March 2007 Vol 7 Isuue 1 FINAL without suicide .indd ABSTRACT Objective: The objective of this study was to evaluate the efficacy of unfractionated heparin, warfarin and low molecular weight heparins (LMWH) used for the prevention of venous thromboembolism in arthroplastic surgery of the knee joint. Methods: In this prospective study from August 2002 to November 2004, 60 patients were included and divided into three groups with equal numbers, with each group receiving different treatment protocol. Postoperatively, the occurrence of symptomatic deep vein throm- bosis (DVT) or pulmonary embolism (PE) was recorded during the first 30 days after surgery and at a routine follow-up visit. Results: A significantly lower prevalence of DVT and PE was found in patients using warfarin and LMWH as prophylaxis in comparison with patients using unfractionated heparin. Conclusion: Warfarin and low molecular weight heparins are more beneficial and effective than unfractionated heparin for DVT and PE prophylaxis in arthroplastic knee surgeries. KeyWords: Arthroplasty, Deep vein thrombosis (DVT), Prophylaxis, Low Molecular Weight Heparin, Warfarin. Pharmacologic Prophylaxis and Treatment of Venous Thromboembolism after Knee Arthroplasty *Jamal S Shawabkeh, Malek M Ghnaimat, Ammar M Hijazi SULTAN QABOOS UNIVERSITY MEDICAL JOURNAL APRIL 2007 VOL 7, NO. 1 SULTAN QABOOS UNIVERSITY© Orthopedic Department, Royal Jordanian Medical Services, P O Box 517, Amman 11118, Jordan *To whom correspondence should be addressed. Email: drjamalss@yahoo.com C L I N I C A L & B A S I C R E S E A R C H مفصل رأب بعد الوريدي اخلثاري االنصمام ومعاجلة الوقاية الدوائية الركبة حجازي وعمار غنيمات مالك الشوابكة، جمال اخلثاري االنصمام من استخدامها للوقاية عند املنخفض، اجلزيئي الوزن ذو والهيبارين والوارفيرين ازأ الهيبارين غير فعالية امللخص: الهدف: تقييم جلراحة رأب مفصل خضعوا مريضا ــتني أجريت على س ــتقبلية) (املس ــتِبَاقِيَّة االِسْ ــة الدراس الركبة. الطريقة: هذه مفصل جراحة رأب الوريدي في كل ــاوية، متس ثالث مجاميع وبأعداد ــيمهم إلى تقس 2004 ، ومت ــر عام نوفمب 2002 وحتى عام ــطس أغس من املمتدة الفترة ــالل خ ــى األول ــة الركب يوما ثالثني خالل أول العرضي الرئوي االنصمام أو العرضي العميق الوريدي اخلثار حاالت تسجيل مت عن اآلخرين. مختلف بنظام معني عوجلت مجموعة الرئوي االنصمام و العميق الوريدي اخلثار في حاالت نقص الفت ــكل بش ــة الدراس الروتينية. النتائج: أظهرت املتابعة زيارات خالل ومن اجلراحة بعد غير الهيبارين يستخدمون الذين مع املرضى باملقارنة وقائي بشكل املنخفض اجلزيئي الوزن ذو الوارفيرين والهيبارين يستخدمون املرضى الذين عند العميق الوريدي اخلثار غير ازأ في حاالت الهيبارين من وفعالية فائدة اكثر املنخفض اجلزيئي ــوزن ال ذو الهيبارين و ــزأ. اخلالصــة: يعد الوارفيرين ا اجلراحية. الركبة رأب مفصل في حاالت الرئوي واالنصمام املنخفض. اجلزيئي الهيبارين ذو الوزن ، الوارفيرين الوقاية، ، العميق الوريدي اخلثار من الوقاية ، الكلمات: رأب املفصل مفتاح Patients having primary or revision total knee arthroplasty have an increased risk of the de-velopment of thromboembolism. Without prophylaxis, the overall prevalence of thromboembo- lism has been reported to range from 40% to 84%, with proximal thrombi in 9% to 24% of patients.1 Sympto- matic pulmonary embolism (PE) has been reported to occur in up to 7% of patients having total knee arthro- plasty without prophylaxis, being fatal in 2% of them.2 Most surgeons recommend routine prophylaxis against thromboembolism, but there is controversy about the optimal method. M E T H O D S This is a study of three consecutive anti-thromboembo- lism regimens after total knee arthroplasty conducted in the Farah Royal Rehabilitation Centre, Jordan, dur- ing the period August 2002 to November 2004. A total of sixty patients were included in the study. After the purpose of the study and the possible complications J A M A L S . S H AWA B K E H , M A L E K M . G H N A I M AT A N D A M M A R M . H I J A Z I 48 were explained to the patients, permission was taken. This study has been also authorized by the scientific and research committee of the Royal Jordanian Medi- cal Services. Three prophylactic methods were used and the patients were classified into three groups, Group A (n=20), who