Therapeutics

Review: In renal impairment, apixaban reduces, or does not increase, bleeding compared with other anticoagulants Clinical impact ratings:

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Pathak R, Pandit A, Karmacharya P, et al. Meta-analysis on risk of bleeding with apixaban in patients with renal impairment. Am J Cardiol. 2015;115:323-7.

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Question

*Information provided by author.

In patients with renal impairment, is apixaban better than conventional anticoagulants for major or clinically relevant nonmajor bleeding?

Source of funding: No external funding. For correspondence: Dr. Anil Pandit, Mayo Clinic, Scottsdale, AZ, USA. E-mail [email protected]. 

Review scope

Commentary

Included studies compared apixaban with placebo, no treatment, standard care, or another treatment used for prophylaxis in patients with atrial fibrillation (AF) or for prophylaxis or treatment of venous thromboembolism (VTE), and reported data on renal impairment. Outcomes included a composite of major or clinically relevant nonmajor bleeding. Renal function was classified as normal (Cockcroft-Gault equation creatinine clearance [CrCl] ≥ 80 mL/min), mild impairment (CrCl 50 to 80 mL/min), or moderate-to-severe impairment (CrCl < 50 mL/min).

Pathak and colleagues' finding of a differential safety profile for apixaban according to level of kidney function is important. Patients with CrCl 50 to 80 mL/min had fewer major bleeding episodes with apixaban than comparator drugs including aspirin, warfarin, and enoxaparin. In patients with CrCl < 50 mL/min, no difference in bleeding risk was observed. We do not interpret this as evidence of the safety of apixaban in patients with CrCl 30 to 50 mL/min. The relative safety of interventions may differ according to clinical characteristics or clinical setting. For example, an RCT of patients with AF found that dabigatran, a direct thrombin inhibitor, was associated with reduced bleeding compared with warfarin (1), whereas a study based on administrative data found a 30% increased risk for bleeding compared with warfarin (2).

Review methods MEDLINE, EMBASE/Excerpta Medica, Cochrane Library, and ClinicalTrials.gov (all to Feb 2014), and reference lists were searched for phase 3, randomized, controlled trials (RCTs). 6 RCTs (n = 40 145, {median age 57 to 70 y, median follow-up 0.17 to 1.8 y}*) met the inclusion criteria. 4 were done in patients with, or at risk for, VTE and 2 in patients with AF. All RCTs excluded patients with severe renal impairment (CrCl < 25 mL/min or < 30 mL/min). 5 RCTs used apixaban, 2.5 mg or 5 mg twice daily, and 1 RCT used apixaban, 10 mg twice daily for 1 week followed by 5 mg twice daily for 6 months. 2 RCTs compared apixaban with enoxaparin, 1 with enoxaparin followed by vitamin K antagonists (VKAs), 1 with VKAs, 1 with aspirin, and 1 with placebo. All RCTs used allocation concealment, blinded patients and investigators, and had < 20% withdrawals; all were industry-sponsored.

Why the discrepancy? Low glomerular filtration rate (GFR) is associated with increased risk for acute kidney injury and is prevalent in community-based patients with AF (3). Therefore, fluctuating kidney function may explain the increased bleeding with dabigatran in clinical practice. Because apixaban is partly eliminated by the kidneys, subclinical episodes of acute kidney injury may lead to increased anticoagulant effect and bleeding. This may explain why chronic kidney disease affects the relative safety of apixaban. Until further data are available, use of apixaban should be restricted to patients at low risk for acute kidney injury: those who are clinically stable, have higher GFR or low albuminuria, and, if receiving drugs that block the renin–angiotensin system, are likely to comply with advice to temporarily discontinue these drugs when unwell (Kidney Disease: Improving Global Outcomes CKD Work Group recommendation 4.4.3) (4). Its use in patients with GFR between 30 and 45 mL/min/1.73 m2 should be based on these criteria. Its use in patients with GFR < 30 mL/min/1.73 m2 is not based on clinical outcomes data, and we do not recommend it.

Main results In patients with mild renal impairment, apixaban reduced bleeding compared with control (placebo, aspirin, or conventional anticoagulants) (Table). In patients with moderate-to-severe renal impairment, apixaban did not differ from control for bleeding (Table).

Conclusion

Christine M. Ribic, MD, MSc, FRCPC Catherine M. Clase, MB, BChir, MSc, FRCPC McMaster University Hamilton, Ontario, Canada

Apixaban reduces bleeding compared with conventional anticoagulants in patients with mild, but not moderate-to-severe, renal impairment. References

Apixaban vs control (placebo, aspirin, or conventional anticoagulants) for major or clinically relevant nonmajor bleeding†

1. Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-51.

Population

2. Hernandez I, Baik SH, Pin˜era A, Zhang Y. Risk of bleeding with dabigatran in atrial fibrillation. JAMA Intern Med. 2015;175:18-24.

Number of trials (n)

Weighted event rates Apixaban Control

At a median 0.17 to 1.8 y of follow-up RRR (95% CI)

NNT (CI)

Mild renal impairment‡

6 (14 034)

2.7%

3.4%

20% (4 to 34)

148 (87 to 736)

RRI (CI)

NNH

Moderate-tosevere renal impairment§

6 (4999)

6.9%

6.8%

1% (⫺51 to 110)

Not significant

3. Jun M, James MT, Manns BJ, et al; Alberta Kidney Disease Network. The association between kidney function and major bleeding in older adults with atrial fibrillation starting warfarin treatment: population based observational study. BMJ. 2015;350: h246. 4. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney International Supplements. 2013;3:1-150.

†Abbreviations defined in Glossary. RRR, RRI, NNT, and CI calculated from risk ratios and control event rates in article using fixed-effect (mild renal impairment) or random-effects (moderate-tosevere renal impairment) models. ‡Cockcroft-Gault equation creatinine clearance 50 to 80 mL/min. §Cockcroft-Gault equation creatinine clearance < 50 mL/min.

21 April 2015 Annals of Internal Medicine ACP Journal Club Downloaded From: http://annals.org/ by a Penn State University Hershey User on 05/22/2015

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姝 2015 American College of Physicians

ACP Journal Club: review: in renal impairment, apixaban reduces, or does not increase, bleeding compared with other anticoagulants.

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