Therapeutics
Review: New oral factor Xa inhibitors reduce DVT compared with standard thromboprophylaxis after THR or TKR
Adam SS, McDuffie JR, Lachiewicz PF, Ortel TL, Williams JW. Comparative effectiveness of novel oral anticoagulants and standard thromboprophylaxis in patients having total hip or knee replacement: a systematic review. Ann Intern Med. 2013;159:275-84.
Clinical impact ratings: h ★★★★★★✩ H ★★★★★✩✩ Question
Source of funding: US Department of Veterans Affairs.
What are the effectiveness and safety of novel oral anticoagulants (NOACs) compared with standard thromboprophylaxis after total hip replacement (THR) or total knee replacement (TKR)?
For correspondence: Dr. S.S. Adam, Duke University Medical Center, Durham, NC, USA. E-mail [email protected]. ■
Commentary
Review scope
Unfractionated heparin, LMWH, fondaparinux, aspirin, warfarin, and NOACs are recommended options for thromboprophylaxis after THR or TKR (1). The rigorous systematic review by Adam and colleagues compared NOACs and LMWH, the most widely used thromboprophylaxis options after THR and TKR.
Included English-language systematic reviews comparing NOACs (direct thrombin inhibitors or factor Xa inhibitors) with standard thromboprophylaxis (warfarin, low-molecular-weight heparin [LMWH], unfractionated heparin, or aspirin) in randomized controlled trials (RCTs) of adults ≥ 18 years of age having elective THR or TKR. Primary outcomes were symptomatic deep venous thrombosis (DVT) and nonfatal pulmonary embolism (PE); secondary outcomes were mortality and major bleeding.
NOACs seem to be at least as effective and safe as LMWH for thromboprophylaxis, with a minimal benefit for the oral factor Xa inhibitors for prevention of symptomatic DVT (number needed to treat 322). Inferences about the relative efficacy or safety of individual NOACs cannot be made because there were no head-tohead trials and, in the existing RCTs, the timing of postoperative NOAC initiation (6 to 8 h for dabigatran and rivaroxaban, 12 to 24 h for apixaban) and definitions of bleeding outcomes differed.
Review methods MEDLINE, EMBASE/Excerpta Medica, Cochrane Database of Systematic Reviews (all 2009 to Mar 2013), and reference lists of reviews and guidelines were searched for systematic reviews. 6 reviews (5 to 43 included studies, mean age range 52 to 78 y, 45% to 84% women) met selection criteria; all were rated as good quality. A primary search found no additional RCTs published after the included reviews. Analyses focused on the 2 reviews with the most recent search dates, comprehensive analyses, and outcomes of interest.
For practicing clinicians, although NOACs may be appealing based on their proven efficacy and safety and ease of use, LMWH remains a reasonable alternative for thromboprophylaxis. Specifically, a regimen of twice-daily enoxaparin, 30 mg, is as effective as NOACs for TKR and may be considered for THR (2). Relative costs will also be a factor in prescribing.
Main results
Further research is needed to determine the optimal timing of postoperative NOAC initiation to minimize bleeding, since peak action occurs 1 to 3 hours after intake. Moreover, improvements in surgical and anesthesia techniques and early postoperative mobilization have reduced the perioperative thrombogenic milieu, and this will prompt the reevaluation of less intensive thromboprophylaxis options, such as aspirin, after THR and TKR (3).
The main results are in the Table.
Conclusions After total hip or knee replacement surgery, factor Xa inhibitors reduce symptomatic deep venous thrombosis compared with low-molecular-weight heparin (LMWH); the direct thrombin inhibitor dabigatran does not differ from LMWH. Novel oral anticoagulants do not differ from standard thromboprophylaxis for mortality, nonfatal pulmonary embolism, or bleeding.
