Archives of Academic Emergency Medicine. 2023; 11(1): e43 OR I G I N A L RE S E A RC H The Effects of 3-Month Rosuvastatin Adjuvant Therapy on Post Thrombotic Syndrome following Deep Vein Throm- bosis; a Randomized Clinical Trial Mehdi Pishgahi1, Shirin Ghane Fard2, Rahil Lak Tabriz1, Kimia Karimi Toudeshki1∗, Zahra Talebi3 1. Department of Cardiology, Shohadaye Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 2. Pediatric Endocrinologist, Shohadaye Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 3. School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Received: April 2023; Accepted: May 2023; Published online: 10 June 2023 Abstract: Introduction: Statins are known to have anticoagulation and anti-inflammatory effects. This study aimed to investi- gate the effect of Rosuvastatin in reduction of post thrombotic syndrome (PTS) following deep vein thrombosis (DVT). Methods: In this randomized clinical trial, patients who were diagnosed with DVT of lower extremity were randomly assigned to 4 treatment groups: group 1: Warfarin, group 2: Warfarin + Rosuvastatin, group 3: Rivaroxaban, and group 4: Rivaroxaban + Rosuvastatin. The treatments were followed for 3 months and prevalence of PTS (as primary outcome), as well as the changes in serum levels of D-dimer and C reactive protein (CRP), and the extent of thrombosis before and after the intervention (as secondary outcomes) were compared between groups. Results: 182 patients with the mean age of 55.22 ± 4.1 years finished the trial period (51.64% male). There was no significant difference between the groups regarding the baseline characteristics. Based on the Brandjes score, 31 (17.03%) patients had PTS at the end of the study. The occurrence of PTS was significantly lower in the groups taking statins (p<0.0001). Although the change in the mean difference of legs circumference before and after intervention, were significant in all groups (p < 0.05), the differences was more prominent in groups 2 and 4 (p < 0.0001). After 3 months of taking medication, decrease of CRP was more prominent in the statin groups (p = 0.001), and most cases with normal CRP were in statin groups. Among the patients with the serum D-dimer level above 10000 ng/mL, patients in the statin groups experienced significantly more reduc- tion in D-dimer levels than the other groups (p<0.001). Conclusion: Rosuvastatin administration in combination with rivaroxaban or warfarin significantly reduces the level of inflammatory factors including CRP and D-dimer, compared to patients receiving anticoagulants alone. Rosuvastatin administration can significantly reduce the incidence of PTS and cause a difference in the size of the lower limbs within 3 months. Keywords: Venous thrombosis; Postthrombotic syndrome; Rosuvastatin calcium; Rivaroxaban; Warfarin; Anticoagulants Cite this article as: Pishgahi M, Ghane Fard S, Lak Tabriz R, Karimi Toudeshki K, Talebi Z. The Effects of 3-Month Rosuvastatin Adjuvant Therapy on Post Thrombotic Syndrome following Deep Vein Thrombosis; a Randomized Clinical Trial. Arch Acad Emerg Med. 2023; 11(1): e43. https://doi.org/10.22037/aaem.v11i1.1972. 1. Introduction Deep vein thrombosis (DVT) and acute pulmonary em- bolism (PE) are two presentations of venous thromboem- bolism (VTE). DVT can impose a significant burden on the patient’s life; especially when it leads to pulmonary em- bolism (1). It has been reported that DVTs of the proximal veins of the lower extremities may be more likely to create ∗Corresponding Author: Kimia Karimi Toudeshki; Cardiology De- partment, Shohada-e-Tajrish Hospital, Qods Sq., Tajrish, Tehran, Iran. Tel: (+98)2122718000, Email: kymya77@yahoo.com, ORCID: https://orcid.org/0000-0001-7560-7091. edema compared to others; resulting in different circumfer- ences of the lower limbs in unilateral cases (2). DVT treat- ment mainly involves anticoagulation when there is no con- traindication. Afterwards, measures are taken to prevent fu- ture recurrences, embolism, and thrombosis-related compli- cations (1). It has been shown that treatment with novel oral anticoagulants (NOACs) reduces the duration of hospitaliza- tion of patients in comparison to low molecular weight hep- arin (LMWH), warfarin