Vol 3 | Issue 2 | Sep-Dec 2017 | page: 03-07 |S K Rai*, V P Raman, Naveen Shejale, S S Wani , Rohit Varma
Author: SK Rai*, VP Raman, Naveen Shejale, SS Wani  , Rohit Varma 
1Department of Orthopaedics, Indian Naval Hospital Ship Asvini, Colaba, Mumbai, India.
2Department of Orthopedics, Malla Reddy Institute of Medical Sciences, Suraram, Hyderabad, India.
3Department of Orthopaedics, Indian Naval Hospital Ship Kalyani, Visakhapatnam, India.
Address of Correspondence
Dr. S K Rai,
Department of Orthopaedics, Indian Naval Hospital Ship Asvini, Colaba, Mumbai, India.
Objective: Development of venous thrombo-embolism (VTE) including deep venous thrombosis (DVT) is a common complication after total hip and total knee Arthroplasty, pelvic fracture or long bone fractures especially in lower limb. Currently used drugs for DVT prophylaxis after these procedures have important limitations, including parenteral administration, and unpredictable plasma levels requiring frequent monitoring and dose adjustment leading to decreased patient compliance. In our study we used oral Rivaroxaban, which is one of the newer oral anticoagulants and is a direct factor Xa inhibitor that has demonstrated superior efficacy, compared to that of enoxaparin or any parenteral LMWH.
Materials & Methods: In our study, 180 patients who underwent Total knee replacement (TKR) or Total hip replacement (THR) in our centre were included. They were put on oral Rivaroxaban, 10 mg once daily, started 6 hours after surgery and continued for 03 weeks in case of TKR and 6 weeks in case of THR.
Results: Venous thrombo-embolism (VTE) and Deep vein thrombosis (DVT) are common complications after THR and TKR and cause a substantial burden to patients, healthcare providers, increase costs to the patients and increase both morbidity and mortality, if not addressed promptly. Currently available anticoagulants in the form of subcutaneous injection have limitations that lead to decreased compliance with DVT prophylaxis guidelines. Rivaroxaban which is oral 10 mg once daily has superior efficacy compared to enoxaparin or any parenteral LMWH for the prevention of the same and the patient compliance is also very good. There were no incidences of increased bleeding or wound infection in our study as compared to control group which were given subcutaneous enoxaparin.
Key words: Venous thrombo-embolism, deep vein thrombosis, Total knee replacement, Total hip replacement, Rivaroxaban, DVT prophylaxis.
Venous thrombo-embolism (VTE) including deep vein thrombosis (DVT) is a major medical problem characterized by thrombi formation in the deep venous system and can sometimes result in a fatal pulmonary embolism (PE). DVT occurs most commonly in the legs, although thrombi can also form in the veins of the arms as well .
Deep vein thrombosis (DVT) is an important complication following total knee and hip arthroplasty, especially when the patient remains in bed for prolonged periods after surgery. However, the incidence of DVT is often underestimated due to subclinical or minimal symptoms and signs. In Western countries, prophylactic agents against DVT are administered routinely after TKA. However, in a developing country like India, regular DVT prophylaxis is often not given to patients undergoing TKA or THA.
As the number of total joint arthroplasties being performed worldwide continues to grow, a commensurate increase in the number of venous thromboembolism (VTE) events can be anticipated. Although the incidences of symptomatic deep vein thrombosis (DVT) and pulmonary embolism (PE) are low, the incidence of asymptomatic DVTs has been estimated to be 20 %–40 % of inpatients undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA) . Therefore, the use of effective and safe chemoprophylaxis is crucial for minimizing the risk of VTE events in these patients.
In literature, despite hundreds of clinical studies, there is still no consensus on the ideal method of thromboprophylaxis for patients undergoing THA and TKA. This inconsistency has raised the concern that many patients are at risk for insufficient prophylaxis or excessive bleeding risks. In a retrospective study involving 3497 patients who had THAs or TKAs between April 1, 2004 and December 31, 2006, Selby et al. found that only 40 % of patients received the 8th edition American College of Chest Physicians (ACCP) recommended thromboprophylaxis . In the United States, DVT and PE result in up to 600000 hospitalizations a year, and nearly 50000 individuals die annually as a result of Pulmonary embolism .
