Therapeutics
Review: New oral anticoagulants increase GI bleeding in venous thrombosis and ACS
Holster IL, Valkhoff VE, Kuipers EJ, Tjwa ET. New oral anticoagulants increase risk for gastrointestinal bleeding: a systematic review and meta-analysis. Gastroenterology. 2013;145:105-12.e15.
Clinical impact ratings: h ★★★★★★✩ C ★★★★★★✩ g ★★★★★★✩ H ★★★★★✩✩ N ★★★★★✩✩ Question Do new oral anticoagulants (NOACs) increase risk for gastrointestinal (GI) or clinically relevant bleeding?
Review scope Included studies compared NOACs (rivaroxaban, apixaban, dabigatran, edoxaban, or betrixaban) with standard care (low-molecularweight heparin, vitamin K antagonist, antiplatelet therapy, no additional therapy, or placebo) in the target population for the drug and reported bleeding as a safety outcome. Outcomes were GI bleeding or clinically relevant major or nonmajor bleeding.
Review methods MEDLINE, EMBASE/Excerpta Medica, Cochrane Central Register of Controlled Trials to Jul 2012, and reference lists were searched for full-text randomized controlled trials (RCTs). 43 RCTs (n = 151 578, mean or median age range 56 to 73 y, 17% to 82% men, follow-up range 3 wk to 31 mo) met the inclusion criteria: 21 used NOACs in orthopedic surgery, 8 in atrial fibrillation (AF), 7 in acute deep venous thrombosis or pulmonary embolism, 5 in the acute coronary syndrome (ACS), and 2 in medically ill patients. 16 RCTs evaluated rivaroxaban, 12 apixaban, 10 dabigatran, 4 edoxaban, and 1 betrixaban. All RCTs excluded patients with increased risk for GI bleeding. 31 RCTs had adequate allocation concealment, 30 were reported as double-blind and all 43 blinded outcome assessors, and 23 reported loss to follow-up (0% to 2.5%).
Main results Results of meta-analysis of NOACs vs standard care in different settings are reported in the Table. In subgroup analyses by drug, rivaroxaban increased risk for GI bleeding (5 RCTs, 2.1% vs 1.4%, relative risk increase [RRI] 47%, 95% CI 21 to 80) and clinically relevant bleeding (16 RCTs, 12% vs 9.7%, RRI 27%, CI 4 to 54) compared with standard care, and dabigatran increased risk for GI bleeding (3 RCTs, 3.3% vs 2.1%, RRI 56%, CI 28 to 89); other NOACs were not associated with increased risk for bleeding.
Conclusion In patients with deep venous thrombosis or pulmonary embolism, or the acute coronary syndrome, new oral anticoagulants increase risk for gastrointestinal bleeding compared with standard care.
Source of funding: Not stated. For correspondence: Dr. I.L. Holster, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. E-mail [email protected]. ■
Commentary NOACs have been reported to be at least as effective and safe as standard therapies and are more convenient (1). Holster and colleagues now report that these agents are associated with an increased risk for GI bleeding compared with standard therapies, and an accompanying editorial questions whether the greater convenience of NOACs is worth the risk (2). The meta-analysis by Holster and colleagues shows that NOACs increase GI bleeding compared with standard therapies in patients with ACS and venous thromboembolism, but not in those with AF. We urge cautious interpretation of these data. First, in the individual trials, the effects of NOACs differed by indication and the NOAC and control used, as reflected by substantial heterogeneity in the pooled estimates. The largest increase in GI bleeding was in ACS trials, where NOACs were compared with placebo on a background of dual-antiplatelet therapy. We question whether the results of placebo-controlled trials should be pooled with those from active-controlled trials. Individual trials, each involving > 10 000 patients with AF, have shown that dabigatran, 150 mg twice daily, and rivaroxaban, 20 mg daily (15 mg daily in patients with creatinine clearance 30 to 49 mL/min), but not apixaban, increase GI bleeding compared with warfarin (3-5), which raises questions about the results of the meta-analysis in patients with AF. Second, despite increases in GI bleeding, NOACS are not associated with excess clinically relevant bleeding in the activecontrolled trials because increases in GI bleeding were offset by decreases in bleeding at other sites. What are the implications of these results for clinical practice? The data by Holster and colleagues are a timely reminder that NOACs can increase the risk for bleeding but also highlight differences between drugs. Clinicians should consider risk for GI bleeding when making treatment recommendations, but in the context of NOAC effects on all patient-important outcomes.
