Comparative effectiveness and safety of four traditional Chinese medicine injections with invigorating blood circulation, equivalent effect of anticoagulation or antiplatelet in acute myocardial infarction: a Bayesian network meta-analysis

Background: Traditional Chinese medicine injections with invigorating blood circulation (TCMI-IBCs), which have been used as antithrombosis therapies, are widely employed by Chinese clinicians as adjuvant therapy for acute myocardial infarction (AMI). Objective: A Bayesian network meta-analysis was conducted to contrast the effectiveness and safety of four TCMI-IBCs in AMI. Methods: Eight Databases were thoroughly searched before 31 December 2023, for randomized controlled trials (RCTs) focusing on the application of TCMI-IBCs combined with conventional treatments (CT) to treat AMI. All-cause mortality (ACM) was the major endpoint. Secondary outcomes included bleeding events, malignant arrhythmia (MA), recurrent myocardial infarction (RMI), left ventricular ejection fraction (LVEF), and adverse events. Stata17.0 and GeMTC software were employed for Bayesian network meta-analysis. Results: A total of 73 eligible RCTs involving 7,504 patients were enrolled. Puerarin injection (PI), Danhong injection (DI), sodium Tanshinone IIA Sulfonate injection (STSI), and Danshen Chuanxiongqin injection (DCI) combined with CT can significantly reduce the occurrence of ACM and improve LVEF in AMI (P < 0.05), while without significant impact on bleeding events or MA (P > 0.05). STSI + CT would be the optimal treatment strategy in lowering RMI and ACM. DI + CT was the most likely to be the optimal strategy in reducing MA occurrence and improving LVEF. CT was likely the most effective strategy in reducing bleeding events. However, DI + CT exhibited the least favorable safety. Conclusion: TCMI-IBCs + CT had potential benefits in the treatment of AMI. STSI + CT showed the most favorable performance in treating AMI, followed by DI combined with CT. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=384067, identifier CRD42022384067.

into mixture to make the alcohol content up to 80-85%, and the supernatant was taken.About 1% activated carbon of the mixture volume was added by the pharmaceutical factory to the upper liquid, followed by stirring for 30 minutes, being left to stand, and filtration.Ethanol was recycled from the filtrate by the pharmaceutical factory until no alcohol taste remained.Then water for injection was added to reach a volume of 1000ml.The mixture was stirred well, heated and boiled for 40-50 minutes, refrigerated and filtered.Then the mixture was concentrated to about 333ml before being refrigerated again and filtered once more.The pH value of the filtrate was adjusted with a solution containing 40% sodium hydroxide until it reached between 6.5~7.5, after which it was heated and boiled for 40~50 minutes.Adding 0.5% of the liquid volume of activated carbon, then the pharmaceutical factory let the temperature of the liquid reduced to 50~60℃, followed by stewing and filtration.After ultra filtration of the filtrate, a further 0.5% of the liquid volume of activated carbon was added before boiling and filtering.After adding water for injection to the filtrate to 1000m1, the pharmaceutical factory adjusts the pH value to 6.5~7.5, followed by filtration, sterilization, then the Danhoong injection was obtained.chills, fever, facial flushing, nausea, vomiting, diarrhea, chest tightness, dyspnea, laryngeal edema, and convulsions.All symptoms resolve upon discontinuation of use.Rare anaphylactic shock.Contraindications: 1.This product is contraindicated for individuals prone to bleeding, as well as for pregnant and lactating women; 2. Those allergic to this product should not use it.

Sodium Tanshinone IIA Sulfonate injection
The pharmaceutical factory dries the salvia miltiorrhiza residue after boiling into coarse powder (the same process applies to raw materials not boiled).Then they weighs 50kg coarse powder, and adds five times the volume of 95% alcohol into it.The mixture is heated and refluxed for four hours, then it is filtered, followed by adding three Indication: It is used for chest pain and stroke caused by blood stasis.Symptoms include chest pain, chest tightness, palpitations, mouth and eye deviation, speech impediment, limb numbness, and restricted mobility.It is also used for coronary heart disease, angina pectoris, myocardial infarction, blood stasis pulmonary heart disease, ischemic encephalopathy, and cerebral thrombosis.Adverse reactions: This product may occasionally cause allergic reactions, including rash, pruritus, headache, dizziness, palpitations, chills, fever, facial flushing, nausea, vomiting, diarrhea, chest tightness, dyspnea, laryngeal edema, and convulsions.All symptoms resolve upon discontinuation of use.Rare anaphylactic shock.Contraindications: 1.This product is contraindicated for individuals prone to bleeding, as well as for pregnant and lactating women; 2. Those allergic to this product should not use it.anda half times the volume of 95% alcohol.The pharmaceutical factory heats and refluxes the mixture for three hours, followed by filtration, and repeats the process once more.The first alcohol extract is concentrated to approximately 20~25 liters, the second and third reflux extracts are combined and concentrated to the same volume, and each is left for about 15 hours for precipitation (the amount of crude product precipitated varies by variety and content), then the crude product is filtered.The mother liquor is left for about 15 hours for further precipitation, and the precipitates are filtered.The mother liquor is then concentrated to one-third of its volume, and left for over 10 hours, during which time further crude product precipitates.This Indication: The adjuvant treatment of coronary heart disease, angina pectoris and myocardial infarction.Adverse reactions: In some cases, rash, maculopapular rash, dermatitis, anaphylactic shock, chills, fever, hypotensive shock, pain, phlebitis, nausea, abdominal pain and other symptoms may occur.Contraindications: People allergic to this product should not use it.