Hip arthroplasty, knee arthroplasty, and hip fracture surgeries are strongly associated with a risk of developing DVT . The incidence of asymptomatic DVT after a major orthopedic surgery without prophylaxis reportedly ranges from 30% to 80% , whereas the incidence of symptomatic DVT reportedly ranges from 0.5% to 4% . Although the incidence of asymptomatic DVT is greater than that of symptomatic DVT, the clinical importance of asymptomatic DVT remains unclear .
Materials and Methods
In our study, 180 patients who had undergone TKR or THR in our centre (Department of Orthopaedics, Indian Naval Hospital Ship Asvini, Colaba, Mumbai, 400005, India) were included, and they used oral Rivaroxaban 10 mg once daily, started 6 hr after surgery and continued for 3 weeks in case of TKR and 6 weeks in case of THR. The study was conducted between June 2012 and Dec 2016. Patients already on any anticoagulants preoperatively were excluded from the study. In addition to 180 patients 30 patients of TKR and 10 patients of THR were given only subcutaneously Enoxapaerin for prevention of DVT as control group.
All patients were evaluated preoperatively and underwent proper pre anesthesia check up. Patients who were detected to have impaired renal function during pre anesthesia check were excluded from the study, because in patients with impaired renal function, the clearance of Rivaroxaban is decreased moderately, and its use is not recommended for patients with severe renal impairment (creatinine clearance < 30 mL/min).
All total knee arthroplasties were done by us without the use of a tourniquet. A closed drainage system was inserted before closure of the wound, and a light compression dressing was applied to the knee. The drain was usually removed on the third postoperative day and a progressive, continuous passive motion and physical therapy protocol was started on the first or second postoperative days (usually before drain removal). Pre operatively, IV antibiotic Tiecoplanin 400 mg was given just before incision and after 12 hr post operatively and continued for next two days as once daily doses. All patients were given oral Rivaroxaban 10 mg once daily, started 6 hr after surgery and continued for 03 weeks in case of TKR and 6 weeks in case of THR.
All patients were clinically examined daily for calf tenderness and Homan’s sign. All patients were prospectively monitored for deep vein thrombosis using colour Doppler done by intervention radiologist from postoperative day number 3 (range, post op day 3 to 7). Doppler signals were evaluated at the common femoral, popliteal, and posterior tibial vessels. Compression to produce coaptation of the vein walls was applied sequentially and throughout the deep veins beginning at the inguinal ligament and proceeding in scan head width increments through all 3 pairs of tibio peroneal veins, the sural veins, and the soleal sinuses. The Doppler examination was considered normal when the signals showed equal, bilateral, spontaneous, and phasic flow in all veins (except the posterior tibial veins) and good augmentation in response to distal compression of the limb. The image was reported as negative when there was complete coaptation of the vein walls because of local compression.
A Doppler study was considered positive for DVT (a) if distal limb compression produced no or reduced augmentation of flow in comparison with that in the contralateral limb; (b), if both common femoral vein Doppler signals were continuous or (c) if one common femoral vein Doppler signal showed decreased ventilatory phasicity as compared with the contralateral limb. Color flow was used only as an adjunctive measure and not as a diagnostic criterion. Thrombi were classified as proximal if the popliteal or femoral veins were involved and distal if only the veins of the calf were involved. D-dimer test was also performed depending on colour Doppler findings and also for clinical correlation.
At the time of discharge, all patients were instructed to take oral Rivaroxaban 10 mg once daily dose till 3 weeks in case of TKR and 6 weeks in case of THR.
In our study, we followed up 180 patients who had undergone TKR or THR (TKR 120 patients and THR 60 patients) between June 2012 and Dec 2016. Out of 180 patients, 09 patients who developed calf swelling and pain on 5-8 days post operatively with positive Homan’s sign were evaluated by colour Doppler and d-dimer test. Out of these 09 patients, seven patients showed positive color Doppler and positive d- dimer test. All these 07 patients( 05 TKR patients and 02 THR patients) were further treated by parenteral LMWH (enoxaparin). The remaining two patients showed negative color Doppler study. However depending on clinical findings i.e positive Homan sign and calf tenderness, these were also treated by parenteral LMWH (enoxaparin) and improved over 2 weeks.
