Total Hip Arthroplasty (THA) and Total Knee Arthroplasty (TKA) are major surgical procedures which can cause high morbidity and even mortality. Among these complications is venous thrombo embolism (VTE) comprising deep vien thrombosis (DVT) and pulmonary embolism (PE). Therefore, after these operations, thromboprophylaxis is routinely used. However, it has some complications such as bleeding, adverse effect of chemical agents for using prevention of DVT. Anti-thrombotic prophylaxis includes: low molecular weight heparin (LMWH), fondaparinux, apixaban, dabigatran, rivaroxaban, low dose unfractionated heparin (LDUH), adjusted dose vitamin K antagonist (VKA), aspirin, or mechanical thromboprophylaxis devices. All over the World, orthopaedic surgeons consider a balance between thromboprophylaxis and bleeding. However, it has been still controversy about optimum prophylaxis for DVT. In this current paper, we aimed to review the literature under light of the current studies.
As well known by orthopaedic surgeons, Total Hip Arthroplasty (THA) and Total Knee Arthroplasty (TKA) are major surgical procedures which they can cause high morbidity and even mortality. Among these complications is venous thrombo embolism (VTE) comprising deep vien thrombosis (DVT) and pulmonary embolism (PE). While incidence of asymptomatic VTE after these orthopaedic surgeries is about 40% - 60%, symtomatic DVT is 4.3% without any thromboprophylaxis [
Although thromboprophylaxis after THA and TKA have been ruotinely used, it has some complications such as bleeding, adverse effect of chemical agents for using prevention of DVT. Bleeding is a main complication including minor bleeding (hemorrhage, wound hematoma, persisting wound drainage, failure of wound healing, risk of infection) and major bleeding (transfusion demand two or more units of blood products, life threatening hemoglobin levels, intra-cranial, intra-abdominal and retroperitoneal bleeding events) [
Although many guidelines exist for thromboprophylaxis, in orthopaedic thromboprophylaxis, American Col- lege of Chest Physicians (ACCP) and American Academy of Orthopaedic Surgeons (AAOS) guidelines are generally used. Therefore, we will briefly mention these guidelines.
The ACCP has published reguler guidelines for the prevention of VTE since 1986. The ninth ACCP provides evidence-based guidelines in 2012 for VTE prevention in patients who have undergone THA and TKA. İt has based on the use of prophylaxis to reduce the patient important outcomes of fatal and symptomatic DVT, whis is balanced against the hazard of an increase in symtomatic bleeding [
For patients who have increased bleeding risk, the ACCP recommends an intermittent pneumatic com- pression device or no prophylaxis.
Among recommended drugs by ACCP which needs parenteral application or labratory monitorization, in patients undergoing major orthopaedic surgery and who decline ora re uncooperative with injection or an IPCD, ACCP recommends using Apixaban or Debigatran [
The American Academy of Orthopaedic Surgeons has developed its own guideline recommendations that were updated most recently in September 2011 [
VTE prophylaxis after major orthopaedic surgeries such as THA and TKA are available in chemical and/or mechanical forms. Chemical agent has been rapidly developed in recent years. These chemical agents included in guidelines were low molecular weight heparin (LMWH), fondaparinux, apixaban, dabigatran, rivaroxaban, low dose unfractionated heparin (LDUH), adjusted dose vitamin K antagonist (VKA), aspirin. These drugs are all approved in United States and some other countries. In this current paper we will briefly describe above mentioned agents with studies has been publised in the availeble literature.
LMWH is generated from unfractionated heparin via physical, chemical, enzymatic depolarization. Its com- monly used forms are enoxaparine, dalteparin and tinzaparin. For prevention of VTE after major orthopaedic surgery only enoxaparin and dalteparin are used [
LMWHs are applied subcutaneously, with enoxaparin prescribed either as a 30 mg dose given twice a day (North American regimen) or as a 40 mg dose given once a day (European standart). According to ACCP guidelines prophylaxis should started 12 hours before surgery and 12 - 24 h after surgery and using of LMWH should continiue minimum 10 - 14 days postoperativelly [
LMWHs have rapid antithrombotic effect and do not necessitate any daily laboratory monitoring. Several prospective comparative randomize control trials have been performed to assess the effectiveness of LMWH after THA and TKA surgeries. In studies compared UFH and warfarin, LMWH have shown superior efficiency to preventing DVT [
Including compared enoxaparin with the novel oral anticoagulants (NOAC) (rivaroxaban, dabigatran, apixaban) a meta-analysis study performed by Outes et al., demonstrated that NOAC are higher in efficacy, but also have higher risk of bleeding [
Since 1954 in United states, widely using warfarin is a vitamin K antagonist and inhibits vitamin K dependent cloting factors. Althoug it is used orally, it has some restriction such as bleeding risk, potantial drug interaction and requirement for constant monitoring (INR) [
Although warfarin orally administrated, there are some limitation in clinical practice such as narrow the- rapeutic window, exhibit a variable and unpredictable dose response and assosiated with several food and drug interaction.
