Introduction: Chronic kidney disease (CKD) increases the risk of venous thromboembolism (VTE) among affected patients. Vitamin K antagonists (VKA) and warfarin remains the main stay of its treatment. Due to novelty and unclear risk-to-benefit ratio of direct oral anti-coagulants (DOAC), they remain underutilized in preventing VTE among CKD patients. We aim to assess the efficacy and safety of DOACs and other oral anticoagulants in preventing recurrent VTE among high-risk population.
Material methods: We conducted a literature search using PubMed, Embase, Cochrane, Web of Science and Clinicaltrials.gov for randomized controlled trials (RCTs) comparing anti-coagulants like DOAC, LMWH or VKA or any oral anti-coagulant (OAC) (This includes VKAs and DOACs) with either placebo or another anti-coagulant. Two independent reviewers screened the retrieved articles and extracted data using a piloted data extraction sheet. The primary outcome of interest was number of recurrent VTE and other side effects among CKD patients receiving respective treatment. Secondary outcomes were risk of major, non-major and intra-cranial bleed.
Results: We retrieved 7244 titles on initial search, reviewed full text of 818 articles, and selected 10 phase III RCTS for quantitative meta-analysis. Out of 36,326 patients in these trials, only 10,840 (29.8%) were evaluable. We stratified patients into four categories based on severity of renal impairment using serum creatinine clearance (SCr) as the marker e.g. mild (>50 - <80) moderate (>30 - ≤50) severe (<30) and any level (from <30 to <80). There was no difference between DOACs vs VKA in decreasing the risk of recurrent VTE among patients with mild (RR:0.86, 95% CI:0.61-1.22, I2 = 25%) moderate/severe (RR:0.72, 95% CI:0.44-1.17, I2 = 0%) or any level of renal impairment (RR:0.83, 95% CI:0.60-1.14, I2 = 34%). No difference in efficacy between LMWH vs VKA among patients with moderate (RR:2.40, 95% CI:0.44-12.96, I2 = 76%) and any level (RR:2.59, 95% CI:0.66-10.16, I2 = 71%) of renal impairment respectively. Similarly, no difference in efficacy between LMWH vs any OAC (This includes VKAs and edoxaban) among patients with (RR:2.16, 95% CI:0.66-7.-06, I2 = 51%) and any level (RR:1.48, 95% CI:0.79-2.78, I2 = 78%) of renal impairment. DOACs compared to VKAs had significantly lower risk of combined major and non-major bleeding (RR: 0.74, 95% CI:0.65-0.84, I2 = 26%), major bleeding (RR: 0.51, 95% CI:0.38-0.69, I2 = 7%) and non-major clinically relevant bleeding (RR: 0.73, 95% CI:0.57-0.94, I2 = 45%) respectively. Risk of intracranial bleeding was comparable (RR: 0.68, 95% CI:0.19-2.44, I2 = 0%). There was no difference in the risk of major bleeding between LMWH vs any OAC (RR: 0.83, 95% CI:0.46-1.51, I2 = 0%).
Conclusion: DOACS and other anticoagulants (VKA and LMWH) showed no statistical difference in preventing recurrent VTEs among CKD patients but DOACs had significantly lower risk of major and non-major clinically relevant bleeding irrespective of the level of renal impairment compared to VKAs. There was no difference in risk of intra-cranial bleeding between DOACs and VKAs.
Keywords: Chronic kidney disease; Direct oral anti-coagulants; Major bleeding; Venous thromboembolism; Vitamin-K antagonists.
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