Enrique Gómez-Barrena, Per Kjaesgard-Andersen.
Response/Recommendation: Patients undergoing total hip arthroplasty/total knee arthroplasty (THA/TKA) who received thromboprophylaxis are at an increased risk of bleeding. Higher bleeding rates were detected for low-molecular-weight heparin (LMWH) versus aspirin (ASA) and for rivaroxaban versus LMWH and other novel oral anticoagulants (NOAC), while the lowest bleeding rates in patients receiving NOAC were observed for apixaban. Drug dosage and patient characteristics (age, renal dysfunction) may complicate the data on bleeding risk as may changes in clinical practice (particularly with the wide use of tranexamic acid (TXA) currently).
Rationale: Thromboprophylaxis by different strategies has proven effective in decreasing the risk of venous thromboembolism (VTE)1 associated with both THA, and TKA. VTE can include distal or proximal deep venous thrombosis (DVT) and occasionally pulmonary embolism (PE). The use of thromboprophylaxis trades off the decreased risk of VTE with the potential for increased bleeding.
Bleeding as a complication of THA/TKA surgery under pharmacological thromboprophylaxis is a safety issue usually incorporated into clinical trials, even if the definition and adjudication of bleeding outcomes may be inhomogeneous and therefore inconclusive2. Major bleeding may account for up to 8.9% of total perioperative deaths3 following total joint arthroplasty (TJA) and therefore is a concerning complication. While major bleeding and hemorrhage is usually detected and reported in trials, minor bleeding remains subjective whilst occult blood loss may be underdiagnosed. Two large phase 4 trials reported a 0.1% major bleeding risk following TJA when rivaroxaban was used for thromboprophylaxis4,5. Heterogeneity increases when specific bleeding complications are investigated, such as gastrointestinal bleeding6. Furthermore, a meta-analysis with trial sequential analysis to test the robustness of findings related to rivaroxaban7 concludes that major bleeding (not included as primary endpoint) did not reach the required information size and therefore more evidence may be needed to verify the risk. However, when surgical-site bleeding is incorporated in a risk-benefit analysis of NOAC, the clinical net benefit is not so clear in THA while maintained in TKA8. Despite these inconsistencies, efficacy and safety is universally confirmed and accepted for all thromboprophylaxis agents in clinical use today, after clinical trials and meta-analysis.
An important body of literature is available about the results of early and pivotal clinical trials for all pharmacological agents in the market. Individual trials may offer different reporting criteria for bleeding events, and therefore, comparative trials and meta-analysis should be preferred to define bleeding rates and risks, even if sometimes limited strength of the recommendations is observed, due to limited or conflicting evidence. Systematic reviews and particularly meta-analysis of these trials offer the best evidence and data to conclude on some comparisons. But even those may be conflicting due to heterogeneity in reported bleeding and in surgical or patient confounding factors. A recent meta-analysis with pooled analysis of bleeding events in the rivaroxaban trials9 showed that the overall rate of major bleeding events, overt bleeding events associated with fall in hemoglobin (Hb) of > 2 g/dL, clinically overt bleeding events leading to transfusion of > 2 units of blood, clinically overt bleeding events leading to further surgeries, and non-major bleeding events were < 1%, < 1%, < 1%, < 1%, and 3%, respectively. Many procedural factors may apply. Differences in clinical practice such as the use of TXA and transfusion indications means that conclusions are hard to establish.
Three major studies of safety comparisons were identified in the literature: LMWH versus ASA10, non-vitamin K oral anticoagulants (NOAC, including direct factor Xa inhibitors and other, such as rivaroxaban, dabigatran, apixaban, ximelagatran, etc.) versus LMWH11–24 or ASA25–27, and NOAC of different groups comparing to each other14,28. Bleeding rates are not always reported, and bleeding risks may be used as the surrogate. Rarely, meta-analysis have been published focusing on the surgical site bleeding risks29, reporting higher relative risks for LMWH and rivaroxaban, and lower for apixaban. Network meta-analysis comparing all options30 seems to confirm a decreased hemorrhage risk with oral anti-Xa compared with LMWH, also lower for both anti-Xa and LMWH to vitamin-k antagonists (VKA) with international normalized ratio (INR) between 2 and 3.
When comparing ASA and LMWH10 in a meta-analysis (4 trials, 1507 patients), no significant difference in the bleeding risk was detected (major bleeding, relative risk [RR]=0.84; minor bleeding, RR=0.77).
