SM Javad Mortazavi, Kirill Lobastov.

Response/Recommendation: In patients with chronic renal disease, pharmacological agents used in venous thromboembolism (VTE) prophylaxis may need a dose adjustment to prevent major bleeding or other complications based on their biochemical properties. In unstable advanced renal disease, unfractionated heparin (UFH) or mechanical prophylaxis alone may be preferred as VTE prophylaxis.

Strength of Recommendation: Limited.

Rationale: Chronic kidney disease (CKD) increases the risk for both VTE and bleeding due to specific changes in the hemostatic system (platelet alteration, endothelial injury, loss of natural coagulation, and anticoagulation factors), uremic toxins, and proinflammatory shifts¹. Compared to CKD patients with a 10 – 50 percentile of renal function, there is a 2.6-fold increase in the odds ratio of VTE in cases with less than one percentile of renal function². Decreased levels of Factor VIII, von Willebrand factor and albuminuria, are the most predicting factors of thrombotic events in CKD cases^2,3. Central venous catheters and arteriovenous fistula predispose end-stage renal disease (ESRD) patients to thrombosis secondary to disturbance and activation of the platelets. CKD significantly alters VTE outcomes in the population by increasing the risk of all-cause mortality, recurrent VTE, and major bleeding by approximately 1.4 times⁴. In patients undergoing major orthopaedic procedures, the prevalence of CKD varies from 3.9% to 17%, and it increases with age^5-9. Analysis of a large cohort of patients undergoing total knee arthroplasty (TKA) (n = 41,852) and total hip arthroplasty (THA) (n = 20,720) by Miric et al., considering the International Classification of Diseases version 9 (ICD-9) codes and the Diagnosis Related Groups (DRG) to identify patients with CKD, did not reveal a significant increase in the risk of deep venous thrombosis (DVT) and pulmonary embolism (PE) after both procedures^7,8. However, numerically higher incidence of DVT was reported in CKD patients. In contrast, another analysis of a big dataset of more than one million patients demonstrated an increased risk of DVT by 1.38 times (95% confidence interval [CI], 1.04 – 1.84) in patients with CKD according to the disease codes⁹. However, this tendency was not confirmed for patients with ESRD on dialysis. In an analysis of a prospective registry by Warth et al., with the estimation of glomerular filtration rate (GFR) by pre-operative serum creatinine level, there was a significantly greater rate of overall complications in patients with moderate to severe renal impairment, as compared to patients with no or mild disease but without a significant difference for DVT and PE⁵. Another retrospective study with the calculation of GFR showed a 2.68-fold (95% CI, 1.28 – 5.59) increase in the risk of DVT after total joint arthroplasty in those with GFR < 60 mL/min⁶. A meta-analysis by Zhang et al., suggested that CKD can increase VTE risk by 8.31 times (95% CI, 1.98 – 34.93) after spine surgeries¹⁰.

Besides a higher rate of VTE events, patients with CKD have an increased risk of receiving blood transfusion after major orthopaedic procedures, especially if they have preoperative anemia^11-13. CKD with albuminuria is associated with 1.4-2.7 fold increase in bleeding risk, including intracranial hemorrhages, regardless of the GFR^2,3,14,15. As a double-edged sword, dialysis can decrease the chance of bleeding by eliminating uremic toxins but lead to bleeding episodes by continuous activation and consumption of the coagulation factors². Decreased renal function (GFR < 30 mL/min) is one of the accepted bleeding risk factors in several risk assessment models, including the Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile international normalized ratio [INR], Elderly, Drugs/Alcohol Concomitantly (HAS-BLED)¹⁶, the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA)¹⁷, and the Hepatic or Renal Disease, Ethanol Abuse, Malignancy, Older Age, Reduced Platelet Count or Function, Re-bleeding [Previous Bleed], Hypertension [Uncontrolled], Anaemia, Genetic Risk Factors [CYP 2C9 snp], Excessive fall risk, Stroke (HEMORR₂HAGES)¹⁸.

There is no strong evidence comparing the efficacy and safety of chemoprophylaxis (with/without mechanical prophylaxis) versus mechanical prophylaxis alone after major orthopaedic procedures in CKD patients. The 2011 American College of Chest Physicians (ACCP) guidelines, however, recommended mechanical prophylaxis only after orthopaedic surgery in those with increased risk of bleeding, including CKD patients (Grade 2C)^19,20. The American Academy of Orthopaedic Surgeons (AAOS) guidelines also recommended aspirin, warfarin, or no chemoprophylaxis after orthopaedic surgery in those having both risks of bleeding and thrombosis²¹. In 2018 the European guidelines for perioperative chemoprophylaxis recommended using weight-adjusted low-molecular-weight heparin (LMWH) or low-dose UFH for VTE prophylaxis in elderly patients with CKD (Grade 2C) and low-dose UFH (Grade 2C), or reduced doses of enoxaparin (Grade 2C), or dalteparin (Grade 2B) for critically ill CKD patients²². The United Kingdom National Institute for Health and Care Excellence (NICE) 2018 guidelines also preferred low-dose LMWH or UFH²³.

Pharmacological agents require following the specific instructions and related restrictions for kidney function while choosing an appropriate drug and dosage for chemoprophylaxis^1,24. Thus warfarin and UFH could be used without limitation. Low-dose UFH may be appropriate in unstable renal disease as it has a short half-life and non-renal metabolism, and its anticoagulant effect can easily be reversed. LMWH may be preferred to UFH as it can be administered once daily and has decreased risk of heparin-induced thrombocytopenia. Also, evidence suggests no bioaccumulation of LMWH in patients with GFR > 30 mL/min. Enoxaparin should be used according to the official restrictions by GFR with the possible dose correction and may require control of anti-factor Xa activity. Dalteparin was not associated with bioaccumulation in CKD patients²⁵ and was equivalent in terms of safety and superior in terms of PE risk reduction compared with UFH in critically ill patients, of whom 2.1% had CKD²⁶. Tinzaparin also showed no bioaccumulation in patients with GFR > 20 mL/min²⁷. The dose of fondaparinux should be adjusted if GFR < 50 mL/min, and it is restricted if GFR is lower than 30 mL/min^24,28,29.

Direct oral anticoagulants (DOAC) such as dabigatran should be used appropriately depending on GFR with required dose correction. There is emerging evidence from the non-surgical population that although DOAC are non-inferior regarding their efficacy for prevention of recurrent VTE in CKD patients, they are superior in terms of safety compared to warfarin^30-32. A subgroup analysis of CKD patients from DOAC phase III orthopaedic trials is available for rivaroxaban, apixaban, and dabigatran, and it shows no interaction of efficacy and safety with the kidney function^33-35. In retrospective studies on patients with CKD stage of 4 – 5, no significant difference was observed between apixaban and warfarin in terms of major bleeding or VTE, if usage was less than 3 months^36,37. A similar analysis is not available for edoxaban^38,39.

A direct thrombin inhibitor, e.g., desirudin, may be suggested for thromboprophylaxis in CKD patients. Compared to enoxaparin after THA, it was non-inferior in terms of bleeding regardless of the CKD stage but superior in terms of VTE risk reduction in the CKD stage 3b (GFR of 30 – 45 mL/min)⁴⁰. This effect may be related to the lower levels of antithrombin in advanced renal disease. Antithrombin is required for the action of LMWH but not necessary for direct thrombin inhibitors which function through inactivation of circulating and clot-bound thrombin.

In patients with GFR < 30 mL/min, the evidence regarding the efficacy and safety of DOAC agents is insufficient³³.

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