or unfractionated heparin (UFH) (3). Post Thrombosis Syndrome (PTS) is the most common long- term complication of deep venous thrombosis (DVT) (4). PTS is the result of chronic venous insufficiency, which develops following deep vein thrombosis (DVT). This chronic venous This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index M. Pishgahi et al. 2 insufficiency is due to valvular incompetence and venous hypertension that follows the thrombotic obstruction. Ele- vated D-dimer level is commonly used as a predictor of post- thrombotic syndrome, since it is the consequence of persis- tent activation of clotting or inflammatory pathways (5). PTS significantly reduces the quality of life with a wide range of adverse effects from minor inflammation, edema, and pain to severe complications such as venous stasis ulcers (6). Patients with extensive DVT, recurrence of thrombosis on the same side of the body, a history of varicose veins, obesity, or residual thrombosis are at increased risk of developing PTS (6). The best treatment strategy for prevention of PTS is still un- clear (7). Maintaining an appropriate International Nor- malized Ratio (INR) for Warfarin, use of the Catheter Lysis method, and long-term treatment with low molecular weight heparin (LMWH) are suggested to reduce the risk of develop- ing PTS (8, 9). On the other hand, The JUPITER trial (2009) demonstrated a significant improvement in non-hyperlipidemic DVT pa- tients, with elevated C-reactive protein (CRP) levels, when treated with rosuvastatin. In addition to decreasing choles- terol levels and CRP, treatment with statin seems to influence the process of coagulation by inhibiting tissue factor activity and activating platelets by reducing the expression of CD40L or P-selectin (10). But the ability of statins to reduce the in- cidence of PTS is still unclear for physicians and researchers. San Norberto et al. evaluated the use of statin therapy (ro- suvastatin 10 mg or 5 mg) in prevention of PTS in DVT pa- tients over 70 years old (11). In this study, although a sta- tistically significant difference in the primary outcome (D- Dimer) was not observed, a significant reduction in serum CRP levels and the incidence of PTS was seen in participants treated with rosuvastatin (Villalta score higher than 5, 38.3% vs. 48.5%, p =0.019) (11). It has been hypothesized that in- flammatory mediators released due to thrombus formation may induce valvular damage, leading to PTS (12-14). Also, a positive association between level of inflammatory markers (such as CRP, and intercellular adhesion molecule 1 (ICAM- 1)) with PTS development have been reported. Considering the effect of rosuvastatin for inhibition of ICAM-1 expression (15), the idea of investigating its effect on prevention of PTS may be considered. Statins are easy to use, cheap and very safe and do not in- crease the risk of bleeding; and according to available data, they can be valuable in the treatment and prevention of re- currence of VTE. This study aimed to evaluate the effect of rosuvastatin adjuvant therapy along with common anticoag- ulants on the improvement of treatment outcome and reduc- tion of PTS incidence in patients with acute DVT. 2. Methods 2.1. Study design and setting This randomized controlled trial was conducted on patients with established acute DVT, admitted to Shohadaye Tajrish, Modarres, and Labbafi Nejad Hospitals (affiliated to Shahid Beheshti University of Medical Sciences), Tehran, Iran, from September 25, 2017 to September 20, 2018 to evaluate the ef- fects of rosuvastatin on 3-mounth outcomes. The study protocol was approved by Research Ethics Com- mittee of Shahid Beheshti University of Medical Sciences, Tehran, Iran (IR.SBMU.REC.1396.651), registered in Iranian Registry of Clinical Trials (IRCT20150621022852N4), and conducted adhering to principles of Helsinki Declaration. Patients were assured that all information will remain con- fidential and anonymous. All patients provided written in- formed consent for participation. 