SPH
NO. process is repeated until no more precipitates are observed.Then the extract is the Sodium Tanshinone IIA Sulfonate.

Chuanxiongqin injection
The pharmaceutical factory processes 200g Salvia miltiorrhiza, which is extracted with water and then treated with the sulfuric acid method.The extract is then refined through two alcohol precipitations (with the first reaching 60% and the second 70% alcohol content) to recycle the ethanol.This results in a clear liquid containing 0.4g of medicinal materials per 1ml, with the pH value adjusted for use as a stock solution.To prepare, mix 20g ligustrazine hydrochloride, 200ml glycerol, and the aforementioned solution thoroughly.Then the pharmaceutical factory adds water for injection and adjust the pH with hydrochloric acid solution, making a total volume of 1000ml.This mixture is then filtered, filled into 5ml ampoules, and sterilized at 115℃ for 30 minutes, then the Danshen Chuanxiongqin was obtained.
Indication: It is used for occlusive cerebrovascular diseases, such as cerebral insufficiency, cerebral thrombosis, cerebral embolism and other ischemic cardiovascular diseases, such as chest tightness of coronary heart disease, angina pectoris, myocardial infarction, ischemic stroke, thromboangiitis obliterans, and so on.Adverse reactions: Patients with cerebral hemorrhage and bleeding tendency should not use it.250nm.The number of theoretical plates shall not be less than 5000 according to puerarin peak, and the separation between puerarin peak and adjacent impurity peak shall meet the requirements.
Determination method: Take an appropriate amount of this product, accurately weigh it, quantitatively dilute it with mobile phase to make a solution containing about 50 μg puerarin per 1mL as the test solution.Then we accurately measure 10 μL test solution, and inject it into the liquid chromatograph to record the chromatogram; Take another puerarin as a control and determine it with the same method.Calculate the peak area according to the external standard method.
(1) Dispense an appropriate amount of the product, add 2-3 drops of a 0.5% ferric chloride solution, shake well, followed by the addition of 2-3 drops of a 0.5% potassium ferricyanide solution, shake again to mix thoroughly, and observe the resulting blue-green color.
(2) Dispense an appropriate amount of this product and add ethanol to prepare a solution with approximately 10 μg of puerarin per 1mL.
According to the UV-spectrophotometry, there is a maximum absorption at the wavelength of 250nm.

Pharmacopoeia of the
People's Republic of China Danhong injection A

Salvia miltiorrhiza
Determining content using high-performance liquid chromatography Octadecylsilane bonded silica gel was used as filler, methanol-1% glacial acetic acid solution (13:87) was used as mobile phase, and the detection wavelength was 280nm.The number of theoretical plates shall not be less than 5000 according to the peak of Danshensu.
Preparation of reference solution: Accurately weigh an appropriate amount of Danshensu Sodium and Protocatechualdehyde reference, add water to make a solution containing 50 g per 1mL.
Preparation of total test solution: Precisely measure 5mL of this product, put it into a 20mL measuring flask, add water to dilute to the scale, shake well, and then get.
The determination method is to precisely aspirate 10mL of each of the reference and test solution, inject them into the liquid chromatograph, and determine.
This product contains no less than 0.5mg of Salvia miltiorrhiza per 1mL based on the total amount of Danshensu (c9h1005) and protocatechuic aldehyde (c7h603)

