Clinical Review & Education
JAMA Clinical Evidence Synopsis
Long-term vs Short-term Therapy With Vitamin K Antagonists for Symptomatic Venous Thromboembolism Saskia Middeldorp, MD, PhD; Barbara A. Hutten, PhD, MSc
CLINICAL QUESTION Is long-term (ⱖ3 months) vs short-term therapy with vitamin K antagonists (VKAs) associated with differences in the incidence of recurrent venous thromboembolism (VTE), major bleeding, and mortality in patients with symptomatic VTE? BOTTOM LINE Long-term treatment with VKAs is associated with a reduced risk for recurrent VTE and an increased risk for major bleeding compared with short-term treatment in patients with VTE, but is not associated with differences in mortality.
The optimal duration of treatment with vitamin K antagonists (VKAs) for patients with acute venous thromboembolism (VTE) is unclear. Decisions on the duration of treatment with VKAs must balance the benefit of reducing Related article page 31 the risk of recurrent VTE against the increased risk of bleeding. This JAMA Clinical Evidence Synopsis summarizes an updated Cochrane review1 of the association of long-term duration vs short-term duration of VKA therapy for the outcomes of recurrent VTE, major bleeding, and mortality.
Summary of Findings All trials included in the meta-analysis randomized patients to longterm or short-term treatment with VKA and all patients were followed up until the end of the trial. The most often used VKA was warfarin, but also acenocoumarol, fluindione, and sodium dicoumarol were studied. Long-term VKA therapy was associated with lower rates of thromboembolic events compared with short-term VKA therapy (30 of 1771 patients [1.7%] for long-term therapy vs 155 of 1765 patients [8.8%] for short-term therapy; relative risk [RR], 0.20 [95% CI, 0.11-0.38]) (Figure).
Evidence Profile No. of randomized clinical trials: 11 Study years: Conducted, 1987-2009; published, 1995-2010 Date of literature search: 1940-October 16, 2013 No. of patients: 3716 Men: 54% Women: 46%
Discussion We found that long-term VKA therapy was associated with lower rates of thromboembolic events and an increase in bleeding complications compared with short-term VKA therapy. There was no difference in mortality rates between the 2 groups. There was some overlap in the durations of VKA treatment that were classified as short-term or long-term in the included studies, but this does not affect the relative risk estimates of associations of longer vs shorter therapy durations on study outcomes. The observed relative risk for recurrent VTE varied around 0.20 (RR, 0.20 [95% CI, 0.11-0.38]) in the individual studies (Figure). Several studies reported a decline in the incidence of recurrent VTE over time.2,3 This suggests that longer therapy duration is needed to prevent 1 recurrent VTE as the time from the initial VTE increases. This is further complicated by a clinically important increase in bleeding events with greater VKA therapy duration. The literature search was updated on February 3, 2015. No additional studies were identified that met eligibility criteria for this review. Limitations
Race/ethnicity: Unavailable Age, mean (range): 60 years (53-67) Settings: Hospital and medical centers Countries: Austria, Canada, France, Italy, Sweden, United States Comparison: Long-term duration (median [range], 12 months [3-48]) vs short-term duration (median [range], 3 months [1-6]) of treatment with VKA in patients with symptomatic VTE Primary outcome: Recurrent VTE Secondary outcomes: Major bleeding and all-cause mortality
72
Long-term VKA therapy was associated with a higher rate of major bleedings compared with patients with short-term VKA therapy(14 of 675 patients [2.1%] for long-term therapy vs 3 of 675 patients [0.4%] for short-term therapy; RR, 3.44 [95% CI, 1.229.74]). Long-term VKA therapy was not associated with reduced mortality compared with short-term VKA therapy (75 of 1753 patients [4.3%] for long-term therapy vs 83 of 1749 patients [4.7%] for short-term therapy; RR, 0.89 [95% CI, 0.66-1.21]).