In our study 120 patients underwent TKR and out of 120 patients only 05( 04%) patient developed DVT while 60 patients underwent THR and out of 60 patients only 02( 03%) patient developed DVT.
Table 1: Development of DVT post operatively
|Joint replacement||No of patients (n)||No of patients who developed clinical sign of DVT post operatively||No of patients showed positive Colour Doppler & d-Dimer|
|TKR||120||06(05%)||05/120 (04%) Positive for DVT|
|THR||60||03(01%)||02/60 (03%) Positive for DVT|
Table 2 : Patients demographic details
|Age||No of TKR patients||No of THR patients||Patient developed DVT after TKR with positive colour Doppler & d-Dimer||Patient developed DVT after THR with positive colour Doppler & d-Dimer|
|More than 75 years||26||07||02||01|
Thrombo-prophylaxis and anti-thrombotic therapy when indicated, remains crucial in the peri- and post-operative management of patients who undergo major orthopaedic surgical procedures, particularly total knee and hip arthroplasty and major fracture surgery, especially around the hip . Optimal thromboprophylaxis is currently mandatory in most orthopaedic practices to avoid the dreaded complications of venous thrombo-embolism (VTE). The pathogenesis of VTE is multifactorial and includes the well-known Virchow’s triad of hypercoagulability, venous stasis, and endothelial damage. With current advances in orthopaedic surgery, a multimodal approach to thromboprophylaxis, optimum anaesthetic management, and decreased post-operative convalescence/bed rest, have reduced the risks of venous thromboembolism after total knee, hip arthroplasty and major fracture surgery in the lower extremity. The rates of venous thromboembolism (VTE) complications such as deep vein thrombosis (DVT) and pulmonary embolism (PE) have been shown to be around 40–60% within 7 to 14 days following orthopaedic lower limb surgery without thromboprophylaxis . Most of these thrombi resolve spontaneously; however, a small percentage (1–4%) will develop into symptomatic VTE . The incidence of fatal pulmonary embolisms in patients not receiving thromboprophylaxis ranges from 0.3–1% following total knee and hip joint arthroplasty and around 3.6% after major long bone fracture surgery . A prescient and rational approach to reduce the incidence of VTE is therefore of paramount importance.
Thromboprophylaxis options for prevention of DVT
For prevention of DVT, the following modalities are available, which can be used depending upon patient characteristics, medical and surgical co-morbidities and what is most suitable for the individual patient.
- Mechanical methods
Many centres still use mechanical thromboprophylaxis as an adjunct in the prevention of VTE. These include the use of graduated compression stockings, venous foot pumps, and active external compression devices (continuous and intermittent). The benefits of these include the non-invasive nature of its application, the fact that it requires no monitoring and the fact that it poses no increased risk of bleeding . The virtue of external pressure applied to the limb, is that it promotes blood flow velocity, reduces venous stasis, and increases levels of systemic fibrinolysins . Intermittent pneumatic compression devices have been shown to reduce significantly the incidence of DVT when combined with chemoprophylaxis compared to either therapy in isolation .
- Pharmacological methods
Warfarin is a vitamin K antagonist which expresses its anticoagulant properties via the inhibition of clotting factors (namely II, VII, IX and X) and continues to be used in orthopaedic centres to this day. The level of anticoagulation achieved can be determined by close monitoring of the patient’s INR (International Normalised Ratio). When compared to low molecular weight heparin (LMWH) for thromboprophylaxis following hip and knee replacement , warfarin showed statistically significant higher rates of asymptomatic clot formation. It must be noted, however, that in cases of symptomatic VTE, there was no significant difference between the two chemo-prophylactic agents . Although studies have shown that LMWH is associated with increased bleeding complications in the short term, when given for an extended period (six weeks), more symptomatic bleeds were observed in the warfarin group .