Total flavonoids
Preparation of reference solution: Accurately weigh 20mg of rutin reference substance dried at 120 ℃ to constant weight, put it into a 100m1 volumetric flask, add an appropriate amount of 50% methanol, shake to dissolve and dilute to the scale, and shake well to obtain (0.2mg of anhydrous rutin per 1m1).
Preparation of standard curve accurately measure 1.0mL, 2.0mL, 3.0mL, 4.0mL and 5.0mL of the reference solution, put them into 10mL volumetric flasks respectively, add 50% methanol to 5mL each, add 0.3mL of 5% sodium nitrite solution, shake well, place for 6 minutes, add 0.3mL of 10% aluminum nitrate solution, shake well, place for 6 minutes, add 4mL of sodium hydroxide test solution, add 50% methanol to the scale, shake well.
Take the corresponding solution as blank.500nm, and draw a standard curve with the absorbance as the ordinate and the concentration as the abscissa.
Determination method: Accurately suck 5mL of this product, place it in a 100mL measuring flask, add water to dilute to the scale, shake well, accurately measure 1mL, place it in a 10mL measuring flask, add 50% methanol to the scale, shake well, and serve as a blank control.In addition, accurately measure 1mL, put it into a 10mL measuring flask, measure the absorbance according to the method under the preparation of the standard curve, read the weight equivalent to Rutin in the test solution from the standard curve, and calculate.
The total flavonoids contained in this product per 1mL shall not be less than 5.0mg based on rutin (c27h30016).

Sodium
Tanshinone IIA Sulfonate injection A Take about 25mg of the product, accurately weigh it, put it into a 250ml measuring bottle, add water to dilute to the scale, shake it well, accurately measure 5ml, put it into a 100ml measuring bottle, add water to dilute to the scale, shake it well, use spectrophotometry, measure the absorbance at the wavelength of (271 ± 2) nm, and calculate according to the absorption coefficient of C19H17O3• SO3Na is 767.
⑴ Take approximately 0.5mg of this substance, place it on a white porcelain plate, add 1 to 2 drops of sulfuric acid.It immediately turns dark blue, gradually changing to dark green.
⑵ Take 10mg of the substance, ignite to ash, add 5mL of 1mol/L hydrochloric acid solution, filter the mixture, then add 5mL of barium oxide test solution to the filtrate.This results in a white precipitate.
Additionally, it displays a characteristic peak at a wavelength of ( 280± 2) nm.should not be less than 1500 according to the tanshinol peak.

Standards of China
Preparation of reference solution take an appropriate amount of Danshensu Sodium reference, accurately weigh, add methanol to dissolve and quantitatively dilute to make a solution containing about 90mg per 1mL (1mg of Danshensu Sodium is equivalent to 0.875mg of Danshensu).
Preparation of test solution accurately measure 5~25mL of this product, place it in a volumetric flask, add methanol to dilute to the scale, shake well, filter with a microporous filter membrane (0.45mm), and take the filtrate as the test solution.
Determination method take 10mL of the reference solution and 10mL of the test solution respectively, inject them into the chromatograph, record the chromatogram, and calculate the peak area according to the external standard method.

Ligustrazine hydrochloride
Determining content using high-performance liquid chromatography Octadecylsilane bonded silica gel was used as filler; Methanol-0.4% phosphoric acid (10∶90) was used as the mobile phase, the flow rate was 1.0mL/min, the detection wavelength was 292nm, and the number of theoretical plates according to the peak of ligustrazine hydrochloride should not be less than 2000.
Preparation of reference solution: Take an appropriate amount of tetramethylpyrazine hydrochloride standard, accurately weigh it, dissolve it with methanol and quantitatively dilute it to make a solution containing about 40mg per 1mL.
Preparation of test solution: Accurately measure 1mL of this product into a 50mL volumetric flask, add methanol to dilute to the scale, shake, take 1mL of diluted solution into a 10mL volumetric flask, add methanol to dilute to the scale, shake, filter with a microporous filter membrane (0.45mm), take the filtrate as the test solution.
For the determination method, 5mL of the reference solution and 5mL of the 2002) test solution were accurately aspirated, injected into the chromatograph, and the chromatogram was recorded.The peak area was calculated according to the external standard method.

Supplementary table S4
The principal chemical constituents of four TCMI-ABCs under fingerprint methods.

TCMI-ABCs
Spectrophotometric method: Determine the absorbance at the wavelength of Evaporate 4mL of this product to dryness, add 1mL of absolute ethanol to the residue, dissolve, centrifuge, and use the supernatant as the test solution.Additionally, take 1g of Carthamus tinctorius control medicinal material, add 10mL of water, sonicate for 30 minutes, filter, concentrate the filtrate to dryness, add 1mL of absolute ethanol to the residue, dissolve, centrifuge, and use the supernatant as the control medicinal material solution.Conduct a thin-layer chromatography test by applying 1μL of each solution to the same silica gel G plate, using n-butanol-glacial acetic acid-water(6:2.4:5)as the developer, develop, remove, dry, and inspect under ultraviolet light (365nm).In the chromatogram of the test sample, fluorescent spots of the same color appear at the position corresponding to the chromatogram of the control medicinal material.

Supplementary table S3 Analytical
methods for the chemical profile of the four kinds of TCMI-ABCs according to ConPhyMP