Stringent inclusion and exclusion criteria were applied in the randomized clinical trials, resulting in exclusion of the sickest and frailest people. The patients included in our systematic review may not be fully representative of the general population with this disorder. Comparison of Findings With Current Guidelines
The findings and conclusions of this Cochrane review are consistent with 2 recent evidence-based guidelines on duration of anticoagulant treatment after unprovoked VTE suggesting that long-
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JAMA Clinical Evidence Synopsis Clinical Review & Education
Figure. The Incidence of Recurrent Venous Thromboembolism During Long-term and Short-term Therapy With Vitamin K Antagonists Long-term VKA Therapy
Short-term VKA Therapy
No. With Total RecVTE Participants
No. With Total RecVTE Participants
Favors Long-term VKA Therapy
Risk Ratio (95% CI)
Favors Short-term VKA Therapy
Study
Duration of Therapy, mo
Agnelli, 2001
3 vs 12
4
134
11
133
0.36 (0.12-1.11)
14.1
Agnelli, 2003
3 vs 6; 3 vs 12a
1
165
6
161
0.16 (0.02-1.34)
6.5
Eischer, 2009
6 vs 30
2
17
2
17
1.00 (0.16-6.30)
7.9
Kearon, 1999
3 vs 27
1
79
17
83
0.06 (0.01-0.45)
7.1
Kearon, 2004
1 vs 3
1
81
2
84
0.52 (0.05-5.61)
5.4
Levine, 1995
1 vs 3
1
109
9
105
0.11 (0.01-0.83)
6.8
Pinede, 2001
1.5 vs 3; 3 vs 6a
1
361
6
375
0.17 (0.02-1.43)
6.5
Ridker, 2003
4 vs 27
14
255
37
253
0.38 (0.21-0.68)
21.1
Schulman, 1995
1.5 vs 6
2
454
42
443
0.05 (0.01-0.19)
11.1
Schulman, 1997
6 vs 48
3
116
23
111
0.12 (0.04-0.40)
13.5
30
1771
155
1765
0.20 (0.11-0.38)
100.0
Overall
0.01
0.1
1.0
Weight, %
10
Risk Ratio (95% CI)
Source: Data have been adapted with permission from Wiley.1 RecVTE indicates recurrent venous thromboembolism; VKA, vitamin K antagonist. Ten of the 11 included studies reported on the outcome of VTE recurrence. Randomization was stratified for type of first VTE. The size of the data marker indicates the weight of the study. a
Short-term and long-term durations of therapy.
term therapy with VKAs or other forms of oral anticoagulant therapy should be considered if bleeding risk is low or moderate and patient preferences are consistent with this treatment course (American College of Chest Physicians 4 and European Society of Cardiology5). There is no defined duration for long-term treatment. The guidelines also suggest reevaluating the risk-benefit ratio in individual patients on a regular basis. ARTICLE INFORMATION Author Affiliations: Department of Vascular Medicine, University of Amsterdam, Academic Medical Center, Amsterdam, the Netherlands (Middeldorp); Department of Clinical Epidemiology, Biostatistics and Bioinformatics, University of Amsterdam, Academic Medical Center, Amsterdam, the Netherlands (Hutten). Corresponding Author: Barbara A. Hutten, PhD, MSc, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, PO Box 22660, 1100 DD Amsterdam, the Netherlands ([email protected]). Section Editor: Mary McGrae McDermott, MD, Senior Editor. Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for
Areas in Need of Further Study
The optimal duration may vary according to patient characteristics and risk. Further studies are required to determine which patient characteristics are associated with beneficial effects of extended duration of treatment with VKAs. Therefore, clinicians should carefully consider the risk-benefit ratio for each individual patient when deciding on duration of VKA therapy.
Disclosure of Potential Conflicts of Interest. Dr Middeldorp reports receiving consulting fees to her institution from Bayer, Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim, and Daiichi Sankyo; grant funding from Aspen, Bayer, GlaxoSmithKline, Bristol-Myers Squibb/Pfizer, and Sanquin; and receiving personal fees from GlaxoSmithKline, Bayer, Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim, and Daiichi Sankyo. No other disclosures were reported. Submissions: We encourage authors to submit papers for consideration as a JAMA Clinical Evidence Synopsis. Please contact Dr McDermott at [email protected]. REFERENCES 1. Middeldorp S, Prins MH, Hutten BA. Duration of treatment with vitamin K antagonists in
jama.com
symptomatic venous thromboembolism. Cochrane Database Syst Rev. 2014;8:CD001367. 2. Prandoni P, Lensing AWA, Cogo A, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med. 1996;125(1):1-7. 3. van Dongen CJ, Vink R, Hutten BA, Büller HR, Prins MH. The incidence of recurrent venous thromboembolism after treatment with vitamin K antagonists in relation to time since first event. Arch Intern Med. 2003;163(11):1285-1293. 4. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease. Chest. 2012;141(2 suppl):e419S-494S. 5. Konstantinides SV, Torbicki A, Agnelli G, et al. 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014;35(43):3033-3069, 3069a-3069k.
