Therapeutics
Review: In CKD, novel oral anticoagulants do not differ from vitamin K antagonists for efficacy or bleeding
Harel Z, Sholzberg M, Shah PS, et al. Comparisons between novel oral anticoagulants and vitamin K antagonists in patients with CKD. J Am Soc Nephrol. 2014;25:431-42.
Clinical impact ratings: F ★★★★★★✩ h ★★★★★✩✩ C ★★★★★✩✩ H ★★★★★★✩ c ★★★★★★✩ n ★★★★★★✩ O ★★★★★✩✩ p ★★★★★✩✩
Question
Conclusion
In patients with chronic kidney disease (CKD), what are the efficacy and safety of novel oral anticoagulants (NOACs) compared with vitamin K antagonists (VKAs)?
In patients with chronic kidney disease (creatinine clearance 30 to 50 mL/min [0.58 to 0.84 mL/s]), novel oral anticoagulants did not differ from vitamin K antagonists for stroke or thromboembolism outcomes or bleeding.
Review scope Included studies compared a NOAC (dabigatran, apixaban, or rivaroxaban) with a VKA (warfarin or acenocoumarol) in patients who had atrial fibrillation (AF) or venous thromboembolism (VTE) and CKD (estimated creatinine clearance [CrCl] ≤ 50 mL/min [0.84 mL/s] by the Cockcroft–Gault equation) for ≥ 4 weeks. Outcomes were a composite of stroke (ischemic or hemorrhagic) or systemic embolism; a composite of recurrent thromboembolism or thromboembolism-related death; and a composite of major bleeding or clinically relevant nonmajor bleeding.
Review methods MEDLINE, EMBASE/Excerpta Medica, Cochrane Central Register of Controlled Trials (all to March 2013); reference lists; ClinicalTrials.gov; databases of Boehringer Ingelheim, BristolMyers Squibb, and Bayer; and abstracts of the American Society of Nephrology (2010 to 2013) were searched for randomized controlled trials (RCTs). 8 RCTs (n = 10 616) met selection criteria: 2 compared rivaroxaban with warfarin, 2 compared rivaroxaban with acenocoumarol, 3 compared dabigatran with warfarin, and 1 compared apixaban with warfarin. AF and VTE were treated in 4 RCTs each. Patients with CrCl < 30 mL/min (0.58 mL/s) were excluded from 5 RCTs and with CrCl < 25 mL/min (0.42 mL/s) from 1 RCT. Risk for bias was low for all trials: 7 had adequate randomization and concealed allocation; all had blinding of patients, personnel, and outcome assessors; and all had withdrawal rates < 20%.
Main results NOACs did not differ from VKAs for stroke or systemic embolism, recurrent thromboembolism or thromboembolism-related death, or major or clinically relevant nonmajor bleeding (Table). Novel oral anticoagulants (NOACs) vs vitamin K antagonists (VKAs) in patients with chronic kidney disease* Outcomes
Number of Weighted trials (n) event rates NOACs VKAs
Stroke or systemic embolism†
4 (9693)
3.6%
5.7%
Recurrent thromboembolism or thromboembolismrelated death‡
4 (891)
2.6%
2.7%
Major or clinically relevant nonmajor bleeding
8 (10 616) 8.4%
9.5%
At ≥ 4 wk
I2
RRR (95% CI) 36% (−4 to 61) 3% (−115 to 57)
11% (−16 to 32)
82% 0%
Source of funding: No external funding. For correspondence: Dr. Z. Harel, St. Michael’s Hospital, Toronto, ON, Canada. E-mail [email protected]. ■
