Safety and efficacy of salvianolate injection in preventing deep vein thrombosis after total hip replacement

Purpose: To investigate the safety and efficacy of salvianolate injection in preventing deep vein thrombosis (DVT) following total hip replacement. Methods: A total of 114 patients who underwent total hip replacement at Department of Trauma, Fengfeng General Hospital of North China Medical and Health Group, Handan City, China from March 2019 to March 2022 were enrolled. Patients were randomly divided into study group (n = 57) and control group (n = 57). The control group received conventional treatment (low molecular weight heparin) while the study group was administered salvianolate injection combined with conventional treatment. Incidence of deep vein thrombosis (DVT) at 7 and 14 days after surgery, platelet function indices, including platelet count, glycoprotein Ⅱ b/ Ⅲ a (GP Ⅱ b/ Ⅲ a), and CD62P, coagulation function indices (prothrombin time (PT), fibrinogen (FIB) and D-dimer), and hemodynamics indices, viz, peak blood flow velocity (Vp) and average velocity (Va) were investigated and compared. Results: Incidence of DVT was 1.75 % (1/57) at 7 days and 5.26 % (3/57) at 14 days in the study group, and 5.26 % (3/57) at 7 days and 17.54 % (10/57) at 14 days in control group. Incidence of DVT in the study group was significantly reduced compared to control group 14 days after surgery (p < 0.05). Also, the study group had significantly lower visual analog scale (VAS) scores at 7 days and 1 month after surgery compared to control group (p < 0.05). Platelet count, GP Ⅱ b/ Ⅲ a, and CD62P in the study group were significantly lower than in control group (p < 0.05). Conclusion: Salvianolate injection significantly prevents DVT after total hip replacement, improves hemodynamics, and coagulation function, and thus contributes to recovery of hip function. Further clinical trials are, however, required to validate these findings.


INTRODUCTION
Deep venous thrombosis (DVT) is caused by pathological accumulation of blood clots (thrombi) in deep veins, typically in legs.These clots can obstruct normal blood flow in affected vein, causing some clinical symptoms such as swelling, pain, and potentially severe complications.Patients with pulmonary embolism have the highest fatality rate [1].Hip surgery affects blood flow to limbs, and DVT easily occurs due to impaired blood circulation [2].Some studies have pointed out that DVT after total hip replacement does not facilitate postoperative recovery of hip function in patients [3].Low molecular weight heparin is currently the primary drug for thrombosis treatment, and it downregulates DVT incidence.However, many surgical patients still have a high incidence of thrombotic disease even after receiving treatment with low molecular weight heparin, suggesting that relevant drugs may be given for treatment on this basis [4].
Salvia miltiorrhiza, a traditional Chinese medical herb, is known for improving circulation of blood and alleviating blood stasis.Salvianolate is a bioactive compound extracted from Salvia miltiorrhiza and exhibits high clinical efficacy in improving hematological abnormalities [5,6].Therefore, this study aimed to investigate safety and efficacy of salvianolate injection in preventing lower limb DVT after total hip replacement.

Patient information
A total of 114 patients who underwent total hip replacement at Department of Trauma, Fengfeng General Hospital of North China Medical and Health Group, Handan City, China March 2019 to March 2022 were enrolled.The patients were randomly divided into study group (n = 57) and control group (n = 57).This study was approved by Ethics Committee of Fengfeng General Hospital of North China Medical and Health Group (approval no.20181220F) and written informed consent was obtained from participants.All processes were conducted in compliance with ethical standards of the Institutional Review Board and the guidelines of Declaration of Helsinki [7], and its subsequent amendments or analogous ethical standards.

Inclusion criteria
Patients undergoing total hip replacement surgery, with normal coagulation function before surgery, without evidence of DVT after examination with Doppler ultrasound, and who have complete clinical information were included in the study.

Exclusion criteria
Patients with severe cardiac, liver, and renal dysfunction; active bleeding or bleeding tendency; acute and chronic infectious diseases; allergic constitution, severe cognitive dysfunction, coagulation dysfunction before surgery, old fracture, and previous history of hip surgery were excluded from the study.

Procedures and management
Both groups underwent total hip replacement.In control group, patients were given targeted intervention in perioperative period based on recommendations outlined in guidelines for preventing venous thromboembolism in major orthopedic surgery in China.After surgery, heparin sodium injection (Qianhong Bio-pharma, Hangzhou, China; batch number: H32022088) was administered as an adjunct to standard treatment (5000 U subcutaneous injection for first treatment and 5000 U/12 h subcutaneous injections for a total of 14 days).After surgery, patients were instructed to perform ankle flexion and extension exercises, family members were instructed to massage lower limbs and elevate the affected limbs, and plantar vein pump was actively given for physical intervention.
Study group was additionally given salvianolate injection (GreenValley, Shanghai, China; batch number: Z20050248).Salvianolate injection (200 mg) was added to 250 mL normal saline and administered as intravenous drip, once daily for 14 days.