(Reprinted) JAMA July 7, 2015 Volume 314, Number 1
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of York User on 07/07/2015
73
JAMA Clinical Evidence Synopsis
Long-term vs Short-term Therapy With Vitamin K Antagonists for Symptomatic Venous Thromboembolism Saskia Middeldorp, MD, PhD; Barbara A. Hutten, PhD, MSc
CLINICAL QUESTION Is long-term (ⱖ3 months) vs short-term therapy with vitamin K antagonists (VKAs) associated with differences in the incidence of recurrent venous thromboembolism (VTE), major bleeding, and mortality in patients with symptomatic VTE? BOTTOM LINE Long-term treatment with VKAs is associated with a reduced risk for recurrent VTE and an increased risk for major bleeding compared with short-term treatment in patients with VTE, but is not associated with differences in mortality.
The optimal duration of treatment with vitamin K antagonists (VKAs) for patients with acute venous thromboembolism (VTE) is unclear. Decisions on the duration of treatment with VKAs must balance the benefit of reducing Related article page 31 the risk of recurrent VTE against the increased risk of bleeding. This JAMA Clinical Evidence Synopsis summarizes an updated Cochrane review1 of the association of long-term duration vs short-term duration of VKA therapy for the outcomes of recurrent VTE, major bleeding, and mortality.
Summary of Findings All trials included in the meta-analysis randomized patients to longterm or short-term treatment with VKA and all patients were followed up until the end of the trial. The most often used VKA was warfarin, but also acenocoumarol, fluindione, and sodium dicoumarol were studied. Long-term VKA therapy was associated with lower rates of thromboembolic events compared with short-term VKA therapy (30 of 1771 patients [1.7%] for long-term therapy vs 155 of 1765 patients [8.8%] for short-term therapy; relative risk [RR], 0.20 [95% CI, 0.11-0.38]) (Figure).
Evidence Profile No. of randomized clinical trials: 11 Study years: Conducted, 1987-2009; published, 1995-2010 Date of literature search: 1940-October 16, 2013 No. of patients: 3716 Men: 54% Women: 46%
Discussion We found that long-term VKA therapy was associated with lower rates of thromboembolic events and an increase in bleeding complications compared with short-term VKA therapy. There was no difference in mortality rates between the 2 groups. There was some overlap in the durations of VKA treatment that were classified as short-term or long-term in the included studies, but this does not affect the relative risk estimates of associations of longer vs shorter therapy durations on study outcomes. The observed relative risk for recurrent VTE varied around 0.20 (RR, 0.20 [95% CI, 0.11-0.38]) in the individual studies (Figure). Several studies reported a decline in the incidence of recurrent VTE over time.2,3 This suggests that longer therapy duration is needed to prevent 1 recurrent VTE as the time from the initial VTE increases. This is further complicated by a clinically important increase in bleeding events with greater VKA therapy duration. The literature search was updated on February 3, 2015. No additional studies were identified that met eligibility criteria for this review. Limitations
Race/ethnicity: Unavailable Age, mean (range): 60 years (53-67) Settings: Hospital and medical centers Countries: Austria, Canada, France, Italy, Sweden, United States Comparison: Long-term duration (median [range], 12 months [3-48]) vs short-term duration (median [range], 3 months [1-6]) of treatment with VKA in patients with symptomatic VTE Primary outcome: Recurrent VTE Secondary outcomes: Major bleeding and all-cause mortality
72
Long-term VKA therapy was associated with a higher rate of major bleedings compared with patients with short-term VKA therapy(14 of 675 patients [2.1%] for long-term therapy vs 3 of 675 patients [0.4%] for short-term therapy; RR, 3.44 [95% CI, 1.229.74]). Long-term VKA therapy was not associated with reduced mortality compared with short-term VKA therapy (75 of 1753 patients [4.3%] for long-term therapy vs 83 of 1749 patients [4.7%] for short-term therapy; RR, 0.89 [95% CI, 0.66-1.21]).
