Clinical Evidence for Rebound Hypercoagulability After Discontinuing Oral Anticoagulants for Venous Thromboembolism

David Keith Cundiff, MD

Medscape J Med. 2008;10(11):258

Abstract

Context: In vitro studies and anecdotal clinical reports have suggested that clinically significant rebound hypercoagulability may occur after discontinuation of oral anticoagulants (OACs), such as vitamin K antagonists and ximelagatran, for venous thromboembolism (VTE).
Objective: Assess the extent to which rebound hypercoagulability-related VTE recurrences occur in the 2 months following discontinuation of OACs.
Data sources: Published, randomized controlled trials (RCTs) of OAC treatment of VTE.
Study selection: RCTs of varying durations of OAC treatment of VTE that include VTE recurrence (or extension) data for more than 2 months after discontinuation of anticoagulants.
Data extraction: Rates of VTE recurrences (1) while taking OACs, (2) within 2 months of discontinuing OACs, and (3) from > 2 months until the end of the study were extracted along with major bleeding episodes while on OACs. The rate of VTE recurrences possibly attributable to rebound hypercoagulability was estimated by subtracting the VTE recurrence rate after the 2-month rebound period from the rate during the rebound period.
Data synthesis: In 20 trials (n = 5822), VTE recurrences were 2.62 times as frequent in the 2 months following discontinuation of OACs as subsequently (1.57% VTE recurrences per month falling to 0.56% per month, odds ratio = 2.62, 95% confidence interval: 2.19-3.14), corresponding to 2.02% of patients with rebound hypercoagulability-related VTE recurrences (1.57% per month - 0.56% per month x 2 months = 2.02%). In the 11 trials with evaluable data from the shorter- and longer-duration OAC arms, total adverse events (VTE recurrences plus major bleeding) over the entire durations of the trials were not significantly different.
Conclusions: Rebound hypercoagulability accounts for about 2% of patients having recurrent VTE in the first 2 months after discontinuing OACs. RCTs evaluating the efficacy of OACs should include data for at least 2 months following OAC treatment. Increasing the duration of OAC treatment does not reduce the overall adverse events.

Reader Comments on: Clinical Evidence for Rebound Hypercoagulability After Discontinuing Oral Anticoagulants for Venous Thromboembolism
See reader comments on this article and provide your own.

Readers are encouraged to respond to the author at Dkcundiff3@verizon.net or to Peter Yellowlees, MD, Deputy Editor of The Medscape Journal of Medicine, for the editor's eyes only or for possible publication as an actual Letter in the Medscape Journal via email: peter.yellowlees@ucdmc.ucdavis.edu

1 2 3 4 5 6

Next Section

Cite this: Clinical Evidence for Rebound Hypercoagulability After Discontinuing Oral Anticoagulants for Venous Thromboembolism - Medscape - Nov 11, 2008.