received unfractionated heparin in a fixed dose of 5000 IU, beginning at the night of surgery, twice daily subcutaneous; Group B (n=20), who re- ceived warfarin 10 mg daily two days prior to surgery, the dose being titrated according to INR (Internation- al Normalized Ratio) level; and Group C (n=20), who received LMWH at the night of surgery in a dose of 20 mg daily one day prior to surgery. All the surgeries were done under general anaesthesia. Patients with a previous history of deep vein thrombosis (DVT), chronic venous insufficiency, stroke, varicose veins, malignancy, renal insufficiency, recent myocardial inf- arction, heart failure, and those taking oral contracep- tives, or steroidal/hormonal/anticoagulant drugs for any medical condition, were excluded from the study. No mechanical devices were used in DVT prophy- laxis in the study. All the patients were mobilized from bed on the first day post-operatively. Post-operative assessment for DVT was done in all patients on both the lower limbs by color Doppler ultrasonography in- cluding an examination of bilateral common femoral, superficial femoral, popliteal, anterior tibial, and pos- terior tibial veins. They were assessed for flow, visual- ized thrombus, compressibility, and augmentation. A diagnosis of DVT was made where there was visualiza- tion of thrombosis, absence of flow, lack of compress- ibility, or lack of augmentation. A Spiral CT scan was used for the diagnosis of PE. Patients on LMWH were discharged from the hos- pital after two weeks with a weekly follow up for two weeks. Those on heparin and warfarin were discharged after PTT (partial thromboplastin time) and INR lev- els were adjusted and followed up in weekly visits. No complications of the drugs used were encountered. Thrombi were classified as proximal if the pop- liteal or femoral veins were involved and distal if only the veins of the calf were involved. If the duplex scan showed a calf vein thrombus and the patient was asymptomatic, the prophylaxis was continued and the scan was repeated in one week. In the asymptomatic patient with a popliteal or femoral vein thrombus, the prophylaxis was considered to have failed and antico- agulation was started with LMWH. Oral anticoagu- lation, with a goal of a prothrombin time of 15 to 18 seconds, was continued for 12 weeks. The symptomatic patients with a calf thrombus were treated according to the surgeon’s judgment, but the symptomatic patients with popliteal or femo- ral thrombi routinely were given heparin followed by warfarin for 6 months. R E S U L T S Postoperatively, occurrence of symptomatic DVT or PE was recorded during the first 30 days after sur- gery and at a routine follow-up visit. In Group A, symptomatic DVT was diagnosed in 4 patients (20%) of which two patients had proximal DVT, while PE occurred in two patients (10%). Patients in Group B showed a lower incidence of symptomatic DVT (5%) than those patients in Group C (10%), with no record- ed cases of PE in both Groups B and C, as shown in Table 1. D I S C U S S I O N Several studies have evaluated the efficacy of LMWH and warfarin for prophylaxis against thromboem- bolism after total knee arthroplasty.3, 4-9 There is no clinically significant difference between warfarin and enoxaparin prophylaxis in terms of efficacy (veno- graphic or clinical events) and safety for hip arthro- plasty patients.7 There is no significant difference in terms of clinical events between warfarin and LMWH prophylaxis in knee arthroplasty patients.9 There are fewer venographic events with LMWH. The safety seems comparable, but LMWH should be started the day after surgery in knee patients. Warfarin is one of the most commonly used pro- phylactic agents against thromboembolic disease in Groups Incidence of Deep Vein Thrombosis (DVT) Incidence of Pulmonary Embolism (PE) A 20% 10% B 5% 0% C 10% 0% Table 1: Incidence of DV T or PE in Groups A, B & C P H A R M A C O L O G I C P R O P H Y L A X I S A N D TR E AT M E N T O F VE N O U S TH R O M B O E M B O L I S M A F T E R K N E E A R T H R O P L A S T Y 49 hip arthroplasty patients. For four