Stringent inclusion and exclusion criteria were applied in the randomized clinical trials, resulting in exclusion of the sickest and frailest people. The patients included in our systematic review may not be fully representative of the general population with this disorder. Comparison of Findings With Current Guidelines
The findings and conclusions of this Cochrane review are consistent with 2 recent evidence-based guidelines on duration of anticoagulant treatment after unprovoked VTE suggesting that long-
JAMA July 7, 2015 Volume 314, Number 1 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of York User on 07/07/2015
jama.com
JAMA Clinical Evidence Synopsis Clinical Review & Education
Figure. The Incidence of Recurrent Venous Thromboembolism During Long-term and Short-term Therapy With Vitamin K Antagonists Long-term VKA Therapy
Short-term VKA Therapy
No. With Total RecVTE Participants
No. With Total RecVTE Participants
Favors Long-term VKA Therapy
Risk Ratio (95% CI)
Favors Short-term VKA Therapy
Study
Duration of Therapy, mo
Agnelli, 2001
3 vs 12
4
134
11
133
0.36 (0.12-1.11)
14.1
Agnelli, 2003
3 vs 6; 3 vs 12a
1
165
6
161
0.16 (0.02-1.34)
6.5
Eischer, 2009
6 vs 30
2
17
2
17
1.00 (0.16-6.30)
7.9
Kearon, 1999
3 vs 27
1
79
17
83
0.06 (0.01-0.45)
7.1
Kearon, 2004
1 vs 3
1
81
2
84
0.52 (0.05-5.61)
5.4
Levine, 1995
1 vs 3
1
109
9
105
0.11 (0.01-0.83)
6.8
Pinede, 2001
1.5 vs 3; 3 vs 6a
1
361
6
375
0.17 (0.02-1.43)
6.5
Ridker, 2003
4 vs 27
14
255
37
253
0.38 (0.21-0.68)
21.1
Schulman, 1995
1.5 vs 6
2
454
42
443
0.05 (0.01-0.19)
11.1
Schulman, 1997
6 vs 48
3
116
23
111
0.12 (0.04-0.40)
13.5
30
1771
155
1765
0.20 (0.11-0.38)
100.0
Overall
0.01
0.1
1.0
Weight, %
10
Risk Ratio (95% CI)
Source: Data have been adapted with permission from Wiley.1 RecVTE indicates recurrent venous thromboembolism; VKA, vitamin K antagonist. Ten of the 11 included studies reported on the outcome of VTE recurrence. Randomization was stratified for type of first VTE. The size of the data marker indicates the weight of the study. a
Short-term and long-term durations of therapy.
term therapy with VKAs or other forms of oral anticoagulant therapy should be considered if bleeding risk is low or moderate and patient preferences are consistent with this treatment course (American College of Chest Physicians 4 and European Society of Cardiology5). There is no defined duration for long-term treatment. The guidelines also suggest reevaluating the risk-benefit ratio in individual patients on a regular basis. ARTICLE INFORMATION Author Affiliations: Department of Vascular Medicine, University of Amsterdam, Academic Medical Center, Amsterdam, the Netherlands (Middeldorp); Department of Clinical Epidemiology, Biostatistics and Bioinformatics, University of Amsterdam, Academic Medical Center, Amsterdam, the Netherlands (Hutten). Corresponding Author: Barbara A. Hutten, PhD, MSc, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, PO Box 22660, 1100 DD Amsterdam, the Netherlands ([email protected]). Section Editor: Mary McGrae McDermott, MD, Senior Editor. Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for
Areas in Need of Further Study
The optimal duration may vary according to patient characteristics and risk. Further studies are required to determine which patient characteristics are associated with beneficial effects of extended duration of treatment with VKAs. Therefore, clinicians should carefully consider the risk-benefit ratio for each individual patient when deciding on duration of VKA therapy.
Disclosure of Potential Conflicts of Interest. Dr Middeldorp reports receiving consulting fees to her institution from Bayer, Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim, and Daiichi Sankyo; grant funding from Aspen, Bayer, GlaxoSmithKline, Bristol-Myers Squibb/Pfizer, and Sanquin; and receiving personal fees from GlaxoSmithKline, Bayer, Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim, and Daiichi Sankyo. No other disclosures were reported. Submissions: We encourage authors to submit papers for consideration as a JAMA Clinical Evidence Synopsis. Please contact Dr McDermott at [email protected]. REFERENCES 1. Middeldorp S, Prins MH, Hutten BA. Duration of treatment with vitamin K antagonists in
jama.com
symptomatic venous thromboembolism. Cochrane Database Syst Rev. 2014;8:CD001367. 2. Prandoni P, Lensing AWA, Cogo A, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med. 1996;125(1):1-7. 3. van Dongen CJ, Vink R, Hutten BA, Büller HR, Prins MH. The incidence of recurrent venous thromboembolism after treatment with vitamin K antagonists in relation to time since first event. Arch Intern Med. 2003;163(11):1285-1293. 4. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease. Chest. 2012;141(2 suppl):e419S-494S. 5. Konstantinides SV, Torbicki A, Agnelli G, et al. 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014;35(43):3033-3069, 3069a-3069k.
(Reprinted) JAMA July 7, 2015 Volume 314, Number 1
Copyright 2015 American Medical Association. All rights reserved.
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