Study Characteristics
Number	Study	Eligibility	N	OAC Warfarin = 1 Fluindione = 2 Acenocoumarol = 3 Dicumarol = 4 Ximelaga-tran = 5	Trial Schedule: Months of OAC Treatment and Follow-up
Number	Study	Eligibility	N		Pretrial	On-Trial Planned (Actual)	Follow-up of OAC Planned (Actual)
1	Agnelli (2001)^[9]	DVT	133	1 or 3	3	0 (0.0)	24-66 (37.2)
2	Agnelli (2001)^[9]	DVT	134	1 or 3	3	9 (8.8)	15-57 (28.2)
3	Agnelli (2003)^[10]	DVT	161	1 or 3	3	0 (0.0)	36 (32.1)
4	Agnelli (2001)^[9]	DVT	164	1 or 3	3	3-9 (6.3)	30 (26.4)
5	Campbell (2007)^[11]	VTE	369	1	0	3 (3.0)	9 (8.2)
6	Campbell (2007)^[11]	VTE	380	1	0	6 (5.4)	6 (5.9)
7	Daskalopoulos (2005)^[12]	DVT	52	3	0	6 (5.4)	6 (5.9)
8	Fennerty (1987) ^[13]	VTE	49	1	0	0.7 (0.7)	11.3 (10.7)
9	Fennerty (1987)^[13]	VTE	51	1	0	1.4 (1.4)	10.6 (9.8)
10	Harenberg (2006)^[14]	VTE	32	5	6	6 (6.0)	18 (16.6)
11	Harenberg (2006)^[14]	VTE	32	1	6	6 (6.0)	18 (16.9)
12	Harenberg (2006)^[14]	VTE	9	5	18	18 (18.0)	18 (15.0)
13	Harenberg (2006)^[14]	VTE	14	5 or 1	18	0 (0.0)	36 (29.6)
14	Holmgren (1985)^[15]	First DVT	69	OAC not otherwise specified	0	1 (0.9)	11 (10.0)
15	Holmgren (1985)^[15]	First DVT	66	OAC nos	0	6 (5.6)	6 (5.4)
16	Hull (2006)^[16]	DVT in cancer patients	100	1	0	3 (2.5)	9 (4.9)
17	Kearon (1999)^[17]	First VTE	83	1	3	0 (0.00)	1-24 (9.0)
18	Kearon (2004)^[18]	First VTE	58	1	1	0 (0.00)	11 (10.5)
19	Lagerstedt (1985)^[19]	Calf VT	23	1	0	3	9 (9.0)
20	Levine (1995)^[20]	DVT	104	1	1	0 (0.0)	11 (9.9)
21	Levine (1995)^[20]	DVT	109	1	1	2 (2.0)	9 (7.6)
22	Levine (1995)^[20]	DVT	192	1	1	2 (1.8)	9 (8.1)
23	Palareti (2006)^[21]	VTE	624	1 or 3	3-12	0 (0.0)	8-18 (15.6)
24	Pinede (2001)^[22]	VTE	270	2	0	3 (2.8)	12.3 (11.7)
25	Pinede (2001)^[22]	VTE	269	2	0	6 (5.5)	9.5 (8.6)
26	Ridker (2003)^[23]	VTE	253	1	6.4	0 (0.00)	1-52 (25.2)
27	Schulman (1985)^[24]	First DVT	10	1	0	1.5 (1.5)	18-30 (23)
28	Schulman (1985)^[24]	First DVT	10	1	0	3 (3.0)	16-25 (20)
29	Schulman (1985)^[24]	First DVT	17	1	0	3 (2.9)	15-28 (22)
30	Schulman (1985)^[24]	First DVT	18	1	0	6 (5.8)	18-28 (20.5)
31	Schulman (1985)^[24]	Second DVT	9	1	0	6 (6.0)	26-39 (32)
32	Schulman (1985)^[24]	First DVT	9	1	0	1.5 (1.5)	18-30 (23)
33	Schulman (1995)^[25]	Second DVT	443	1 or 4	0	1.4 (1.2)	22.5 (19.8)
34	Schulman (1995)^[25]	First DVT	454	1 or 4	0	6 (5.1)	18 (15.4)
35	Schulman (1997)^[26]	Second DVT	111	1 or 4	0	6 (7.7)	42 (31.4
36	Schulman (2003)^[27]	VTE	611	5	6	0 (0.0)	18 (16.9)
37	van Gogh (2007)^[28]	VTE	353	1 or 3	6	0 (0.0)	12 (8.6)
	Total		5822

DVT = deep venous thrombosis; OAC = oral anticoagulant; VTE = venous thromboembolism

