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.
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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
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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
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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
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