2.2. Participants Inclusion criteria consisted of age over 18 and estab- lished acute DVT diagnosed via Doppler ultrasonography by an expert attending radiologist. Patients with End- Stage Renal Disease (ESRD) who underwent routine dialy- sis and/or patients with glomerular filtration rate (GFR) be- low 30mL/min/1.73 m2, patients diagnosed with cancer be- fore or during the trial, conditions such as infections and/or sepsis, which could affect serum inflammation factors and D-dimer levels, those with prior statin use, a contraindica- tion for statin therapy (such as liver disease, severe myopa- thy during the treatment, etc.), bilateral DVT, loss to follow- up during the 3 months of trial for any reason including un- willingness of participants, and death during the trial period, were excluded. In addition, patients with chronic or acute on chronic DVT (based on the ultrasonography results) were also excluded. 2.3. Data gathering and intervention Demographic data and patient history were obtained through patient interviews and extent and area of thrombo- sis were determined via physical exam and Doppler ultra- sonography. Diagnostic tests such as Serum CRP level, Serum D-dimer, assessment of thrombosis area with Doppler ultra- sonography (by an attending radiologist unaware of patient allocations) were performed. Computer software was used for permuted block randomization of patients into 4 groups (with 52 patients in each group) for treatment regimen allo- cation: Group 1: Warfarin; Group 2: Warfarin + Rosuvastatin; Group 3: Rivaroxaban; Group 4: Rivaroxaban + Rosuvastatin. The first arm received warfarin following initial heparin infu- sion, the standard therapy, with the aim of reaching the tar- get INR of 2-3. In the second arm, in addition to warfarin, This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index 3 Archives of Academic Emergency Medicine. 2023; 11(1): e43 rosuvastatin 20mg (Rosurexin® tablet 20mg, manufactured by ACTOVERCO Pharmaceutical Factory, Karaj, Iran) was ad- ministered once daily. The third arm received rivaroxaban 15mg twice a day in the first 3 weeks and then 20mg once daily. In the fourth arm, rosuvastatin was added to rivaroxa- ban regimen for treatment with the dosage mentioned pre- viously. Dose was adjusted for patients with renal impair- ment. Use of compression stockings was advised for all pa- tients according to treatment protocols in time with the ini- tiation of medications. All patients were followed up every 2 weeks by phone for adherence to treatment regimen. Af- ter 3 months, CRP and D-dimer levels, difference in swelling between two calves-diameter of circumference of calf 4 cm below the tuberosity of tibia bone, and occurrence of PTS were assessed again for all patients and the results were com- pared to previous data of the patient and the data from other groups. If the patients had infections in their second visit for CRP assessment, the assessment was postponed for another 2 weeks. In this study, the occurrence of PTS was confirmed based on Brandjes criteria, which consists of two sets of subjective and objective items. Subjective items (symptoms) include spontaneous pain in calf, spontaneous pain in thigh, pain on standing/walking, pain in thigh on standing/walking, edema of foot/calf, heaviness of leg, spontaneous pain and pain on walking/standing, and impairment of daily activities; each one having one point. Objective items (signs) include calf cir- cumference increase by 1 cm, ankle circumference increase by 1 cm, pigmentation, venectasia, newly formed varicosis, phlebitis, and venous ulcer; each one having one point ex- cept the venous ulcer, which has 4 points. Patients with a score of 3 are considered mild, while 4 is considered moder- ate, and scores 5 or more or any score along with ulceration of the limb are considered severe PTS. 2.4. Outcomes The treatments were followed for 3 months and prevalence of PTS (as primary outcome), as well as the changes in serum levels of D-dimer and C reactive protein (CRP), and the extent of thrombosis before and after the intervention (as secondary outcomes) were compared between groups. 