VTE Recurrences and Major Bleeds While Taking OACs
Number	Trial Lead Author (Year), Intended Duration of On-trial OACs in Months	n/Months on OACs	VTE Recurrences/VTE Recurrences/n (%)/VTE Recurrences per Month (%)	Major Bleeds/Major Bleeds/n (%)/Major Bleeds per Month (%)
1	Agnelli (2001),^[9] 0	No VKA given after trial began
2	Agnelli (2001),^[9] 10	134/1179	3/2.24/0.25	2/2.24/0.25
3	Agnelli (2003),^[10] 0	No VKA given after trial began
4	Agnelli (2001),^[10] 3-9	164/1040	2/1.22/0.19	4/2.44/0.38
5	Campbell (2007),^[11] 3	369/1107	7/1.90/0.63	0/0.00/0.00
6	Campbell (2007),^[11] 6	380/2052	13/3.42/0.63	8/2.11/0.39
7	Daskalopoulos (2005),^[12] 6	52/273	3/5.77/1.10	4/7.69/1.47
8	Fennerty (1987)^[13] 0.75	49/37	0/0.00/0.00	Not reported
9	Fennerty (1987),^[13] 1.4	51/71	0/0.00/0.00	Not reported
10	Harenberg (2006),^[14] 0	No VKAs given after trial began
11	Harenberg (2006),^[14] 6	32/192	0/0.00/0.00	1/3.13/0.52
12	Harenberg (2006),^[14] 6	32/192	0/0.00/0.00	0/0.00/0.00
13	Harenberg (2006),^[14] 18	9/162	0/0.00/0.00	0/0.00/0.00
14	Holmgren (1985),^[15] 1	58/50	3/5.17/6.00	1/1.72/2.00
15	Holmgren (1985),^[15] 6	53/297	3/5.66/1.01	0/0.00/0.00
16	Hull (2006),^[16] 3	100/250	10/10.0/4.00	7/7.00/2.80
17	Kearon (1999),^[17] 0	No VKAs given after trial began
18	Kearon (2004),^[18] 0	No VKAs given after trial began
19	Lagerstedt (1985),^[19] 3	23/69	0/0.00/0.00	0/0.00/0.00
20	Levine (1995),^[20] 0	No VKA given after trial began
21	Levine (1995),^[20] 2	109/189	1/0.92/0.53	1/0.95/0.53
22	Levine (1995),^[20] 2	192/384	0/0.00/0.00	Not reported
23	Palareti (2006),^[21] 0	No VKA given after trial began
24	Pinede (2001),^[22] 3	270/756	2/0.74/0.26	5/1.85/0.66
25	Pinede (2001),^[22] 6	269/1480	5/1.86/0.34	7/2.60/0.47
26	Ridker (2003),^[23] 0	No VKAs given after trial began
27	Schulman (1985),^[24] 1.5	10/15	0/0.00/0.00	0/0.00/0.00
28	Schulman (1985),^[24] 3	10/30	0/0.00/0.00	0/0.00/0.00
29	Schulman (1985),^[24] 3	16/46	1/6.25/2.17	1/6.25/2.17
30	Schulman (1985),^[24] 6	16/93	0/0.00/0.00	1/6.25/1.08
31	Schulman (1985),^[24] 6	9/54	0/0.00/0.00	1/11.1/1.85
32	Schulman (1985),^[24] 1.5	8/90	0/0.00/0.00	1/12.5/1.11
33	Schulman (1995),^[25] 1.4	441/529	6/1.36/1.13	1/0.23/0.19
34	Schulman (1995),^[25] 6	451/2300	7/1.55/0.30	5/1.11/0.22
35	Schulman (1997),^[26] 6	111/855	1/0.90/0.12	3/2.70/0.35
36	Schulman (2003),^[27] 0	Off ximelagatran at start
37	van Gogh (2007),^[28] 0	No VKAs given after trial began
	Total	3418/13,792	67/1.96/0.49	53/1.55/0.38

OACs = oral anticoagulants; VKA = vitamin K antagonists; VTE = venous thromboembolism

