E. Bailey Terhune, Klaas Victor, Vasili Karas, Jan Somers.
Response/Recommendation: Each venous thromboembolism (VTE) prophylactic agent has evidence-based relative and absolute contraindications, which should be considered and balanced with the patient’s VTE risk.
Strength of Recommendation: Strong.
Rationale: Unfractionated heparin (UFH), low-molecular-weight heparin (LMHW), and vitamin K antagonists (VKA) have been used in the prevention of VTE after orthopaedic surgery for more than 30 years1. More recently, VTE prophylaxis after elective hip and knee arthroplasty has evolved with the introduction of direct oral anticoagulants (DOAC) including direct thrombin inhibitors (dabigatran) and Factor Xa inhibitors (rivaroxaban, apixaban). Recent literature also discloses aspirin (ASA) as safe and effective in the prevention of VTE in selected patients2–5.
Prevention of VTE in clinical practice requires an assessment of (i) a patient’s cumulative VTE risk; and (ii) patient characteristics that would contraindicate pharmacological prophylaxis. An important patient characteristic contraindicating the initiation of concurrent post-operative VTE pharmacological thromboprophylaxis is a pre-operative indication for therapeutic dosing of anticoagulation (e.g., atrial fibrillation, prior VTE, or mechanical heart valves). If a patient is on anticoagulant therapy prior to surgery, the same anticoagulant regimen should be safely resumed post-operatively, if appropriate. For the other patients not on anticoagulation prior to surgery, the patient’s cumulative VTE risk is the intrinsic VTE risk resulting from any medical conditions and the added risk resulting from surgery or trauma. Selection of the appropriate VTE prophylactic agent or combination of prophylactic measures for these patients, necessitates consideration of both absolute and relative contraindications to pharmacological prophylactic treatment6.
Vitamin K Antagonists: VKA were the mainstay of oral anticoagulation prior to DOAC development. This class of medications has the advantage of being administered orally, however, VKA are challenging in clinical practice as they exhibit considerable variability in dose-response, have a narrow therapeutic window, and are subject to interactions with many drugs and diets. Additionally, maintenance of a therapeutic level of anticoagulation requires consistent laboratory monitoring and patient compliance7. A patient’s inability or unwillingness to cooperate in frequent laboratory monitoring is a contraindication to use.
Contraindications to VKA for VTE prophylaxis include deficiency of antithrombin III, protein C, or protein S, pregnancy, or severe hepatic failure7. Caution should be used in patients with chronic kidney disease. VKA are almost entirely metabolized before urinary excretion, however, the current recommendations for VKA use in patients with chronic kidney disease (CKD) are mostly extrapolated from trials designed for the general population or based on observational studies, thus international normalized ratio (INR) levels but be watched closely. In patients with liver disease, the metabolism of VKA can be difficult to predict. Liver disease can also independently affect the INR, and thus routine INR monitoring may not be an accurate representation of therapeutic VKA dosing8.
Direct Oral Anticoagulants: DOAC overcome some of the practical limitations associated with VKA therapy due to their more predictable pharmacological properties. These medications have rapid onset and termination of action, fewer drug interactions, lack of dietary vitamin K interactions, and no need for routine drug monitoring9,10. This has led to rapid clinical adoption.
Prior to initiating VTE prophylaxis with any DOAC, renal and liver function testing should be performed. Limited data is available on the use of these agents in patients with severe renal or hepatic impairment, as these patients were excluded from the phase III trials for DOAC. All DOAC have a degree of renal excretion as active metabolites (dabigatran, 80%; rivaroxaban, 33%; apixaban, 27%) thus medication accumulation can occur in patients with impaired renal function8,11,12. Caution should be used when prescribing these medications to patients with CKD13. A recent meta-analysis of DOAC and warfarin use in patients with CKD and dialysis patients showed that DOAC had significantly better efficacy in patients with early-stage CKD14. However, the efficacy and safety profiles were similar in patients with CKD stages 4-5 or dialysis patients14. Because renal function can decline over time, particularly in elderly patients, regular assessment of renal function during the use of anticoagulant therapy is necessary.
Rivaroxaban and apixaban are contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk15–17. Dabigatran is contraindicated in patients with hepatic impairment or liver disease expected to have an impact on survival13. While no dose adjustment is required in cases of mild or moderate hepatic impairment, DOAC should be used with caution in these patients.