2.5. Statistical analysis According to literature, and considering an improvement rate of 0.33-0.65, and using the G power software, the min- imum of 38 patients were allocated to each group; but with considering the dropouts, 208 patients were set out to be ex- amined. Statistical analysis was done using IBM SPSS Statis- tics 25. Continuous variables are described as mean and standard deviation (SD). Categorical variables are described by frequency and percentage. Gender and baseline calf swelling were compared between the four groups using Chi- square. One-way ANOVA analysis was used for comparison of age, BMI, CRP, and D-dimer between the 4 groups. One- way ANOVA analysis was used to investigate the changes in level of CRP, d-dimer, and calf swelling after 3 months. Also post hoc analysis using One-way ANOVA was used to deter- mine the significance of difference between study arms. P value < 0.05 was considered statistically significant. 3. Results 3.1. Baseline characteristics of patients 208 patients (52 patients in each group) with unilateral DVT of lower limbs (62.8% right leg) were included in the study (23% had concomitant PTE). During the trial, there were 26 dropouts due to reasons such as death, cancer, and inabil- ity to follow up and ultimately 182 patients (50 in Warfarin group, 49 Warfarin + Rosuvastatin, 44 in Rivaroxaban and 39 in Rivaroxaban + Rosuvastatin) finished the trial period (51.64% male). The baseline characteristics of studied pa- tients are shown in Table 1. Among the patients, 54 (29.6%) had DVT in the area above the knee (the popliteal area) and 128 (70.4%) had DVT in the area below the knee. There was no significant difference between the groups in the baseline characteristics at the beginning of the study. Five patients had iliac involvement (very proximal DVT), two in the Rivaroxaban + Rosuvastatin group and one in each of the other groups (p = 0.28). 42.8% of the patients had CRP above the normal range (6 mg/L) on presentation. 3.2. Outcomes Table 2 shows the changes in CRP, D-dimer, and calf swelling after 3 months in each study arm. Post hoc analysis of the groups is presented in Table 3 and details are given below: Occurrence of PTS Based on the Brandjes score, 31 (17.03%) patients had PTS at the end of the study (table 4). The occurrence of PTS was significantly lower in the groups taking statins (p<0.0001). In addition, no one in the statin groups had severe PTS. Calf swelling difference > 3 cm At the beginning of the study 140 (76.9%) patients had more than 3 cm difference in circumference diameter between two legs, 24 (17.1%) of which had differences more than 5 cm. Af- ter 3 months of treatment, in 47 (33.5%) patients the differ- ence between circumference diameter of the two calves did not reach normal level (below 2 cm). Although the change in legs circumference diameter before and after intervention was significant in all groups (p < 0.05), the differences were more prominent in groups 2 and 4 (p < 0.0001). The maximum change of circumference diameter was seen in patients with more than 5cm difference between 2 calves at base and those who were in statin groups. CRP This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index M. Pishgahi et al. 4 Table 1: Comparing the baseline characteristics of patients between groups Variables Study groups P 1 (n = 50) 2 (n = 49) 3 (n = 44) 4 (n = 39) Gender Male 27 (54.0) 25 (51.0) 23 (52.3) 19 (48.7) 0.94 Female 23(46.0) 24 (49.0) 21 (47.7) 20 (51.3) Age (years) Mean ± SD 55.01±4.3 54.04±3.9 56.53±4.4 55.2±4.6 0.06 Body mass index (kg/m2) Mean ± SD 30.30±3.2 29.71±3.2 30.09±3.2 30.54±3.3 0.68 CRP (mg/L) Mean ± SD 10.73±1.7 8.31±1.6 10.66±2.6 9.53±1.7 0.084 D-dimer (ng/ml) Mean ± SD 3034.27±1230.1 3029.86±1471.9 2971.93±1730.8 3664.16±1964.6 0.176 Calf size difference# > 3 cm Number (%) 45 (90.0) 37 (75.5) 32 (72.7) 26 (66.7) 0.17 Thrombose location n (%) Above the knee 13 (26.0) 16 (32.7) 13 (29.5) 12 (30.8) 0.28 Below the knee 37 (74.0) 33 (67.3) 31 (70.5) 27 (69.2) #: Compared with unaffected limb. Data are presented as mean ± standard deviation (SD) or frequency (%). Group 1: warfarin; group 2: Warfarin + Rosuvastatin; group 3: Rivaroxaban; group 4: Rivaroxaban + Rosuvastatin. CRP: C-reactive protein. Table 2: Comparing the studied outcomes before and 3 months after intervention Variable Before After P value C-reactive protein (mg/L) Warfarin 11.58±8.3 8.35±2.1 0.09 Warfarin + Rosuvastatin 8.53±3.3 2.24±0.4 0.001 Rivaroxaban 11.69±8.6 