VTE Recurrences and Major Bleeds While Taking OACs
Number	Trial Lead Author (Year), Intended Duration of On-trial OACs in Months	n/Months on OACs	VTE Recurrences/VTE Recurrences/n (%)/VTE Recurrences per Month (%)	Major Bleeds/Major Bleeds/n (%)/Major Bleeds per Month (%)
1	Agnelli (2001),^[9] 0	No VKA given after trial began
2	Agnelli (2001),^[9] 10	134/1179	3/2.24/0.25	2/2.24/0.25
3	Agnelli (2003),^[10] 0	No VKA given after trial began
4	Agnelli (2001),^[10] 3-9	164/1040	2/1.22/0.19	4/2.44/0.38
5	Campbell (2007),^[11] 3	369/1107	7/1.90/0.63	0/0.00/0.00
6	Campbell (2007),^[11] 6	380/2052	13/3.42/0.63	8/2.11/0.39
7	Daskalopoulos (2005),^[12] 6	52/273	3/5.77/1.10	4/7.69/1.47
8	Fennerty (1987)^[13] 0.75	49/37	0/0.00/0.00	Not reported
9	Fennerty (1987),^[13] 1.4	51/71	0/0.00/0.00	Not reported
10	Harenberg (2006),^[14] 0	No VKAs given after trial began
11	Harenberg (2006),^[14] 6	32/192	0/0.00/0.00	1/3.13/0.52
12	Harenberg (2006),^[14] 6	32/192	0/0.00/0.00	0/0.00/0.00
13	Harenberg (2006),^[14] 18	9/162	0/0.00/0.00	0/0.00/0.00
14	Holmgren (1985),^[15] 1	58/50	3/5.17/6.00	1/1.72/2.00
15	Holmgren (1985),^[15] 6	53/297	3/5.66/1.01	0/0.00/0.00
16	Hull (2006),^[16] 3	100/250	10/10.0/4.00	7/7.00/2.80
17	Kearon (1999),^[17] 0	No VKAs given after trial began
18	Kearon (2004),^[18] 0	No VKAs given after trial began
19	Lagerstedt (1985),^[19] 3	23/69	0/0.00/0.00	0/0.00/0.00
20	Levine (1995),^[20] 0	No VKA given after trial began
21	Levine (1995),^[20] 2	109/189	1/0.92/0.53	1/0.95/0.53
22	Levine (1995),^[20] 2	192/384	0/0.00/0.00	Not reported
23	Palareti (2006),^[21] 0	No VKA given after trial began
24	Pinede (2001),^[22] 3	270/756	2/0.74/0.26	5/1.85/0.66
25	Pinede (2001),^[22] 6	269/1480	5/1.86/0.34	7/2.60/0.47
26	Ridker (2003),^[23] 0	No VKAs given after trial began
27	Schulman (1985),^[24] 1.5	10/15	0/0.00/0.00	0/0.00/0.00
28	Schulman (1985),^[24] 3	10/30	0/0.00/0.00	0/0.00/0.00
29	Schulman (1985),^[24] 3	16/46	1/6.25/2.17	1/6.25/2.17
30	Schulman (1985),^[24] 6	16/93	0/0.00/0.00	1/6.25/1.08
31	Schulman (1985),^[24] 6	9/54	0/0.00/0.00	1/11.1/1.85
32	Schulman (1985),^[24] 1.5	8/90	0/0.00/0.00	1/12.5/1.11
33	Schulman (1995),^[25] 1.4	441/529	6/1.36/1.13	1/0.23/0.19
34	Schulman (1995),^[25] 6	451/2300	7/1.55/0.30	5/1.11/0.22
35	Schulman (1997),^[26] 6	111/855	1/0.90/0.12	3/2.70/0.35
36	Schulman (2003),^[27] 0	Off ximelagatran at start
37	van Gogh (2007),^[28] 0	No VKAs given after trial began
	Total	3418/13,792	67/1.96/0.49	53/1.55/0.38

OACs = oral anticoagulants; VKA = vitamin K antagonists; VTE = venous thromboembolism