Aspirin( Acetyl salicylic Acid)
Low dose Aspirin is also used for VTE prevention at present. It inhibits thromboxane, which is necessary for the binding of platelets during the process of clot formation. Apart from orthopaedic surgery, it is widely used in the management of stroke and myocardial infarctions and in hypercoagulopathy. It requires no monitoring and is generally well tolerated. There is evidence to support the notion that aspirin is not inferior to LMWH in VTE prevention; however, the current AAOS and ACCP guidelines do not advise its use in isolation without combined mechanical prophylaxis .
Heparin (unfractionated heparin and low molecular weight heparin LMWH)
Unfractionated heparin (UH) and LMWH have been used for orthopaedic surgery thromboprophylaxis for decades. LMWH has largely replaced UH due to the fact that no monitoring is required and its simple mode of administration via subcutaneous injection. Many studies have shown fewer VTEs and less bleeding complications with LMWH compared with UH in orthopaedic surgery . The current guidelines from the American Academy of Orthopaedic Surgeons (AAOS) and the American College of Chest Physicians (AACP) continue to promote LMWH as the pharmacological thrombo-prophylactic agent of choice following joint replacement .
It is an oral factor Xa inhibitor, and has been approved for VTE prophylaxis following orthopaedic surgery in Europe since May 2011, and is under review by the United States Food and Drug Administration (FDA) at the present time. Compared to LMWH in patients undergoing joint replacement, Apixaban showed significantly superior results in the prevention of DVT and its related mortality.
It is an orally available direct thrombin (factor IIa) inhibitor. Dabigatran has been approved by the European Commission since March 2008 for use in orthopaedic surgery, while FDA approval is reserved for certain indications in patients with atrial fibrillation. Studies on Dabigatran, while emphasizing its efficacy have shown similar but not superior results in DVT prophylaxis compared with LMWH while side effects in terms of bleeding risks are almost the same .
Rivaroxaban, the first orally available factor Xa antagonist, received FDA approval for VTE prophylaxis in July 2011. Four phase III randomized control trials showed Rivaroxaban to be superior to LMWH in preventing total VTE and symptomatic events in patients undergoing hip and knee TJA . Some recent studies have showed an increased risk of re-operation secondary to infection and wound complications in patients receiving Rivaroxaban. This, coupled with a tendency to an increased risk of gastrointestinal bleeding, has given impetus to the continued use of LMWH for thrombo-prophylaxis .
Current Guidelines from AAOS and ACCP
The recent guidelines published by the AAOS and ACCP provide the most widely accepted advice regarding the use of thromboprophylaxis in elective orthopaedic hip and knee arthroplasty. These represent a comprehensive and systematic scrutiny of the literature, an update of previously published guidelines and expert consensus in VTE prevention and management. Differences in opinion between physicians and surgeons were noted especially in regard to bleeding risks. Hence, risk stratification of patients is advised and further research into this area is currently continuing.
Both guidelines emphasize on the importance of DVT prophylaxis using various different regimens as compared to no prophylaxis. The AAOS guidelines from 2016 include a strong recommendation against the use of routine duplex ultrasonography screening post-operatively. Under the moderate recommendations, the group suggests discontinuing anti-platelet agents (clopidogrel & aspirin) pre-operatively and pharmacological thromboprophylaxis with/or without mechanical compressive devices in patients not at risk following joint replacement .
Recommendations based on consensus were developed in several areas where evidence was not sufficiently reliable. These included:-
(a) the duration of thromboprophylaxis treatment to be individually tailored according to patient specifics using a multi-disciplinary approach involving physicians
(b) the combination of mechanical and pharmacological thromboprophylactic agents,
(c) mechanical devices in patients with a higher risk of bleeding,
(d) early mobilisation following joint replacement.