7.69±3.2 0.07 Rivaroxaban + Rosuvastatin 9.78±4.1 1.62±0.5 0.001 D-dimer (ng/ml) Warfarin 3034.27±1230.1 344.54±81.0 <0.0001 Warfarin + Rosuvastatin 3029.86±1471.9 148.48±61.1 <0.0001 Rivaroxaban 2971.93±1730.8 345.33±143.7 <0.0001 Rivaroxaban + Rosuvastatin 3664.16±1964.6 217.83±134.1 <0.0001 Calf swelling difference > 3# cm Warfarin 45 (90.0) 23 (4.0) 0.04 Warfarin + Rosuvastatin 37 (75.5) 8 (16.3) <0.0001 Rivaroxaban 32 (72.7) 11 (25.0) 0.01 Rivaroxaban + Rosuvastatin 26 (66.7) 5 (12.8) <0.0001 #: Compared with unaffected limb. Data are presented as mean ± standard deviation (SD) or frequency (%). After 3 months of medication use, serum CRP levels were re- duced in all 4 groups of the study but was only significant in groups 2 and 4 (p = 0.001 in both groups). In 11% (20 pa- tients) although the CRP had reduced, it had not reached the normal level (below 6 mg/L). According to table 3, post hoc analysis revealed that rivarox- aban + rosuvastatin group had more reduction than warfarin + rosuvastatin group (p = 0.84). D-dimer After 3 months of treatment, serum D-dimer was reduced in all patients but did not reach the normal level (below 500ng/mL) in 8% of them. Between the patients with the serum D-dimer level above 10000 ng/mL, patients in the statin groups experienced significantly more reduction in D- dimer levels than the other groups. In other words, statins were more efficacious in patients with higher levels of serum D-dimer (p<0.001) Although the mean difference of D-dimer before and 3 months after intervention was statistically sig- nificant in all groups, the difference was greater in the ri- varoxaban + rosuvastatin vs non-statin groups (p < 0.001) and warfarin + rosuvastatin (p = 0.017). This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index 5 Archives of Academic Emergency Medicine. 2023; 11(1): e43 Figure 1: General scheme of study design. ESRD: End-Stage Renal Disease. 4. Discussion The present study was conducted as a clinical trial with the aim of investigating the effect of the use of statins along with common anticoagulant therapy on the improvement of pa- tients with acute DVT and reduction of PTS incidence. The results show that the addition of statins to anticoagulants seems to make the regimen more effective in improving the treatment outcomes of DVT patients. Moreover, rosuvastatin administration in combination with rivaroxaban or warfarin significantly reduces the amount of DVT-associated inflam- matory factors including CRP and D-dimer, compared to pa- tients receiving anticoagulants alone. It can significantly re- duce the incidence of PTS and the difference in the size of the lower limbs within 3 months, which is even more effec- tive when difference between two legs is more than 5 cm. Statin use was associated with a decreased rate of DVT, PE, or overall VTE in 7 studies (1 randomized clinical trial, 4 case–controlled studies, 1 retrospective cohort study, and 1 basic science study), including the JUPITER trial. The large randomized trial of JUPITER showed that in 17,802 patients, in 26 countries, with a 5-year follow-up, among people with normal LDL-C levels and elevated CRP, rosuvastatin 20mg reduced the risk of VTE by more than 40% compared with placebo (16). In two registrations based on the Danish pop- ulation, the use of statin among patients with VTE diagno- sis was associated with a lower risk of recurrent VTE (haz- ard ratio (HR)= 0.74, and 95% confidence interval (CI) 0.68- 0.87 and 0.72, 95% CI 0.58- 0.88) compared with the group not consuming statin (17). Adjuvant treatment with statins in patients admitted to the hospital with acute PE was also associated with a reduction in the risk of recurrent PE (HR= 0.50, and 95% CI 0.36-0.70) (18). The effect was maintained during and after stopping the anticoagulant therapy. In ad- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index M. Pishgahi et al. 6 Table 3: Post hoc analysis using one-way analysis of variance (ANOVA) to determine the significance of difference between study arms Variable Mean difference P value Calf swelling difference > 3# cm Rivaroxaban+ Rosuvastatin Reference - Warfarin -1.30342 <0.001 Warfarin +Rosuvastatin 0.73287* 0.06 Rivaroxaban -1.08360* <0.001 