13 – Does the administration of VTE prophylaxis increase the risk for intracranial bleeding in patients undergoing orthopaedic procedures? If so, are there differences between the various prophylactic agents?

Walter Ageno, Daniel Caldeira.

Response/Recommendation: There is a known association between the use of antithrombotic drugs and the risk of intracranial bleeding in patients receiving long-term treatment. Intracranial bleeding has been less commonly reported in patients undergoing orthopedic procedures, probably because of the shorter time of exposure to antithrombotic drugs. The incidence of intracranial bleed seems to be higher with the use of vitamin K antagonists.

Strength of Recommendation: Limited.

Rationale: Intracranial bleeding, encompassing intracerebral, subdural, and subarachnoid hemorrhages, is a potentially fatal complication of antithrombotic treatment1-3. Predisposing factors include, among others, advanced age, concomitant hypertension, and the use of dual or triple antithrombotic therapies such as antiplatelet and anticoagulant drugs. This risk has been extensively studied in the population of patients with atrial fibrillation, where a reduction in the incidence of intracranial bleeding was observed with the use of the direct oral anticoagulants (DOAC) as compared to VKA4. A recent study from Denmark reported a strong association between the use of antithrombotic drugs and the risk of intracranial bleeding in the general population5. This association was weakest for the use of low-dose aspirin (ASA) and clopidogrel and strongest with the use of VKA. The association was weaker for the DOAC than for VKA.

The risk of intracranial bleeding is likely much lower when prophylactic doses of anticoagulant drugs are used for a limited period of time, such as after orthopaedic surgery. However, randomized controlled trials have not consistently reported specific information on the occurrence of intracranial bleeding but instead report major bleeding. The estimated risk of major bleeding with anticoagulants in patients undergoing major orthopaedic surgery is estimated around 4 cases per 1,000 procedures, with no difference between DOAC and low-molecular-weight heparin (LMWH)6. This risk is slightly increased when low dose ASA is used (relative risk [RR] 2.63; 95% confidence interval [CI] 0.64-10.79)6.

When intracranial bleeding was described in placebo-controlled trials, the incidence was very low without differences between pharmacologic prophylaxis and placebo7,8. In one study comparing warfarin and placebo in 160 elderly patients with femoral fracture, there was only one occurrence of intracranial (cerebellar) bleeding in the warfarin group and none in the placebo group7. In the Pulmonary Embolism Prevention (PEP) trial, in which 13,356 patients undergoing hip fracture surgery were randomized to ASA 160 mg or placebo, there were two intracranial bleeding events in the placebo arm and none in the ASA arm8. In more recent trials comparing LMWH with DOAC in patients undergoing major elective orthopaedic surgery, intracranial bleeding occurred in none, and 1 case among a population of 1,146 and 2,673 treated patients, respectively9-16. Finally, no information is available on the risk of intracranial bleeding in patients with previous bleeds who are undergoing orthopaedic surgery and receiving antithrombotic prophylaxis. For these patients, decision-based on individual assessment is suggested.

References:

1.         García-Rodríguez LA, Gaist D, Morton J, Cookson C, González-Pérez A. Antithrombotic drugs and risk of hemorrhagic stroke in the general population. Neurology. 2013;81(6):566-574. doi:10.1212/WNL.0b013e31829e6ffa

2.         Gulati S, Solheim O, Carlsen SM, et al. Risk of intracranial hemorrhage (RICH) in users of oral antithrombotic drugs: Nationwide pharmacoepidemiological study. PLoS One. 2018;13(8):e0202575. doi:10.1371/journal.pone.0202575

3.         McQuaid KR, Laine L. Systematic review and meta-analysis of adverse events of low-dose aspirin and clopidogrel in randomized controlled trials. Am J Med. 2006;119(8):624-638. doi:10.1016/j.amjmed.2005.10.039

4.         Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383(9921):955-962. doi:10.1016/S0140-6736(13)62343-0

5.         Hald SM, Möller S, García Rodríguez LA, et al. Trends in Incidence of Intracerebral Hemorrhage and Association With Antithrombotic Drug Use in Denmark, 2005-2018. JAMA Netw Open. 2021;4(5):e218380. doi:10.1001/jamanetworkopen.2021.8380

6.         Anderson DR, Morgano GP, Bennett C, et al. American Society of Hematology 2019 guidelines for management of venous thromboembolism: prevention of venous thromboembolism in surgical hospitalized patients. Blood Adv. 2019;3(23):3898-3944. doi:10.1182/bloodadvances.2019000975

7.         Morris GK, Mitchell JR. Warfarin sodium in prevention of deep venous thrombosis and pulmonary embolism in patients with fractured neck of femur. Lancet. 1976;2(7991):869-872. doi:10.1016/s0140-6736(76)90536-5

8.         Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet. 2000;355(9212):1295-1302.

9.         Lassen MR, Raskob GE, Gallus A, et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010;375(9717):807-815. doi:10.1016/S0140-6736(09)62125-5

10.       Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009;361(6):594-604. doi:10.1056/NEJMoa0810773

11.       Lassen MR, Gallus A, Raskob GE, et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010;363(26):2487-2498. doi:10.1056/NEJMoa1006885

12.       Turpie AGG, Lassen MR, Davidson BL, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009;373(9676):1673-1680. doi:10.1016/S0140-6736(09)60734-0

13.       Kakkar AK, Brenner B, Dahl OE, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008;372(9632):31-39. doi:10.1016/S0140-6736(08)60880-6

14.       Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358(26):2765-2775. doi:10.1056/NEJMoa0800374

15.       Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358(26):2776-2786. doi:10.1056/NEJMoa076016

16.       Eriksson BI, Dahl OE, Rosencher N, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet. 2007;370(9591):949-956. doi:10.1016/S0140-6736(07)61445-7