New oral anticoagulants (factor Xa inhibitors and dabigatran) vs lowmolecular-weight heparin (LMWH) after total hip or knee replacement* Outcomes
Number of trials (n)
Weighted event rates Factor Xa† LMWH
At 5 to 13 wk RRR/RRI (95% CI) RRR 54% (30 to 70)
NNT (CI)
Symptomatic DVT
18 (22 877)
0.27%
0.58%
Nonfatal PE
20 (26 998)
0.26%
0.25%
RRI 7% (−35 to 73)
322 (249 to 581) NS
Mortality
11 (23 838)
0.24%
0.25%
RRR 5% (−63 to 45)
NS
Major bleeding
21 (31 424)
0.83%
0.66%
RRI 27% (−2 to 64)
NS
Dabigatran‡
LMWH
Symptomatic DVT
4 (10 264)
0.39%
0.48%
RRR 18% (−299 to 83)
NS
Nonfatal PE
4 (10 264)
0.20%
0.29%
RRR 31% (−54 to 69)
NS
Mortality
4 (10 264)
0.08%
0.05%
RRI 54% (−62 to 533)
NS
Major bleeding
4 (10 264)
1.2%
1.3%
RRR 6% (−52 to 42)
NS
*DVT = deep venous thrombosis; NS = not significant; PE = pulmonary embolism; other abbreviations defined in Glossary. RRR, RRI, NNT, and CI calculated from control event rates and odds ratios or relative risks in article using a random-effects model.
Sudeep Shivakumar, MD Dalhousie University Halifax, Nova Scotia, Canada James Douketis, MD McMaster University Hamilton, Ontario, Canada References 1. Falck-Ytter Y, Francis CW, Johanson NA, et al; American College of Chest Physicians. Prevention of VTE in orthopedic surgery patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012; 141:e278S-325S. 2. Gómez-Outes A, Terleira-Fernández AI, Suárez-Gea ML, Vargas-Castrillón E. Dabigatran, rivaroxaban, or apixaban versus enoxaparin for thromboprophylaxis after total hip or knee replacement: systematic review, meta-analysis, and indirect treatment comparisons. BMJ. 2012;344:e3675. 3. Anderson DR, Dunbar MJ, Bohm ER, et al. Aspirin versus low-molecular-weight heparin for extended venous thromboembolism prophylaxis after total hip arthroplasty: a randomized trial. Ann Intern Med. 2013;158:800-6.
†Based on a review of 22 randomized controlled trials comparing oral factor Xa inhibitors with LMWH. ‡Based on a review of 4 randomized controlled trials comparing dabigatran with enoxaparin.
21 January 2014 | ACP Journal Club | Volume 160 • Number 2
© 2014 American College of Physicians
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/929674/ by a University of California San Diego User on 05/15/2017
JC3
Review: New oral factor Xa inhibitors reduce DVT compared with standard thromboprophylaxis after THR or TKR
Adam SS, McDuffie JR, Lachiewicz PF, Ortel TL, Williams JW. Comparative effectiveness of novel oral anticoagulants and standard thromboprophylaxis in patients having total hip or knee replacement: a systematic review. Ann Intern Med. 2013;159:275-84.
Clinical impact ratings: h ★★★★★★✩ H ★★★★★✩✩ Question
Source of funding: US Department of Veterans Affairs.
What are the effectiveness and safety of novel oral anticoagulants (NOACs) compared with standard thromboprophylaxis after total hip replacement (THR) or total knee replacement (TKR)?
For correspondence: Dr. S.S. Adam, Duke University Medical Center, Durham, NC, USA. E-mail [email protected]. ■
Commentary
Review scope
Unfractionated heparin, LMWH, fondaparinux, aspirin, warfarin, and NOACs are recommended options for thromboprophylaxis after THR or TKR (1). The rigorous systematic review by Adam and colleagues compared NOACs and LMWH, the most widely used thromboprophylaxis options after THR and TKR.
Included English-language systematic reviews comparing NOACs (direct thrombin inhibitors or factor Xa inhibitors) with standard thromboprophylaxis (warfarin, low-molecular-weight heparin [LMWH], unfractionated heparin, or aspirin) in randomized controlled trials (RCTs) of adults ≥ 18 years of age having elective THR or TKR. Primary outcomes were symptomatic deep venous thrombosis (DVT) and nonfatal pulmonary embolism (PE); secondary outcomes were mortality and major bleeding.
NOACs seem to be at least as effective and safe as LMWH for thromboprophylaxis, with a minimal benefit for the oral factor Xa inhibitors for prevention of symptomatic DVT (number needed to treat 322). Inferences about the relative efficacy or safety of individual NOACs cannot be made because there were no head-tohead trials and, in the existing RCTs, the timing of postoperative NOAC initiation (6 to 8 h for dabigatran and rivaroxaban, 12 to 24 h for apixaban) and definitions of bleeding outcomes differed.