New oral anticoagulants vs standard care* Outcomes GI bleeding
Setting
Number of trials (n)
Weighted event rates
NNH (CI)
All
17 (74 536)
1.9% vs 1.3%
RRI 44% (7 to 95)†
175 (82 to 1115)
Orthopedic surgery
6 (18 683)
0.13% vs 0.17%
RRR 22% (−96 to 69)
NS
Atrial fibrillation
6 (50 374)
1.9% vs 1.6%
RRI 21% (−9 to 59)†
2 (3727)
3.0% vs 1.9%
RRI 57% (3 to 138)
2 (1691)
5.0% vs 1.0%
RRI 400% (154 to 861)
26 (12 to 65)
8.4% vs 7.3%
RRI 15% (0 to 31)†
NS
DVT or PE ACS Clinically relevant bleeding
RRI/RRR (95% CI)
All
43 (125 354)
Orthopedic surgery
21 (34 341)
4.0% vs 3.8%
Atrial fibrillation
8 (51 097)
10.6% vs 11.3%
Medical illness
NS 92 (39 to 1790)
RRI 4.8% (−6 to 16)
NS
RRR 6.3% (−14 to 23)†
NS NS
2 (6462)
2.7% vs 2.1%
RRI 27% (−7 to 74)
DVT or PE
7 (12 748)
8.7% vs 8.9%
RRR 1.8% (−38 to 30)†
ACS
5 (20 706)
7.7% vs 3.9%
RRI 98% (76 to 122)
NS 27 (22 to 34)
Thomas Vanassche, MD Stuart J. Connolly, MD John W. Eikelboom, MD McMaster University Hamilton, Ontario, Canada References 1. Ruff CT, Giugliano RP, Braunwald E, et al. Lancet. 2013;Dec 3. [Epub ahead of print]. 2. Heitman SJ, Mackay E, Hilsden RJ, Rostom A. Gastroenterology. 2013;145:42-5. 3. Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. N Engl J Med. 2009;361:1139-51. 4. Patel MR, Mahaffey KW, Garg J, et al; ROCKET AF Investigators. N Engl J Med. 2011;365:883-91. 5. Granger CB, Alexander JH, McMurray JJ, et al; ARISTOTLE Committees and Investigators. N Engl J Med. 2011;365:981-92.
*ACS = acute coronary syndrome; DVT = deep venous thrombosis; GI = gastrointestinal; NS = not significant; PE = pulmonary embolism; other abbreviations defined in Glossary. RRI, RRR, NNH, and CI calculated from event rates and odds ratios in article. Only analyses including > 1 randomized controlled trial are reported in the Table. †Heterogeneity P < 0.05 (I2 > 50%)
JC4
© 2014 American College of Physicians
Downloaded From: http://annals.org/ by a Fudan University User on 12/25/2016
18 February 2014 | ACP Journal Club | Volume 160 • Number 4
Review: New oral anticoagulants increase GI bleeding in venous thrombosis and ACS
Holster IL, Valkhoff VE, Kuipers EJ, Tjwa ET. New oral anticoagulants increase risk for gastrointestinal bleeding: a systematic review and meta-analysis. Gastroenterology. 2013;145:105-12.e15.
Clinical impact ratings: h ★★★★★★✩ C ★★★★★★✩ g ★★★★★★✩ H ★★★★★✩✩ N ★★★★★✩✩ Question Do new oral anticoagulants (NOACs) increase risk for gastrointestinal (GI) or clinically relevant bleeding?
Review scope Included studies compared NOACs (rivaroxaban, apixaban, dabigatran, edoxaban, or betrixaban) with standard care (low-molecularweight heparin, vitamin K antagonist, antiplatelet therapy, no additional therapy, or placebo) in the target population for the drug and reported bleeding as a safety outcome. Outcomes were GI bleeding or clinically relevant major or nonmajor bleeding.
Review methods MEDLINE, EMBASE/Excerpta Medica, Cochrane Central Register of Controlled Trials to Jul 2012, and reference lists were searched for full-text randomized controlled trials (RCTs). 43 RCTs (n = 151 578, mean or median age range 56 to 73 y, 17% to 82% men, follow-up range 3 wk to 31 mo) met the inclusion criteria: 21 used NOACs in orthopedic surgery, 8 in atrial fibrillation (AF), 7 in acute deep venous thrombosis or pulmonary embolism, 5 in the acute coronary syndrome (ACS), and 2 in medically ill patients. 16 RCTs evaluated rivaroxaban, 12 apixaban, 10 dabigatran, 4 edoxaban, and 1 betrixaban. All RCTs excluded patients with increased risk for GI bleeding. 31 RCTs had adequate allocation concealment, 30 were reported as double-blind and all 43 blinded outcome assessors, and 23 reported loss to follow-up (0% to 2.5%).
Main results Results of meta-analysis of NOACs vs standard care in different settings are reported in the Table. In subgroup analyses by drug, rivaroxaban increased risk for GI bleeding (5 RCTs, 2.1% vs 1.4%, relative risk increase [RRI] 47%, 95% CI 21 to 80) and clinically relevant bleeding (16 RCTs, 12% vs 9.7%, RRI 27%, CI 4 to 54) compared with standard care, and dabigatran increased risk for GI bleeding (3 RCTs, 3.3% vs 2.1%, RRI 56%, CI 28 to 89); other NOACs were not associated with increased risk for bleeding.