Commentary The trials identified by Harel and colleagues compared NOACs with VKAs and used noninferiority designs. The NOACs were approved for the indications of AF and VTE based on noninferiority compared with VKAs. Harel and colleagues sought to answer 2 questions: Compared with VKAs, do NOACs prevent thromboembolic events? Are they safe in patients with AF or VTE and reduced estimated CrCl (who were well represented in the included trials)? These questions are best answered using 1-sided noninferiority designs; however, the authors adopted a more stringent analytical approach, using 2-sided tests of superiority of 1 strategy over the other for both benefits and harms. Although the results showed no differences between NOACs and VKAs for both intended and unintended consequences, they need further consideration. For the question of efficacy, superiority of 1 strategy over the other was not observed. However, the lower 95% CI of the RRR for stroke or systemic embolism was −4%, indicating that any reasonable noninferiority threshold for NOACs vs VKAs would have been met. This makes intuitive sense—why would NOACs be less effective in patients with kidney dysfunction than in those without kidney dysfunction? For the question of the safety of NOACs compared with VKAs, the results are less clear. Concerns about NOACs in patients with kidney dysfunction are grounded in the reduced renal elimination of these drugs and subsequent potential for overanticoagulation, which may be particularly problematic in the context of acute kidney injury from intercurrent illness. For major bleeding or clinically relevant nonmajor bleeding, the lower limit of the 95% CI for the RRR was −16%. Thus, although the data exclude a reasonably large excess risk for bleeding with NOAC use, moderate increases in bleeding in patients with kidney dysfunction cannot be ruled out. In addition, these findings were from clinical trial settings and may not correspond to the clinical experience of unselected patients treated in more typical care settings. Therefore, postmarketing surveillance studies in patients with reduced kidney function are needed to further determine the risks and benefits of NOACs in this population.
68%
*Abbreviations defined in Glossary. RRR and CI calculated from control event rates and risk ratios in article using a random-effects model.
Wolfgang C. Winkelmayer, MD, ScD Baylor College of Medicine Houston, Texas, USA
†In patients with atrial fibrillation. ‡In patients with venous thromboembolism.
JC10
© 2014 American College of Physicians
Downloaded From: http://annals.org/ by a University of California San Diego User on 12/19/2016
16 September 2014 | ACP Journal Club | Volume 161 • Number 6
Review: In CKD, novel oral anticoagulants do not differ from vitamin K antagonists for efficacy or bleeding
Harel Z, Sholzberg M, Shah PS, et al. Comparisons between novel oral anticoagulants and vitamin K antagonists in patients with CKD. J Am Soc Nephrol. 2014;25:431-42.
Clinical impact ratings: F ★★★★★★✩ h ★★★★★✩✩ C ★★★★★✩✩ H ★★★★★★✩ c ★★★★★★✩ n ★★★★★★✩ O ★★★★★✩✩ p ★★★★★✩✩
Question
Conclusion
In patients with chronic kidney disease (CKD), what are the efficacy and safety of novel oral anticoagulants (NOACs) compared with vitamin K antagonists (VKAs)?
In patients with chronic kidney disease (creatinine clearance 30 to 50 mL/min [0.58 to 0.84 mL/s]), novel oral anticoagulants did not differ from vitamin K antagonists for stroke or thromboembolism outcomes or bleeding.
Review scope Included studies compared a NOAC (dabigatran, apixaban, or rivaroxaban) with a VKA (warfarin or acenocoumarol) in patients who had atrial fibrillation (AF) or venous thromboembolism (VTE) and CKD (estimated creatinine clearance [CrCl] ≤ 50 mL/min [0.84 mL/s] by the Cockcroft–Gault equation) for ≥ 4 weeks. Outcomes were a composite of stroke (ischemic or hemorrhagic) or systemic embolism; a composite of recurrent thromboembolism or thromboembolism-related death; and a composite of major bleeding or clinically relevant nonmajor bleeding.