Review methods MEDLINE, EMBASE/Excerpta Medica, Cochrane Database of Systematic Reviews (all 2009 to Mar 2013), and reference lists of reviews and guidelines were searched for systematic reviews. 6 reviews (5 to 43 included studies, mean age range 52 to 78 y, 45% to 84% women) met selection criteria; all were rated as good quality. A primary search found no additional RCTs published after the included reviews. Analyses focused on the 2 reviews with the most recent search dates, comprehensive analyses, and outcomes of interest.
For practicing clinicians, although NOACs may be appealing based on their proven efficacy and safety and ease of use, LMWH remains a reasonable alternative for thromboprophylaxis. Specifically, a regimen of twice-daily enoxaparin, 30 mg, is as effective as NOACs for TKR and may be considered for THR (2). Relative costs will also be a factor in prescribing.
Main results
Further research is needed to determine the optimal timing of postoperative NOAC initiation to minimize bleeding, since peak action occurs 1 to 3 hours after intake. Moreover, improvements in surgical and anesthesia techniques and early postoperative mobilization have reduced the perioperative thrombogenic milieu, and this will prompt the reevaluation of less intensive thromboprophylaxis options, such as aspirin, after THR and TKR (3).
The main results are in the Table.
Conclusions After total hip or knee replacement surgery, factor Xa inhibitors reduce symptomatic deep venous thrombosis compared with low-molecular-weight heparin (LMWH); the direct thrombin inhibitor dabigatran does not differ from LMWH. Novel oral anticoagulants do not differ from standard thromboprophylaxis for mortality, nonfatal pulmonary embolism, or bleeding.
New oral anticoagulants (factor Xa inhibitors and dabigatran) vs lowmolecular-weight heparin (LMWH) after total hip or knee replacement* Outcomes
Number of trials (n)
Weighted event rates Factor Xa† LMWH
At 5 to 13 wk RRR/RRI (95% CI) RRR 54% (30 to 70)
NNT (CI)
Symptomatic DVT
18 (22 877)
0.27%
0.58%
Nonfatal PE
20 (26 998)
0.26%
0.25%
RRI 7% (−35 to 73)
322 (249 to 581) NS
Mortality
11 (23 838)
0.24%
0.25%
RRR 5% (−63 to 45)
NS
Major bleeding
21 (31 424)
0.83%
0.66%
RRI 27% (−2 to 64)
NS
Dabigatran‡
LMWH
Symptomatic DVT
4 (10 264)
0.39%
0.48%
RRR 18% (−299 to 83)
NS
Nonfatal PE
4 (10 264)
0.20%
0.29%
RRR 31% (−54 to 69)
NS
Mortality
4 (10 264)
0.08%
0.05%
RRI 54% (−62 to 533)
NS
Major bleeding
4 (10 264)
1.2%
1.3%
RRR 6% (−52 to 42)
NS
*DVT = deep venous thrombosis; NS = not significant; PE = pulmonary embolism; other abbreviations defined in Glossary. RRR, RRI, NNT, and CI calculated from control event rates and odds ratios or relative risks in article using a random-effects model.
Sudeep Shivakumar, MD Dalhousie University Halifax, Nova Scotia, Canada James Douketis, MD McMaster University Hamilton, Ontario, Canada References 1. Falck-Ytter Y, Francis CW, Johanson NA, et al; American College of Chest Physicians. Prevention of VTE in orthopedic surgery patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012; 141:e278S-325S. 2. Gómez-Outes A, Terleira-Fernández AI, Suárez-Gea ML, Vargas-Castrillón E. Dabigatran, rivaroxaban, or apixaban versus enoxaparin for thromboprophylaxis after total hip or knee replacement: systematic review, meta-analysis, and indirect treatment comparisons. BMJ. 2012;344:e3675. 3. Anderson DR, Dunbar MJ, Bohm ER, et al. Aspirin versus low-molecular-weight heparin for extended venous thromboembolism prophylaxis after total hip arthroplasty: a randomized trial. Ann Intern Med. 2013;158:800-6.
†Based on a review of 22 randomized controlled trials comparing oral factor Xa inhibitors with LMWH. ‡Based on a review of 4 randomized controlled trials comparing dabigatran with enoxaparin.
21 January 2014 | ACP Journal Club | Volume 160 • Number 2
© 2014 American College of Physicians
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/929674/ by a University of California San Diego User on 05/15/2017
JC3