Conclusion In patients with deep venous thrombosis or pulmonary embolism, or the acute coronary syndrome, new oral anticoagulants increase risk for gastrointestinal bleeding compared with standard care.
Source of funding: Not stated. For correspondence: Dr. I.L. Holster, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. E-mail [email protected]. ■
Commentary NOACs have been reported to be at least as effective and safe as standard therapies and are more convenient (1). Holster and colleagues now report that these agents are associated with an increased risk for GI bleeding compared with standard therapies, and an accompanying editorial questions whether the greater convenience of NOACs is worth the risk (2). The meta-analysis by Holster and colleagues shows that NOACs increase GI bleeding compared with standard therapies in patients with ACS and venous thromboembolism, but not in those with AF. We urge cautious interpretation of these data. First, in the individual trials, the effects of NOACs differed by indication and the NOAC and control used, as reflected by substantial heterogeneity in the pooled estimates. The largest increase in GI bleeding was in ACS trials, where NOACs were compared with placebo on a background of dual-antiplatelet therapy. We question whether the results of placebo-controlled trials should be pooled with those from active-controlled trials. Individual trials, each involving > 10 000 patients with AF, have shown that dabigatran, 150 mg twice daily, and rivaroxaban, 20 mg daily (15 mg daily in patients with creatinine clearance 30 to 49 mL/min), but not apixaban, increase GI bleeding compared with warfarin (3-5), which raises questions about the results of the meta-analysis in patients with AF. Second, despite increases in GI bleeding, NOACS are not associated with excess clinically relevant bleeding in the activecontrolled trials because increases in GI bleeding were offset by decreases in bleeding at other sites. What are the implications of these results for clinical practice? The data by Holster and colleagues are a timely reminder that NOACs can increase the risk for bleeding but also highlight differences between drugs. Clinicians should consider risk for GI bleeding when making treatment recommendations, but in the context of NOAC effects on all patient-important outcomes.
New oral anticoagulants vs standard care* Outcomes GI bleeding
Setting
Number of trials (n)
Weighted event rates
NNH (CI)
All
17 (74 536)
1.9% vs 1.3%
RRI 44% (7 to 95)†
175 (82 to 1115)
Orthopedic surgery
6 (18 683)
0.13% vs 0.17%
RRR 22% (−96 to 69)
NS
Atrial fibrillation
6 (50 374)
1.9% vs 1.6%
RRI 21% (−9 to 59)†
2 (3727)
3.0% vs 1.9%
RRI 57% (3 to 138)
2 (1691)
5.0% vs 1.0%
RRI 400% (154 to 861)
26 (12 to 65)
8.4% vs 7.3%
RRI 15% (0 to 31)†
NS
DVT or PE ACS Clinically relevant bleeding
RRI/RRR (95% CI)
All
43 (125 354)
Orthopedic surgery
21 (34 341)
4.0% vs 3.8%
Atrial fibrillation
8 (51 097)
10.6% vs 11.3%
Medical illness
NS 92 (39 to 1790)
RRI 4.8% (−6 to 16)
NS
RRR 6.3% (−14 to 23)†
NS NS
2 (6462)
2.7% vs 2.1%
RRI 27% (−7 to 74)
DVT or PE
7 (12 748)
8.7% vs 8.9%
RRR 1.8% (−38 to 30)†
ACS
5 (20 706)
7.7% vs 3.9%
RRI 98% (76 to 122)
NS 27 (22 to 34)
Thomas Vanassche, MD Stuart J. Connolly, MD John W. Eikelboom, MD McMaster University Hamilton, Ontario, Canada References 1. Ruff CT, Giugliano RP, Braunwald E, et al. Lancet. 2013;Dec 3. [Epub ahead of print]. 2. Heitman SJ, Mackay E, Hilsden RJ, Rostom A. Gastroenterology. 2013;145:42-5. 3. Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. N Engl J Med. 2009;361:1139-51. 4. Patel MR, Mahaffey KW, Garg J, et al; ROCKET AF Investigators. N Engl J Med. 2011;365:883-91. 5. Granger CB, Alexander JH, McMurray JJ, et al; ARISTOTLE Committees and Investigators. N Engl J Med. 2011;365:981-92.
*ACS = acute coronary syndrome; DVT = deep venous thrombosis; GI = gastrointestinal; NS = not significant; PE = pulmonary embolism; other abbreviations defined in Glossary. RRI, RRR, NNH, and CI calculated from event rates and odds ratios in article. Only analyses including > 1 randomized controlled trial are reported in the Table. †Heterogeneity P < 0.05 (I2 > 50%)
JC4
© 2014 American College of Physicians
Downloaded From: http://annals.org/ by a Fudan University User on 12/25/2016
18 February 2014 | ACP Journal Club | Volume 160 • Number 4