Many medications interfere with the efficacy and safety of DOAC. Nonsteroid anti-inflammatories (NSAID) and ASA are known to affect bleeding risk, but do not directly interact with DOAC8,15. The possibility may exist that patient are at increased risk of bleeding in case of concomitant use with selective serotonin or norepinephrine reuptake inhibitors (SSRI/SNRI) due to their reported effect on platelets. Patients taking these medications in addition to anticoagulants should be observed closely for bleeding. DOAC are a substrate of the P-glycoprotein transporter, and thus concomitant administration of P-glycoprotein inhibitors results in increased DOAC plasma concentration and increased risk of bleeding18. P-glycoprotein inducers may decrease anti-thrombotic efficacy. Concomitant use of mild to moderate P-glycoprotein inhibitors (amiodarone, quinidine, verapamil) should be done with caution, and often requires dose reduction. DOAC are contraindicated in patients taking strong P-glycoprotein inhibitors (ketoconazole, cyclosporine, itraconazole, dronedarone, glecaprevir/pibrentasvir)15,16. Apixaban is contraindicated in patients taking human immunodeficiency virus (HIV) protease inhibitors (e.g., ritonavir).
Low-Molecular-Weight Heparin And Unfractionated Heparin: In addition to patient characteristics that are an absolute contraindication for any type of pharmacological thromboprophylaxis, such as active major bleeding and severe traumatic brain injury, also in the following hematological conditions the use of LMWH or UFH should be done carefully: coagulopathy; disseminated intravascular coagulation; hemophilia or other coagulation factor disorders; platelet function disorders; and thrombocytopenia6,19,20. In a study with thrombocytopenic non-surgical patients, administration of thromboprophylactic dosing of enoxaparin appeared safe provided that the platelet count exceeded 25,000/µl21.
The use of ASA, NSAID, antiplatelets, or anticoagulants concomitant with LMWH treatment increases the risk of bleeding and is not recommended6,19. A prospective observational study, including 339 patients, showed that the strongest correlation with a raise in adverse reactions occurred with coadministration of ASA. For concomitant NSAID treatment, the correlation was very low22.
Clearance of LMWH occurs primarily via renal excretion. This can increase the risk of bleeding in patients with renal impairment23. Smaller LMWH are more dependent on renal excretion than larger ones. Data from three prospective trials confirms that patients with a low creatinine clearance (CrCl) are at risk of accumulation of anti-Xa heparin activity when treated with nadroparin or enoxaparin24–26. The exception appeared to be tinzaparin. A multidose prospective pharmacokinetic trial27 showed that the anti-Xa heparin effect of tinzaparin does not appear to accumulate as CrCl declines. UFH is sometimes preferred in patients with renal impairment28. UFH clearance is dose-dependent, in contrast to LMWH, and can be monitored relatively easy23,29.
The New South Wales Clinical Excellence Commission stated in 2015 that end-stage liver failure in combination with INR > 1.5 is an absolute contraindication for VTE chemoprophylaxis19 reflecting the main perception that thrombocytopenia and elevated INR predict bleeding risk in cirrhotic patients. However, previous studies have shown that elevated INR does not predict the risk of bleeding in patients with cirrhosis30,31. Also, elevated INR and thrombocytopenia do not mean that patients with cirrhosis have a low risk of VTE; these laboratory findings are insufficient to detect the balance between procoagulant and anticoagulant factors in liver cirrhosis32–34. Absolute contraindications for LMWH and UFH in cirrhotic patients are concomitant anticoagulation therapy; and active bleeding, including variceal bleeding35. To conclude, administration of UFH or LMWH can be safe in patients with liver cirrhosis, and the decision to start anticoagulation therapy should not solely depend on INR and platelet count30,36.
Both LMWH and UFH can elicit heparin-induced thrombocytopenia, an immune-mediated complication caused by the formation of antibodies to complexes of heparin and platelet factor 4. These antibodies develop in 2-8% of patients treated with LMWH and 8-17% of patients using UFH. Eventually, only 0.2-3% of sensitized patients will develop thrombocytopenia37. Heparin-induced thrombocytopenia, within the past 100 days or in the presence of circulating antibodies, is an absolute contraindication for the administration of UFH, enoxaparin, nadroparin, dalteparin, and tinzaparin36,38–40. The use in patients with a history >100 days without circulating antibodies is allowed if caution is taken into account36.
In a retrospective review of enoxaparin and UFH administration on twenty-nine hospital wards (accounting for 10,516 patient visits) 11.9% of ordered doses were not administered, primarily due to patient refusal36. In this respect, failure to adhere can be considered as a contraindication for LMWH-administration. Considering using oral VTE prophylaxis for non-adherent patients reporting dislike of needles and pain from injections can improve efficacy41.