decades, low-dose warfarin has been used successfully for prophylaxis against deep vein thrombosis following total knee re- placement, and its efficacy has been proven both in both studies and well-designed clinical trials.16, 17 The reported venographic rates for overall DVT are be- tween 10% and 20% and between 5% and 10% for prox- imal DVT. Major bleeds occur in 1% to 3% of the cases and minor bleeds in 2% to 5%. Warfarin interferes with vitamin K metabolism in the liver and prevents the formation of functional clotting factors II, VII, IX, and X. It takes at least 36 hours to have a measurable effect, and 4 to 5 days to reach effective anticoagulation. Dose response to warfarin, especially in surgical patients, is highly variable, and prothrombin time (PT) monitor- ing is necessary. The anticoagulant effect is expressed in the INR value, which corrects for the variability in sensitivity of the different reagents used in various in- stitutions to measure prothrombin time (PT). High-molecular-weight heparin fractions, howev- er, have a strong affinity for platelets where they inhib- it the aggregation. They also inhibit platelet function and vascular smooth-muscle cell proliferation. These fractions delay hypersensitivity reactions and increase the permeability of vessel walls. Finally, they have been implicated in the regulation of angiogenesis Commercial heparin is a heterogeneous mix- ture of sulfated polysaccharide chains of molecular weights ranging from 3,000 to 30,000 daltons (mean 15,000). One-third of the heparin, mostly low-mo- lecular-weight fractions, binds to antithrombin III and is responsible for most of the anticoagulant activity at therapeutic levels. At the molecular level, heparin acts on antithrombin III by inducing a conformational change which unmasks an arginine center, which in turn inhibits the active serine center of thrombin and other coagulation enzymes. After doing so, heparin dissociates from antithrombin III and can be reused. LMWH is not a homogenous drug, but it contains only polysaccharide chains of less than 8000 daltons. There are many commercially available LMWHs which are prepared by various processes. These preparations are pharmacologically different from each other and, therefore, may not be clinically identical. Compared to standard heparin, LMWH fragments have a better bioavailability, a longer half-life, a lesser platelet in- hibitory effect.10 Clinical studies have reported a 60% to 80% overall radiographic DVT risk reduction in hip arthroplasty patients with LMWH when compared to a placebo. No significant increase in major bleeding complications was found, but a significant increase in minor bleeds (mostly subcutaneous hematomas) has been noted.11 The potential advantages of LMWH compared to unfractionated regular heparin are more predictable dose response, longer half-life and less hemorrhagic ef- fect for a given antithrombotic effect. Recent studies have demonstrated the efficacy and safety of outpatient treatment of acute proximal DVT using LMWH.12,13 In these randomized trials, intravenous heparin was compared with outpatient LMWH, given twice-daily in a weight-adjusted dose regimen. Warfarin therapy was started on the first day of treatment in both study groups. During follow-up, there were no significant differences in the incidence of recurrent venous thromboembolism or bleeding complications.14 Outpatient treatment of acute DVT is a promising and more versatile approach than con- ventional, in-hospital treatment and is likely to be more cost-effective. Outpatient treatment of DVT with the combination of LMWH and warfarin should be employed by centres experienced in the treatment of thromboembolic disorders. An ideal prophylactic regimen has not been identi- fied and the selection of an appropriate agent is usually a balance between efficacy and the risk of bleeding. The most effective prophylactic agents for these pa- tients include low-molecular-weight heparin, warfa- rin, and fondaparinux,15 as we found in our study. We suggest the usage of LMWH or warfarin in the proph- ylaxis of DVT and PE for a