 60 cases in each group.
From 1stOctober 2020 to 30thSeptember 2022.
All the researchers were clinical doctors who have obtained the qualification certificate of medical practitioners issued by the National Health and Family Planning Commission, and have more than three years of clinical experience.
2.7.1. Treatment in the Control group.Basic treatment + placebo (a total of 3g, comprised of 0.3g Panax Notoginseng Powder and 2.7g malt powder, once a day, taken orallyafter dissolved)
2.7.2.Treatment in the experimental group. Basic treatment + Panax Notoginseng Powder (3g, once a day, taken orallyafter dissolved)
Basic treatment: The secondary prevention plan forcerebral stroke is implemented according to the Guidelines for Prevention and Treatment of Cerebrovascular Diseases in China (2014 Edition).Briefly:
(1)Antiplatelet aggregation: Oral administration of enteric-coated aspirin tablets 100 mg, once a day.
(2) Hypertension: Calcium channel antagonists (e.g., nifedipine), ACEI (e.g., Enalapril), ARB (e.g., Valsartan), β-blockers (e.g., metoprolol), and diuretics (e.g., hydrochlorothiazide) are selected according to the patient's condition to optimize blood pressure with the target of ≤ 140/90 mmHg, and it can be reduced to ≤ 130/80 mmHg under the condition of tolerance.
(3) Abnormal lipid metabolism: Long-term treatment with simvastatin, atorvastatin, or rosuvastatin with the target value of LDL-C decrease ≥ 50% or LDL ≤ 1.8 mmol/L.
(4)Diabetes mellitus: Insulin or oral hypoglycemic drugs are given, and the overall goal is HbA1C≤7%.
(5)Hyperhomocysteinemia: Oral administration of folic acid tablets 0.4 mg, once a day; mecobalamin capsules 0.5 mg, 3 times a day.
2.8.Observation of adverse events
Some patients may experience dry lips, restlessness, bleeding tendency in different parts of the body.
Blood samples will be collected from the elbow vein before treatment, at day-14, and day-30 of treatment. The platelet aggregation function, TXB2, PGI2, and ADP will be monitored.
The changes in blood pressure, blood lipid, and blood glucose are recorded before treatment, at day-14, and day-30 of treatment, when the changes of coagulation function are also monitored. The liver and kidney functions are monitored before and after the treatment to ensure safety.
2.11.Sample size estimation
This is a preliminary study that aimed to evaluate the efficacy and mechanism of the treatment. A total of 120 participants will be recruited.
The random distribution method will be operated by the coordinator of the Department of Encephalopathy of Shaanxi Traditional Chinese Medicine Hospital. Random numbers are generated by the SPSS 21.0 software and grouped by unpredictable random sequence block design. Patients are randomly assigned to the control group or the treatment group according to the 1:1 ratio. The serial number will be sealed in an opaque envelope and managed by PI. The random sequence block will not be informed to the research object or the implementer.
Data analysis will account for the lack of data through the principle of intentionality. Continuous variables that conform to normal distribution or approximate normal distribution are represented by mean ± standard deviation (± s), while continuous variables that do not conform to normal distribution are represented by median and quartile [M (P25, P75)]. Categorical variables are described by frequency or percentage. The Chi-square test is used to compare disordered classified variables between groups, and the rank-sum test is used for ordered classified variables.Continuous variables are analyzed by t-test, corrected t-test, or rank-sum test of two samples; repeated measurement data are analyzed by repeated measurement ANOVA; if the conditions of repeated measurement ANOVA are not met, generalized estimation equation analysis will be used; if there is a statistical difference between groups and there is interaction, the single effect analysis will be conducted. All tests are bilateral, with a P-value of< 0.05 considered statistically significant.
2.13.1.Results of primary indicators. Univariate repeated measures ANOVA will be used to compare the differences in platelet aggregation rate, TXA2, PGI2, and ADP between the two groups before treatment, at day-14, and day-30 of treatment.
2.13.2.Results of secondary indicators.Univariate repeated measurement ANOVA will be used to compare the general condition, blood pressure, blood lipid, coagulation function, and blood glucose between the two groups before treatment, at day-14, and day-30 of treatment.
2.13.3.Safety assessment.The T-test will be used to compare the liver and renal functions before treatment and at day-30 after treatment.
2.14. Quality control
The withdrawals and reasons for withdrawal will be fully documented throughout the treatment and follow-up period. To ensure the quality of the study, the quality monitoring will periodically verify all process details and check the authenticity of the data. The Scientific Research Department of Shaanxi Traditional Chinese Medicine Hospital has been invited as the third party to manage the data independently.Given that differences between physicians may result in biases, each assessment is performed by a designated physician who has been trained in the same assessment criteria. Before recruitment, doctors in charge of the treatment will receive special training on research and operation, including randomization, blinding, and key points of diagnosis and treatment. To record the participant’s attendance and compliance, each participant has been made a record card that records the date of treatment, personal information, and the signature of the patient after each treatment.