Study Characteristics
Number	Study	Eligibility	N	OAC Warfarin = 1 Fluindione = 2 Acenocoumarol = 3 Dicumarol = 4 Ximelaga-tran = 5	Trial Schedule: Months of OAC Treatment and Follow-up
Number	Study	Eligibility	N		Pretrial	On-Trial Planned (Actual)	Follow-up of OAC Planned (Actual)
1	Agnelli (2001)^[9]	DVT	133	1 or 3	3	0 (0.0)	24-66 (37.2)
2	Agnelli (2001)^[9]	DVT	134	1 or 3	3	9 (8.8)	15-57 (28.2)
3	Agnelli (2003)^[10]	DVT	161	1 or 3	3	0 (0.0)	36 (32.1)
4	Agnelli (2001)^[9]	DVT	164	1 or 3	3	3-9 (6.3)	30 (26.4)
5	Campbell (2007)^[11]	VTE	369	1	0	3 (3.0)	9 (8.2)
6	Campbell (2007)^[11]	VTE	380	1	0	6 (5.4)	6 (5.9)
7	Daskalopoulos (2005)^[12]	DVT	52	3	0	6 (5.4)	6 (5.9)
8	Fennerty (1987) ^[13]	VTE	49	1	0	0.7 (0.7)	11.3 (10.7)
9	Fennerty (1987)^[13]	VTE	51	1	0	1.4 (1.4)	10.6 (9.8)
10	Harenberg (2006)^[14]	VTE	32	5	6	6 (6.0)	18 (16.6)
11	Harenberg (2006)^[14]	VTE	32	1	6	6 (6.0)	18 (16.9)
12	Harenberg (2006)^[14]	VTE	9	5	18	18 (18.0)	18 (15.0)
13	Harenberg (2006)^[14]	VTE	14	5 or 1	18	0 (0.0)	36 (29.6)
14	Holmgren (1985)^[15]	First DVT	69	OAC not otherwise specified	0	1 (0.9)	11 (10.0)
15	Holmgren (1985)^[15]	First DVT	66	OAC nos	0	6 (5.6)	6 (5.4)
16	Hull (2006)^[16]	DVT in cancer patients	100	1	0	3 (2.5)	9 (4.9)
17	Kearon (1999)^[17]	First VTE	83	1	3	0 (0.00)	1-24 (9.0)
18	Kearon (2004)^[18]	First VTE	58	1	1	0 (0.00)	11 (10.5)
19	Lagerstedt (1985)^[19]	Calf VT	23	1	0	3	9 (9.0)
20	Levine (1995)^[20]	DVT	104	1	1	0 (0.0)	11 (9.9)
21	Levine (1995)^[20]	DVT	109	1	1	2 (2.0)	9 (7.6)
22	Levine (1995)^[20]	DVT	192	1	1	2 (1.8)	9 (8.1)
23	Palareti (2006)^[21]	VTE	624	1 or 3	3-12	0 (0.0)	8-18 (15.6)
24	Pinede (2001)^[22]	VTE	270	2	0	3 (2.8)	12.3 (11.7)
25	Pinede (2001)^[22]	VTE	269	2	0	6 (5.5)	9.5 (8.6)
26	Ridker (2003)^[23]	VTE	253	1	6.4	0 (0.00)	1-52 (25.2)
27	Schulman (1985)^[24]	First DVT	10	1	0	1.5 (1.5)	18-30 (23)
28	Schulman (1985)^[24]	First DVT	10	1	0	3 (3.0)	16-25 (20)
29	Schulman (1985)^[24]	First DVT	17	1	0	3 (2.9)	15-28 (22)
30	Schulman (1985)^[24]	First DVT	18	1	0	6 (5.8)	18-28 (20.5)
31	Schulman (1985)^[24]	Second DVT	9	1	0	6 (6.0)	26-39 (32)
32	Schulman (1985)^[24]	First DVT	9	1	0	1.5 (1.5)	18-30 (23)
33	Schulman (1995)^[25]	Second DVT	443	1 or 4	0	1.4 (1.2)	22.5 (19.8)
34	Schulman (1995)^[25]	First DVT	454	1 or 4	0	6 (5.1)	18 (15.4)
35	Schulman (1997)^[26]	Second DVT	111	1 or 4	0	6 (7.7)	42 (31.4
36	Schulman (2003)^[27]	VTE	611	5	6	0 (0.0)	18 (16.9)
37	van Gogh (2007)^[28]	VTE	353	1 or 3	6	0 (0.0)	12 (8.6)
	Total		5822

DVT = deep venous thrombosis; OAC = oral anticoagulant; VTE = venous thromboembolism

Comments

Commenting is limited to medical professionals. To comment please Log-in.

Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.

processing....

Clinical Evidence for Rebound Hypercoagulability After Discontinuing Oral Anticoagulants for Venous Thromboembolism

Abstract

Tables

Tables

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

Comments

Email This

Feedback