NOAC comparisons report slightly different bleeding rates for each agent against LMWH (usually enoxaparin) and among them. A synthesis includes: major bleeding in 1.4% (220mg) or 1.1% (150mg) vs 1.4% (3 trials and 8,135 patients in dabigatran vs enoxaparin,13); major or non-major, clinically relevant bleeding RR vs enoxaparin of 1.52 (ribaroxaban), 0.34 (betrixaban), 0.88 (apixaban), 0.85 (darexaban), 1.30 (edoxaban)12; better preventive effects on bleeding with apixaban14; RR of major bleeding of oral direct factor Xa inhibitors vs enoxaparin, 1.27 (5 trials, 12,184 patients with THA) and 0.94 (5 trials, 13,169 patients with TKA) being non significantly different from enoxaparin15; less bleeding (and less efficacy) of enoxaparin vs immediately postop ximegalatran with hip odds ratio (OR)=0.30 and knee OR=0.71 (6 trials, 10,051 THA or TKA patients)16; compared to enoxaparin, the RR of clinically significant risk of bleeding was higher with rivaroxaban (RR=1.25), similar with dabigatran (RR=1.12) and lower with apixaban (RR=0.82) in a meta-analysis of 16 trials, 38,747 THA or TKA patients18; compared with dabigatran, enoxaparin similarly efficacious and similar risk of bleeding (OR=0.90), while compared with rivaroxaban, enoxaparin less efficacious but lower risk of bleeding (OR= 0.79) in a meta-analysis with 6 trials, 18,405 THA or TKA patients19; in a network meta-analysis with 19 trials and 43,838 THA or TKA patients, OR were also calculated against enoxaparin 30mg bid or 40mg daily, and bleeding (major/non-major clinically relevant) was significantly increased for fondaparinux (vs 40mg daily, OR=0.67) and rivaroxaban (vs 40mg daily, OR=0.77)20, while apixaban as the comparator (2.5mg bid) showed increased bleeding with enoxaparin 30mg bid (OR=0.75), dabigatran (OR=0.73), fondaparinux (OR=0.56), and rivaroxaban (OR=0.65); a meta-analysis with 21 randomized control trials (RCT)21 produced major bleeding rates with enoxaparin of 1.32%, dabigatran 1.25%, rivaroxaban 2.02%, apixaban 0.70%, ximegalatran 0.93%; a pooled analysis of 2 RCT with 8,464 THA or TKA patients comparing apixaban and enoxaparin showed a major bleeding rate of 0.7% and 0.8%, but when non-major clinically relevant bleeding was summed, the rates were 4.4% for apixaban and 4.9% for enoxaparin22. As a summary, major bleeding rates for enoxaparin were reported from 0.8 to 1.3%, for dabigatran 1.1 to 1.4%, for apixaban around 0.7, for rivaroxaban around 2%. Other clinically relevant bleeding may account for about 4%, but minor bleeding rates are difficult to establish.
When comparing ASA and NOAC, the former had less risk of blood transfusion than rivaroxaban (RR=0.94)26. A large trial (3,424 patients) did not find significant differences between ASA and rivaroxaban in clinically important bleeding (1.29% vs 0.99%) or major bleeding (0.47% vs 0.29%)25, and a recent meta-analysis31 could not find any significant differences in any bleeding, major bleeding, minor bleeding, gastrointestinal tract bleeding or wound hematoma, between ASA or any other comparator.
Risks associated to dosage were studied between anti-Xa agents and LMWH17,32. With LMWH as a comparator, enoxaparin 30mg bid may decrease the VTE risk but may increase the clinically significant hemorrhage (in32 significantly, in17 non-significantly). Of note, many clinical trials of NOAC have used enoxaparin 40mg once daily, the standard in many centers at the time of trials. ASA dosage in thromboprophylaxis has been studied (81mg bid vs 325mg bid) showing similar bleeding rates with an overall rate of 0.9%, although 325mg produced more gastrointestinal symptoms33. Prolonged administration of thromboprophylaxis with LMWH was not associated with changes in major bleeding but there was an increase in minor bleeding (3.7% in long-term administration vs 2.5% in short-term prophylaxis)34, although a registry study35 did not associate any increased bleeding risk. Again, the definition and reporting may be different.
There is little contemporary literature with warfarin as a comparator and most studies compare different doses36,37. Early trials with warfarin and LMWH38 seemed to highlight higher bleeding risks with LMWH vs. adjusted warfarin (2.8% vs 1.2% incidence of major bleeding events).
Risks may be increased in case of renal dysfunction39, and concomitant medications or age may also affect bleeding. Non-steroidal anti-inflammatory drugs40,41 did not increase the risk of bleeding for dabigatran40, and age older than 7542 showed a lower risk of bleeding with anti-Xa medications than with LMWH (OR=0.71).
Fibrinolysis and antifibrinolytic agents (such as TXA) may have an impact on bleeding43–46, and it is worth considering that many of the above-mentioned meta-analyses were based on trials performed without perioperative TXA. Today’s standard-of-care incorporating TXA may have produced different bleeding rates. Hidden blood loss after TXA in patients receiving enoxaparin, rivaroxaban, or nadroparin was not statistically significant in a trial with 150 patients43, but this will need further investigation.
Although all investigated thromboprophylaxis agents have a reasonable safety profile, bleeding events are a matter of concern for all surgeons. Variability in patients and procedures may apply, but careful attention to outweigh risks and benefits, personalize the thromboprophylaxis regime and early detection of related bleeding complications is required to improve the standard of health care invasive measures such as anticoagulant prescription in the perioperative period of total joint replacement, particularly when no specific antidote is available for most NOAC47, and anticoagulant overtreatment represents a serious risk of bleeding in our surgical patients.
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2. Harenberg J, Marx S, Dahl OE, et al. Interpretation of endpoints in a network meta-analysis of new oral anticoagulants following total hip or total knee replacement surgery. Thromb Haemost. 2012;108(5):903-912. doi:10.1160/TH12-07-0482
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40. Friedman RJ, Kurth A, Clemens A, Noack H, Eriksson BI, Caprini JA. Dabigatran etexilate and concomitant use of non-steroidal anti-inflammatory drugs or acetylsalicylic acid in patients undergoing total hip and total knee arthroplasty: no increased risk of bleeding. Thromb Haemost. 2012;108(1):183-190. doi:10.1160/TH11-08-0589
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46. Yoshida K, Wada H, Hasegawa M, et al. Increased fibrinolysis increases bleeding in orthopedic patients receiving prophylactic fondaparinux. Int J Hematol. 2012;95(2):160-166. doi:10.1007/s12185-012-1004-2
47. Raval AN, Cigarroa JE, Chung MK, et al. Management of Patients on Non-Vitamin K Antagonist Oral Anticoagulants in the Acute Care and Periprocedural Setting: A Scientific Statement From the American Heart Association. Circulation. 2017;135(10):e604-e633. doi:10.1161/CIR.0000000000000477