For last decades, aspirin has been widely using as antitrombotic agent after major orthopaedic surgery. Its phar- macological effects on platelet aggregation via inhibiting thromboxan A2 and thus decreasing thrombus for- mation [
As a synthetic pentasaccaride, fondaparinux indirectly inhibits factor Xa through binds to anti-thrombin and prevents thrombus formation [
In literature, a study performed by Bauer et al., in which they performed a double-blind, randomized control trial comparing fondaparinux 2.5 mg once daily to enoxaparin 30 mg given twice a day in patients who under- went major elective orthopaedic surgery. They found that despite of fondaparinux decrease DVT compared to LMWH, it had significantly higer rates of bleeding [
This group includes rivaroxaban, apixaban, endoxaban and betrixaban as orally administreted anti thrombotic agents. After THA and TKA, rivaroxaban and apixaban are roccomended by ACCP guideline [
Rivaroxaban is an first orally bioavailable, direct and selective factor Xa inhibitor. It has been approved by FDA. Following ingestion it reaches plasma peak level after 2 - 4 h. Its half life is 5 - 9 h. Approximately two-thirds of rivaroxaban is metabolised through renal and faecal route. The remain one-third is excreted unchanged in urine [
Rivaroxaban was studied in four Phase Ш trials called RECORD (Regulation of Coagulation in Orthopaedic Surgery to prevent deep venous thrombosis and pulmonary embolism) for prevention of VTE. Among these studies, two after THA (RECORD 1 and 2) and the others after TKA (RECORD 3 and 4). In RECORD 1 - 3 investigators used 40 mg enoxaparin once daily and in RECORD 4 they used enoxaparin 30 mg twice daily as comparator, it was started 12 h before surgery and restarted 6 - 8 h after wound closure. All in four trials dose of rivaroxaban was 10 mg once daily started 6 - 8 h after wound closure. All in these trials, rivaroxaban was highly effective compared with enoxaparin. Althhough the number of bleeding events were higher in rivaroxaban treatment group, incidence of advers events and bleeding rates were similar with enoxaparin [
The recommended dose of rivaroxaban is 10 mg orally once daily starting 6 - 10 h after surgery. For patients undergoing THA , treatment duration of 35 days is recommended; for TKA this duration is 12 days [
Also apixaban is an oral highly selective, reversible and directly acting factor Xa inhibitor. This drug has not been approved by FDA. Following ingestion, more than 50% of apixaban has had bioavailability and it has arrived peak plasma concentration in 30 minutes to 2 hours, with a terminal half life of approximately 12 h. Totally it has been metabolised both liver and renal. Approximately 30% of the drug has been metabolised through renal and the remained amount faecal route [
In three large phase III studies, Apixaban was compared with enoxaparin. ADVANCE 1 and 2 have been studied in patients with TKA, ADVANCE 3 in patients with THA. All in these three trials, dose of apixaban was 2.5 mg twicw daily starting 12 - 24 hours after surgery. While in ADVANCE 1, dosage of enoxaparin was 30 mg twice daily starting 12 - 24 hours after surgery, in ADVANCE 2 and 3 dosage of enoxaparin was 40 mg once daily 12 hours starting after surgery. At the end of these trials, apixaban was superior to enoxaparin in terms of reducing total VTE and all cause death. It had similar bleeding rates with enoxaparin. Thus, apixaban is approved by European Union as 2.5 mg orally twice/day and its initial dose taken 12 - 24 hours after surgery [
As competitive and reversible direct thrombin inhibitor dabigatran etexilate is a prodrug form. Following its orally taken, it is rapidly converted to dabigatran by esterases in the blood and liver [
Dabigatran was studied in four phase III trials to prevention of VTE. In RE-NOVATE and RE-NOVATE 2 are after THA and RE-MODEL, RE-MOBILIZE are after TKA. While in RE-NOVATE and RE-MODEL da- bigatran was compared with enoxaparin 40 mg once daily, in RE-MOBILIZE dabigatran was compared with enoxaparin 30 mg twice daily. Dosage of dabigatran was 220 mg and 150 mg once daily in RE-NOVATE, RE- MODEL and RE-MOBILIZE. In RE-NOVATE 2 dosage of dabigatran was 220 mg once daily. All these trials demonstrated that dabigatran had no inferiority and in terms of bleeding outcomes were similar between enoxaparin and dabigatran group [
Various type of external compression devices are available to provide DVT prophylaxis such as graduated compression stocking (GCS), intermittent pneumatic compression devices (IPCD) [
GCSs are widely used for prvention and treatment of DVT in nontrauma patients [
IPCD is the other mechanical prophylaxis device. Main disadvantage of this device is compliance that the device need to be removed during washing and ambulation. Also after hospital discharge the device require an external power source. However this problem has been solved by technical improvement as new portable and battery powered devices. The comperative study performed by colwell et al. demonstrated that IPCD was effective as much as effect of enoxaparin. In this multicenter randomized conrolled study also demontrated that IPCD had lower bleeding rate as per enoxaparin as expected [
Total knee arthroplasty and total hip arthroplasty are commonly performed by orthopaedic surgeon. These sur- geries are open to complication especially deep vein thrombosis, venous thromboembolism and pulmonary embolism. To avoid these complications orthopaedic surgeons should consider to use anti thrombotic agents and devices. Under light of the ACCP and AAOS guidelines, the treatment and prophylaxy are succesfully applied. In selected treatment, patient compliance is crucial to prevent VTE especially after hospital discharge. Not require monitoring and self administrating drugs are recently favour. These new oral anticoagulant drugs are closer to the ideal antithrombotic drug. However, long term well conducted trials are required to make desicion safety and efficacy of the new drugs.