As neither UFH, nor LMWH cross the placenta, heparins are the preferred anticoagulants in pregnancy36,42. There is no evidence for fetotoxicity or teratogenicity of enoxaparin, tinzaparin, or dalteparin36,39,40. For pregnant women using enoxaparin, there is no evidence for an increased risk of hemorrhage, thrombocytopenia or osteoporosis when compared to non-pregnant women36. Furthermore, enoxaparin treatment can be continued during breastfeeding because expected passage in human milk is very low, and oral absorption of enoxaparin is unlikely36.
Fondaparinux: Elimination of fondaparinux occurs primarily by urinary excretion of its non-metabolized form and is therefore prolonged in patients with renal insufficiency. The use of fondaparinux is contraindicated in patients with severe renal insufficiency (CrCl < 30 mL/min) and in patients with body weight less than 50 kg. As fondaparinux clearance is decreased by 30% in the latter patient population, the incidence of major bleeding is doubled compared with patients weighing > 50 kg43,44.
No evidence exists of fetotoxicity due to fondaparinux administration. However, this might be due to a lack of adequate research in pregnant patients44.
Acetylsalicylic Acid: Acetylsalicylic acid (ASA) or aspirin is a nonselective NSAID as it irreversibly binds to both cyclooxygenase-1 and cyclooxygenase-2, leading to enzyme inactivation through acetylation45. Low doses of ASA mainly inhibit cyclooxygenase-1, thereby opposing thromboxane synthesis in platelets and preventing platelet aggregation46,47.
The use of ASA is contraindicated in patients with hemophilia or congenital coagulopathies; in patients with thrombocytopenia; and in the presence of an acquired bleeding diathesis, e.g., dengue or yellow hemorrhagic fever48–50.
The risk of gastro-intestinal bleeding is increased by ASA in patients with active peptic ulcer disease or gastritis; in patients with a history of recurrent peptic ulcer or a history of gastro-intestinal hemorrhage50; in patients on warfarin; or if there is concomitant alcohol consumption48,49. Susceptibility for gastro-intestinal bleeding due to administration of ASA is particularly high in elderly patients50.
Administration of ASA is not recommended in children under 16 years unless the predicted benefits outweigh potential risks50. ASA can elicit Reye’s syndrome in children suffering from a viral infection. Reye’s syndrome causes coagulopathy, and in its most severe form cerebral edema and liver failure51.
ASA is renally cleared. If administered in a low-dose regimen, it does not accumulate in patients with renal insufficiency and can be used if the benefits outweigh the risks50.
The antiplatelet effect of ASA can be attenuated through competitive binding of other NSAID to cyclooxygenase-1. However, this interaction is highly variable amongst different types of NSAID and depends on timing of administration, dose of ASA, and dose of the concomitantly administered NSAID52,53. This competitive effect is reported for ibuprofen and naproxen54–58, but not for diclofenac54,55. Findings for celecoxib are conflicting: in vivo studies by Renda et al., and Wilner et al., showed no attenuating effect of platelet inhibition by ASA59,60, whereas an in vitro study by Saxena et al., and a study on dog models by Rimon et al., demonstrated interference with ASA47,58. Another study found that administration of ASA 2 hours before single-dose ibuprofen could prevent the interaction with ASA, although this strategy did not prevent interference when multiple doses of ibuprofen were given54. In conclusion, the choice to administer ASA concomitantly with other NSAID should be guided by clinical decision-making at patient level53.
Low doses of ASA (up to 100 mg/day) appear safe in the first six months of pregnancy61. Clinical data concerning the administration of doses above 100 mg/day are lacking. During the third trimester of pregnancy, prescription of ASA at doses higher than 100 mg/day is contraindicated50,61, because of the risk of premature closure of the ductus arteriosus and fetal renal dysfunction. Furthermore, all prostaglandin synthesis inhibitors may cause inhibition of uterine contractions and, consequently, delayed, or prolonged labor50. Suspending lactation is not required for short-term use of ASA in its recommended dose. However, discontinuation of breastfeeding is necessary in patients using ASA for longer periods of time50.
Recommendations for Future Research: As the number of elective arthroplasties performed annually continues to rise, optimization of the perioperative care continues to be a priority. Selection of an effective thromboprophylaxis protocol is critical, and should take into account patient characteristics, medication safety profile, and drug metabolism. Solid evidence is still lacking to formulate clear guidelines, in particular for drug interaction patterns and for patients with renal or hepatic disease. Prospective study designs in an orthopaedic setting will be necessary to draw firm conclusions for VTE prophylaxis in these populations.
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