Change in C-reactive protein level Rivaroxaban+ Rosuvastatin Reference - Warfarin -1.47436* .003 Warfarin +Rosuvastatin -0.32620 .864 Rivaroxaban -1.74709* .000 Change in D-dimer level Rivaroxaban+ Rosuvastatin Reference - Warfarin -126.70677* <0.001 Warfarin +Rosuvastatin 69.35699* 0.017 Rivaroxaban -127.49775* <0.001 Occurrence of post thrombotic syndrome Rivaroxaban+ Rosuvastatin Reference - Warfarin -1.25562* 0.034 Warfarin +Rosuvastatin -1.31674* 0.001 Rivaroxaban -1.03977* 0.044 #: Compared with unaffected limb. *: One-way ANOVA. The difference seems to be significant between the Rivaroxaban-Rosuvastatin group and warfarin alone, or Rivaroxaban alone. Table 4: Comparing the severity of post thrombotic syndrome (PTS) based on Brandjes score between the 4 studied groups Severity of PTS 1 (n =50) 2 (n = 49) 3 (n =44) 4 (n =39) P value Mild (score ≤ 3) 6 (12.0) 5 (10.2) 4 (9.1) 4 (10.2) Moderate (score= 4) 6 (12.0) 2 (4.1) 3 (6.8) 1 (2.5) < 0.0001 Severe (score ≥5) 4 (8.0) 0 (0.0) 2 (4.5) 0 (0.0) Data are presented as frequency (%). Group 1: warfarin; group 2: Warfarin + Rosuvastatin; group 3: Rivaroxaban; group 4: Rivaroxaban + Rosuvastatin. dition, there was a dose-response relationship in the effect of statin therapy. Interpretation of these effects is however lim- ited due to retrospective nature of the study. The results of existing studies have been controversial about the effect of rosuvastatin on incidence of PTS. A multicenter randomized controlled pilot trial on 312 patients with acute DVT receiving standard anticoagulation has shown that the addition of rosuvastatin 20 mg once daily for 180 days, does not significantly decrease PTS incidence (19). On the other hand, similar to our results, a randomized controlled trial in- cluding 230 patients with DVT, reported the reduction of PTS incidence following rosovastatin administration. The results did not show significant differences in D-dimer levels follow- ing rosuvastatin administration in addition to low molecu- lar weight heparin (LMWH); but patients who had received statin had significantly lower levels of CRP and showed a sig- nificant decrease in PTS incidence after 3 months of follow- up (11). In confirmation of these findings, various stud- ies have shown that statin therapy, can reduce the level of plasminogen activator inhibitor-1 (PAI-1) as a fibrinolytic in- hibitor and the level of tissue factor as a coagulation cascade initiator (20, 21). Decrease in the level of PAI-1 or TF alone can increase net intravenous and intra-arterial clot fibrinol- ysis (22). The inhibitory mechanism of statins on TF con- sists of inhibiting synthesis of the isoprenoid mediator and in vitro inhibition of geranylgeranylation in the Rho / Rho ki- nase pathway (23). Reducing the activation of the Rho family reduces the expression of one of the key transcription fac- tors called NF-KB; this transcription factor induces positive TF regulation. In addition, statins increase the expression of kruppel like factor 2 (KLF2), a positive regulator of eNOS and thrombomodulin, and an inhibitor of TF and PAI-1 (24). Clinical and experimental studies also show that statins in- hibit the activation of cyclooxygenase 1 (COX-1) and enhance the activity of nitric oxide synthase (NOS), thereby reducing the activation and accumulation of platelets (25). Results of this study also suggest a stronger protective ef- fect against VTE with rivaroxaban compared with warfarin. The effect of rivaroxaban on D-dimer levels was mentioned in other studies as well (26). Rivaroxaban, as an inhibitor of This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index 7 Archives of Academic Emergency Medicine. 