thirty day period. More prolonged prophylaxis should be considered following total joint arthroplasties in patients who are at higher risk, including those with a history of venous throm- boembolic disease, limited mobilisation, obesity, and cancer.18, 19 C O N C L U S I O N The usage of LMWH and warfarin is a more benefi- cial and effective method for the prophylaxis of deep vein thrombosis and pulmonary embolism after knee arthroplasty than unfractionated heparin. This finding corroborates other studies in the literature. R E F E R E N C E S 1. Francis CW, Pellegrini VD, Stulberg BN, et al. Preven- tion of venous thrombosis after total knee arthroplasty. J Bone Joint Surg Am 1990; 72:976-982. J A M A L S . S H AWA B K E H , M A L E K M . G H N A I M AT A N D A M M A R M . H I J A Z I 50 2. Khaw FM, Moran IM, Smith SR: The incidence of fatal pulmonary embolism after knee replacement with no prophylactic anticoagulation. J Bone Joint Surg Br 1993; 75:940-941. 3. Fitzgerald RH: Preventing DVT following total knee re- placement: a review of recent clinical trials. Orthoped- ics 1995; 18 (suppl):10-11. 4. Pulmonary Embolism Prevention (PEP) Trial Collabo- rative Group: Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmo- nary Embolism Prevention (PEP) Trial. Lancet 2000; 355:1295-1302. 5. Colwell CW, Spiro TE, Trowbridge AA, et al. Efficacy and safety of enoxaparin versus unfractionated heparin for prevention of deep venous thrombosis after elective knee arthroplasty. Clin Orthop 1995; 321:19-27. 6. Hull RD, Raskob GE. Current concepts review. Prophy- laxis of venous thromboembolic disease following hip and knee surgery. J Bone Joint Surg Am 1986; 68:146- 150. 7. Leclerc JR, Geerts WH, Desjardins L, et al. Prevention of deep vein thrombosis after major knee surgery, a ran- domized, double-blind trial comparing a low molecu- lar weight heparin fragment (enoxaparin) to placebo. Thromb Haemost 1992; 67:417-423. 8. RD Heparin Arthroplasty Group: Heparin compared with warfarin for prevention of venous thromboem- bolic disease following total hip or knee arthroplasty. J Bone Joint Surg Am 1994; 76:1174-1185. 9. Spiro TE, Fitzgerald RH, Trowbridge AA, et al. Enoxa- parin (a low molecular weight heparin) and warfarin for the prevention of venous thromboembolic disease after elective knee replacement surgery. Blood 1994; 84 (suppl 1):246a 10. Carter C, Kelton J, Hirsh J, et al. The relationship be- tween the hemorrhagic and antithrombotic properties of low molecular weight heparin in rabbits. Blood 1982; 59:1239-1245 11. Colwell CW, Spiro TE, Trowbridge AA, et al. Use of enoxaparin, a low molecular weight heparin, and un- fractionated heparin for the prevention of deep vein thrombosis after total hip replacement. J Bone Joint Surg Am 1994; 76:3-14. 12. Levine MN, Gent M, Hirsh, et al. A comparison of low molecular weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. New Engl J Med 1996; 334:677-681. 13. Koopman MMW, Prandoni P, Piovella P, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared to subcutaneous low molecular weight heparin adminis- tered at home. New Engl J Med 1996; 334:682-687 14. O’Reilly RF, Burgess IA, Zicat B. Prevalence of venous thromboembolism after hip and knee replacement sur- gery, Med J Aust 2005; 182:154-159. 15. Lieberman JR, Wellington KH. Prevention of Venous Thromboembolic Disease after Total Hip and Knee Ar- throplasty, J Bone Joint Surg Am 2005; 87:2097-2112. 16. Fitzgerald RH Jr, Spiro TE, Trowbridge AA, et al. Pre- vention of venous thromboembolic disease following primary total knee arthroplasty. J Bone Joint Surg Am 2001; 83:900-906 17. Heit JA, Elliott CG, et al. Ardeparin sodium for extend- ed out-of-hospital prophylaxis against venous throm- boembolism after total hip or knee replacement. Ann Intern Med 2000; 132:853-861. 18. Geerts WH, Pineo GP, Heit JA, et al. Prevention of ve- nous thromboembolism: the Seventh ACCP Confer- ence on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126 (Suppl 3):338S-400S. 19. Kearon C. Duration of venous thromboembolism prophylaxis after surgery. Chest 2003; 124(Suppl 6):386S -392S.