Incidence of DVT
Incidence of DVT was compared at 7 and 14days post-surgery.Diagnostic criteria for DVT are as follows: acute onset, swelling, skin temperature rise, pain, positive Homans sign, and color Doppler ultrasonography showing no color blood flow signal in venous blood vessels.

Pain degree
Visual analog scale (VAS) evaluated pain degree [8], with scores ranging from 0 to 10. Higher scores indicate greater pain.

Platelet function indices
A 3 mL sample of fasting venous blood was obtained a day prior to surgery and 14 days after surgery.
Serum was obtained through centrifugation.Levels of glycoprotein Ⅱb/Ⅲa (GPⅡb/Ⅲa) and CD62P in serum were measured using Beckman Coulter Navios flow cytometry.Platelet count was determined using ethylene diamine tetra-acetic acid (EDTA) method.

Coagulation function indices
Fasting venous blood (3 mL) was collected a day before surgery and 14 days after surgery.Serum was obtained through centrifugal.Level of prothrombin time (PT) was determined using Quaker phase I method, fibrinogen level was determined by test single diffusion method, and D-dimer level was determined by monoclonal antibody method.

Lower limb hemodynamics
Mindray DC-8 color Doppler ultrasonography device was used to determine femoral vein peak velocity (Vp) and average velocity (Va) before and 14 days after surgery.

Hip function
Harris score was used to analyze hip function before surgery and 3 months after surgery [9], including pain, function, deformity and motion.Score rating from 0 to 100, with a higher score indicating better hip function.

Statistical analysis
Data were analyzed using Statistical Packages for Social Sciences software (version 22.0).Enumeration data are presented as percentages and analyzed using Chi-square test.Measurement data are expressed as mean ± standard deviation (SD) and comparisons were done using t-test.P < 0.05 was considered statistically significant

Compared
to control group, additional salvianolate treatment (study group) significantly reduced VAS scores 7 days and 1 month before surgery in patients (Figure 1).

Coagulation function indices
Compared to control group, study group had significantly greater efficacy in reducing levels of fibrinogen (Figure 2 A), and D-dimer (Figure 2 B), and also, shortening prothrombin time (Figure 3  C).

Incidence of adverse reactions
No noticeable side effects occurred in all patients during treatment.

DISCUSSION
Lower limb DVT is a common clinical disease in vascular surgery.Its high incidence is in patients requiring prolonged bed rest due to surgical operations, chronic diseases, and limb movement restriction, which often results in symptoms such as pain swelling, and further induces pulmonary embolism, disability, and even death [10].During hip replacement, veins may be damaged, and intraoperative vein blood may become hypercoagulable or stagnant, potentially increasing risk of venous thrombosis.Heparin is the main drug used in postoperative anticoagulant therapy, but it still has limitations in elderly due to large doses and clearance primarily through the kidneys.It is believed that traditional Chinese medicine has therapeutic effects on postoperative DVT [11].
Salvia miltiorrhiza is a traditional Chinese medical herb for stimulating circulation of blood and removing blood stasis.Pharmacological studies have demonstrated that pharmacological components of Salvia miltiorrhiza inhibit platelet aggregation, and thrombosis, and promote microcirculation [12].Other studies on animal experiments have found that Salvia miltiorrhiza significantly reduced whole blood viscosity and inhibited platelet aggregation under conditions of low shear rate [13] This research revealed that salvianolate led to an improvement in pain, function, deformity, mobility, and Harris scores.Simultaneously, it resulted in a reduction in VAS scores at both 7 days and 1 month after surgery.These findings suggest that salvianolate alleviates postoperative pain and enhances hip joint function, which may be linked to enhanced coagulation function and reduction in DVT occurrence In addition, results showed that no significant side effects occurred in all patients during treatment, suggesting that salvianolate injection has a high safety in preventing DVT formation after total hip replacement.

Limitations of the study
This was a single-center study with a relatively small sample size.Consequently, larger-scale stochastic clinical study is necessary to verify the reliability of these findings.

CONCLUSION
Salvianolate injection is effective in preventing DVT after total hip replacement, improves hemodynamics and coagulation function, and contributes to postoperative hip function recovery.Nonetheless, there is a need to validate these findings in further clinical trials.
treatment combined with conventional treatment (study group) significantly increased Vp (Figure 4 A) and Va values (Figure 4 B) after treatment.