The latest ACCP guidelines from 2016 have suggested starting anticoagulant prophylaxis 12 or more hours pre-operatively or postoperatively rather than four hours or less preoperatively or post-operatively. In the absence of a bleeding disorder and not including major fracture surgery, any form of thromboprophylaxis is recommended above no prophylaxis for a minimum of 10 to 14 days. LMWH is preferred above all other pharmacological agents, and the addition of a mechanical device like intermittent pneumatic compression device (IPCD) is recommended. An extended duration of thromboprophylaxis of up to 35 days is suggested following surgery. When subcutaneous injections are rejected or unacceptable to the patient, the oral thrombo-prophylactic agent Apixaban or Dabigatran is advisable. Individuals with bleeding disorders are recommended to receive either mechanical prophylaxis in the form of ICPD in isolation or no thromboprophylaxis. No VTE prophylaxis is considered necessary when dealing with lower limb immobilisation following isolated injuries and low-risk patients undergoing elective knee arthroscopy.
In patients undergoing surgery for hip fractures, the United Kingdom National Institute for Health and Clinical Excellence (NICE) have published guidelines covering the overall management of the individual and places significant emphasis on thromboprophylaxis. It recommends mechanical agents (compression stockings, foot pumps and IPCD) at the time of admission and pharmacological agents (i.e. LMWH or UH) provided that there are no contraindications. Pharmacological agents are stopped prior to surgery (12 hours for Fondaparinux and six hours for LMWH) and recommenced six to 12 hours post-operatively. Thromboprophylaxis is continued for up to 28–35 days following surgery.
Each orthopaedics surgeon must have a good knowledge and understanding of the various mechanical and pharmacological thromboprophylactic agents will significantly help them to reduce the incidence of venous thromboembolism following major orthopaedic elective joint arthroplasties and other major orthopaedic surgeries, especially involving lower limbs. The usage guidelines for the various pharmacological agents continue to be updated constantly. Newer studies in this area will help prepare appropriate prophylactic strategies and bring about new options in the treatment and prevention of VTE. More independent studies may improve our pharmacological experience in thrombo-prophylactic protocols following major elective orthopaedic surgery . Appropriate risk stratification measures need to be continuously developed to ensure the right thrombo-prophylactic protocol for the right patient in the right clinical setting. In our study, patients given Rivaroxaban 10 mg orally once daily showed good results with no increased incidence of local or gastrointestinal bleeding . There were also no wound infections while receiving Rivaroxaban .
Based on our study, we can conclude that an ideal thrombo-prophylactic agent should be effective , with nil or minimal chance of bleeding or wound infection, high patient compliance and be economically affordable.
- Kucher N. Clinical practice. Deep-vein thrombosis of the upper extremities.N Engl J Med. 2011;364:861–869. [PubMed]
- Ciccone WJ, II, Fox PS, Neumyer M, Rubens D, Parrish WM, Pellegrini VD., Jr Ultrasound surveillance for asymptomatic deep venous thrombosis after total joint replacement.J Bone Joint Surg Am. 1998;80:1167–74. [PubMed].
- Selby R, Borah BJ, McDonald HP, Henk HJ, Crowther M, Wells PS. Impact of thrombo-prophylaxis guidelines on clinical outcomes following total hip and total knee replacement. Thromb Res. 2012;130(2):166–72.[PubMed].
- Prevention of venous thrombosis and pulmonary embolism. NIH Consensus Development. 1986;256:744–749. [PubMed].
- Cohen AT. Asia-Pacific Thrombosis Advisory Board. Asia-Pacific Thrombosis Advisory Board consensus paper on prevention of venous thromboembolism after major orthopaedic surgery.Thromb Haemost. 2010;104:919–930. [PubMed].
- Piovella F, Wang CJ, Lu H, Lee K, Lee LH, Lee WC, et al. Deep-vein thrombosis rates after major orthopedic surgery in Asia. An epidemiological study based on postoperative screening with centrally adjudicated bilateral venography.J Thromb Haemost. 2005;3:2664–2670. [PubMed]
- Januel JM, Chen G, Ruffieux C, Quan H, Douketis JD, Crowther MA, et al. Symptomatic in-hospital deep vein thrombosis and pulmonary embolism following hip and knee arthroplasty among patients receiving recommended prophylaxis: a systematic review. 2012;307:294–303. [PubMed]
- Eikelboom JW, Karthikeyan G, Fagel N, Hirsh J. American Association of Orthopedic Surgeons and American College of Chest Physicians guidelines for venous thromboembolism prevention in hip and knee arthroplasty differ: what are the implications for clinicians and patients? 2009;135:513–520. [PubMed]
- Kubitza, M. Becka, W. Mueck et al., “Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct Factor Xa inhibitor,” British Journal of Clinical Pharmacology, vol. 70, no. 5, pp. 703–712, 2010.
- Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, et al. Prevention of venous thromboembolism: American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition)Chest. 2008;133(6 Suppl):381S–453S. doi: 10.1378/chest.08-0656 . [PubMed]
- Kim YH, Oh SH, Kim JS. Incidence and natural history of deep-vein thrombosis after total hip arthroplasty. A prospective and randomised clinical study.J Bone Joint Surg Br. 2003;85(5):661–665.[PubMed]
- Stringer MD, Steadman CA, Hedges AR, Thomas EM, Morley TR, Kakkar VV. Deep vein thrombosis after elective knee surgery. An incidence study in 312 patients.J Bone Joint Surg Br. 1989;71(3):492–497.[PubMed]
- Fisher CG, Blachut PA, Salvian AJ, Meek RN, O’Brien PJ. Effectiveness of pneumatic leg compression devices for the prevention of thromboembolic disease in orthopaedic trauma patients: a prospective, randomized study of compression alone versus no prophylaxis.J Orthop Trauma. 1995;9(1):1–7. [PubMed]
- Lachiewicz PF, Kelley SS, Haden LR. Two mechanical devices for prophylaxis of thromboembolism after total knee arthroplasty. A prospective, randomised study.J Bone Joint Surg Br. 2004;86(8):1137–1141.[PubMed]
- Hull R, Raskob G, Pineo G, Rosenbloom D, Evans W, Mallory T, et al. A comparison of subcutaneous low-molecular-weight heparin with warfarin sodium for prophylaxis against deep-vein thrombosis after hip or knee implantation.N Engl J Med. 1993;329(19):1370–1376. [PubMed]
- Hull RD, Pineo GF, Francis C, Bergqvist D, Fellenius C, Soderberg K, et al. Low-molecular-weight heparin prophylaxis using dalteparin extended out-ofhospital vs in-hospital warfarin/out-of-hospital placebo in hip arthroplasty patients: a doubleblind, randomized comparison. North American Fragmin Trial Investigators.Arch Intern Med. 2000;160(14):2208–2215. [PubMed]
- Stewart DW, Freshour JE. Aspirin for the prophylaxis of venous thromboembolic events in orthopedic surgery patients: a comparison of the AAOS and ACCP guidelines with review of the evidence.Ann Pharmacother. 2013;47(1):63–74. [PubMed]
- Palmer AJ, Koppenhagen K, Kirchhof B, Weber U, Bergemann R. Efficacy and safety of low molecular weight heparin, unfractionated heparin and warfarin for thrombo-embolism prophylaxis in orthopaedic surgery: a meta-analysis of randomised clinical trials.Haemostasis. 1997;27(2):75–84. [PubMed]
- Mont MA, Jacobs JJ. AAOS clinical practice guideline: preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. [[cited 2014 Jan 19]];J Am Acad Orthop Surg.2011 Dec 19(12):777–8. [Internet] Available from: http://www.ncbi.nlm.nih.gov/pubmed/22134210 . [PubMed]
- Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement.N Engl J Med. 2010;363(26):2487–2498. [PubMed]
- Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial.J Thromb Haemost. 2007;5(11):2178–2185. [PubMed]
- Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty.N Engl J Med. 2008;358(26):2765–2775.[PubMed]
- Jameson SS, Rymaszewska M, Hui ACW, James P, Serrano-Pedraza I, Muller SD. Wound complications following rivaroxaban administration: a multicenter comparison with low-molecular-weight heparins for thromboprophylaxis in lower limb arthroplasty.J Bone Joint Surg Am. 2012;94(17):1554–1558. [PubMed]
|How to Cite this article: Rai S K, V P Raman, Shejale N, Wani S S, Varma R. To Study The Efficacy And Safety Of Rivaroxaban In The Prevention Of Venous Thromboembolism (VTE) After Total Hip And Knee Arthroplasty. Trauma International Sep-Dec 2017;3(2):03-07.|