Review methods MEDLINE, EMBASE/Excerpta Medica, Cochrane Central Register of Controlled Trials (all to March 2013); reference lists; ClinicalTrials.gov; databases of Boehringer Ingelheim, BristolMyers Squibb, and Bayer; and abstracts of the American Society of Nephrology (2010 to 2013) were searched for randomized controlled trials (RCTs). 8 RCTs (n = 10 616) met selection criteria: 2 compared rivaroxaban with warfarin, 2 compared rivaroxaban with acenocoumarol, 3 compared dabigatran with warfarin, and 1 compared apixaban with warfarin. AF and VTE were treated in 4 RCTs each. Patients with CrCl < 30 mL/min (0.58 mL/s) were excluded from 5 RCTs and with CrCl < 25 mL/min (0.42 mL/s) from 1 RCT. Risk for bias was low for all trials: 7 had adequate randomization and concealed allocation; all had blinding of patients, personnel, and outcome assessors; and all had withdrawal rates < 20%.
Main results NOACs did not differ from VKAs for stroke or systemic embolism, recurrent thromboembolism or thromboembolism-related death, or major or clinically relevant nonmajor bleeding (Table). Novel oral anticoagulants (NOACs) vs vitamin K antagonists (VKAs) in patients with chronic kidney disease* Outcomes
Number of Weighted trials (n) event rates NOACs VKAs
Stroke or systemic embolism†
4 (9693)
3.6%
5.7%
Recurrent thromboembolism or thromboembolismrelated death‡
4 (891)
2.6%
2.7%
Major or clinically relevant nonmajor bleeding
8 (10 616) 8.4%
9.5%
At ≥ 4 wk
I2
RRR (95% CI) 36% (−4 to 61) 3% (−115 to 57)
11% (−16 to 32)
82% 0%
Source of funding: No external funding. For correspondence: Dr. Z. Harel, St. Michael’s Hospital, Toronto, ON, Canada. E-mail [email protected]. ■
Commentary The trials identified by Harel and colleagues compared NOACs with VKAs and used noninferiority designs. The NOACs were approved for the indications of AF and VTE based on noninferiority compared with VKAs. Harel and colleagues sought to answer 2 questions: Compared with VKAs, do NOACs prevent thromboembolic events? Are they safe in patients with AF or VTE and reduced estimated CrCl (who were well represented in the included trials)? These questions are best answered using 1-sided noninferiority designs; however, the authors adopted a more stringent analytical approach, using 2-sided tests of superiority of 1 strategy over the other for both benefits and harms. Although the results showed no differences between NOACs and VKAs for both intended and unintended consequences, they need further consideration. For the question of efficacy, superiority of 1 strategy over the other was not observed. However, the lower 95% CI of the RRR for stroke or systemic embolism was −4%, indicating that any reasonable noninferiority threshold for NOACs vs VKAs would have been met. This makes intuitive sense—why would NOACs be less effective in patients with kidney dysfunction than in those without kidney dysfunction? For the question of the safety of NOACs compared with VKAs, the results are less clear. Concerns about NOACs in patients with kidney dysfunction are grounded in the reduced renal elimination of these drugs and subsequent potential for overanticoagulation, which may be particularly problematic in the context of acute kidney injury from intercurrent illness. For major bleeding or clinically relevant nonmajor bleeding, the lower limit of the 95% CI for the RRR was −16%. Thus, although the data exclude a reasonably large excess risk for bleeding with NOAC use, moderate increases in bleeding in patients with kidney dysfunction cannot be ruled out. In addition, these findings were from clinical trial settings and may not correspond to the clinical experience of unselected patients treated in more typical care settings. Therefore, postmarketing surveillance studies in patients with reduced kidney function are needed to further determine the risks and benefits of NOACs in this population.
68%
*Abbreviations defined in Glossary. RRR and CI calculated from control event rates and risk ratios in article using a random-effects model.
Wolfgang C. Winkelmayer, MD, ScD Baylor College of Medicine Houston, Texas, USA
†In patients with atrial fibrillation. ‡In patients with venous thromboembolism.
JC10
© 2014 American College of Physicians
Downloaded From: http://annals.org/ by a University of California San Diego User on 12/19/2016
16 September 2014 | ACP Journal Club | Volume 161 • Number 6