2023; 11(1): e43 factor Xa, disrupts the intrinsic and external pathways of co- agulation cascade, and ultimately inhibits the formation of thrombin, subsequent fibrinolysis, and the production of D- dimer (27). D-dimer not only acts as an indicator of throm- botic activity, but also correlates to the size and the burden of the thrombosis (28). Due to the 8-hour half-life of D-dimer (25), reduction of D-dimer levels during the first 24 hours of drug therapy is expected. Similar effects was seen with other anticoagulants, including heparin, warfarin and apixaban (27). However, data seems to be more robust for rivaroxaban. In a study by Utne et al., rivaroxaban showed an absolute 14% reduction of PTS two years after an acute DVT episode and also improved quality of life compared to treatment with war- farin. It was suggested that the effect of rivaroxaban on PTS is related to its rapid time to peak concentration and its stable anticoagulation effect. Rivaroxaban’s other properties such as its binding and inhibition of the thrombus bound factor X can also be involved in this effect (29). Another suggested mechanism is the involvement of residual vein thrombosis as a main factor in the development of PTS. In a study by Pran- doni et al., residual vein thrombosis formation in patients with proximal DVT was compared between direct oral anti- coagulants (DOACs) and vitamin K antagonists (VKAs) after three and/or six months. DOACs showed more protective ef- fect against residual vein thrombosis compared with VKAs (41% and 21% after 3 and six months respectively, vs 52.3% and 54.5%) (30). In another study by Cheung et al., rivaroxaban showed a nu- merically lower but statistically non-significant risk of PTS compared to enoxaparin/VKA treatment in acute DVT pa- tients. Non adherence when using VKAs was suggested as the main reason for better long term clinical outcomes regarding PTS when using rivaroxaban compared to VKAs (31). Regarding controversial results of studies on rosuvastatin ad- juvant therapy, the anticoagulant used for the treatment may affect the incidence of PTS. The results of our study show a more significant difference for PTS incidence between the administration of rivaroxaban+rosuvastatin with war- farin alone or warfarin+rosuvastatin compared to rivaroxa- ban alone; which may propose the hypothesis of the syner- gistic effect of rivaroxaban and rosuvastatin for PTS preven- tion. 5. Limitations The strength of our study is that besides investigating the effect of rosuvastatin, the effect of two types of anticoagu- lants with and without rosuvastatin was. So far, no study has investigated the effect of rosuvastatin alongside rivaroxaban and compared rivaroxaban and warfarin in this context. Our study has several limitations. First, the trial was not aimed to study the effects of rivaroxaban. Second, a single ultra- sound sonographer was used for sonography, therefore hav- ing a second opinion might change results. Third, the same brand of rosuvastatin was used for all groups (Rosurexin, Ac- toverco), the issue of bias in the results can be raised, of course, the pharmaceutical company had no involvement in the study and interpretation of the results, and only supplied the drug. 6. Conclusion The addition of rosuvastatin to anticoagulants seems to be effective in improving the treatment outcomes of DVT pa- tients. Rosuvastatin administration in combination with ri- varoxaban or warfarin significantly reduces the level of in- flammatory factors including CRP and D-dimer, compared to patients receiving anticoagulants alone. Furthermore, it can significantly reduce the incidence of PTS and the difference in the size of the lower limbs within 3 months. 7. Declarations 7.1. Acknowledgments We would like to thank ACTOVERCO Pharmaceutical Factory, Karaj, Iran for supplying rosuvastatin for participants. 7.2. Conflict of Interest Statement For decreasing the risk of potential bias ACTOVERCO Phar- maceutical Factory had no involvement in the study and in- terpretation of the results, and only supplied rosuvastatin. 7.3. Fundings This study has been funded by Shahid Beheshti University of Medical Sciences; also, ACTOVERCO Pharmaceutical Factory supplied rosuvastatin. 7.4. Authors’ contribution MP and RB: designed the study. RL and ZT: collected the data. KKT drafted the manuscript and edited final manuscript. All authors have read and approved the manuscript. References 1. Hull RD, Lip GY, Leung L. Venous thromboembolism: anticoagulation after initial management. U: UpTo- Date, Leung LLK, Mandel J ur UpToDate available from https://www.uptodate.com/contents/venous- thromboembolism-anticoagulation-after-initial- management/print. 2017. 2. 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