duration of therapy for venous...
TRANSCRIPT
Duration of Therapy for Venous Thromboembolism
Michael B Streiff, MD FACP
Associate Professor of Medicine and Pathology
Medical Director, Johns Hopkins Anticoagulation Service
Chairman, VTE Guideline Committee for the National Comprehensive Cancer Network
Disclosures- Michael B. Streiff, MD
• Consulting
– CSL Behring
– Janssen
– Portola
• Educational Grants
– Covidien
• Research support
– AHRQ
– Boehringer-Ingelheim
– Janssen
– NIH/NHLBI
– PCORI
– Portola
– Roche
VTE Duration of Therapy Principles
• Optimal duration of therapy balances the risk of harm from recurrent VTE and AC-associated bleeding
• VTE recurrence risk is highest in the first 3 months after the event and declines thereafter
• Bleeding risk is highest in the first 3 months and declines and stabilizes thereafter
Transient risk factors influence recurrence risk
• Metaanalysis of 15 RCT or observational studies
• Follow up 12- 24 months
• Recurrent VTE
– Provoked 3.3% per pt.-yr
– Unprovoked 7.4% per pt-yr
• Duration of therapy does not influence recurrence rate in provoked VTE (Boutitie F et al BMJ 2011)
0.7
4.2
7.4
0
1
2
3
4
5
6
7
8
Re
curr
en
t V
TE (
% p
er
pat
.-yr
)
N=5159
Iorio A et al Arch Intern Med 2010
VTE location influences recurrence risk
• Pooled analysis of 7 RCT including 2925 patients
• Follow up – 4023 pt-years (mean 1.4 years)
• Compared with proximal DVT , distal DVT at lower risk of recurrence (HR 0.49 [95%CI 0.34 to 0.71])
Boutitie F et al BMJ 2011
Duration of therapy influences recurrence risk
• Pooled analysis of 7 RCT including 2925 patients
• Follow up – 4023 pt-years (mean 1.4 years)
• Compared with longer durations, 1-1.5 months of therapy associated with higher risk of recurrence (HR 1.52 [95% CI 1.14 to 2.02])
Boutitie F et al BMJ 2011
Cancer patients are at high risk for recurrent VTE
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0 1 2 3 4 5 6 7 8 9 10 11 12
Rec
urr
ent
VT
E (
%)
Months
Cancer (N=181) No cancer (N=661)
Prandoni P et al. Blood 2002
Hazard Ratio 3.2
Hormonal therapy-associated VTE poses a lower recurrence risk
• Prospective cohort of 630 women followed for 69 months
• Cumulative recurrent VTE after 1,2 and 5 years 1%, 1%, and 6%
• Recurrent VTE lower in estrogen OCP (RR 0.4) and HRT (RR 0.7)
Eischer L et al J Thromb Haemost 2014
Men are at two-fold higher risk for recurrent VTE
• Kyrle P et al. – Prospective cohort of 826 patients with unprovoked VTE
– Recurrent VTE- Relative Risk (RR) 3.6 (2.3-5.5)
• McRae S et al.- study level meta-analysis of 5416 patients
– Recurrent VTE- RR 1.6 (1.2-2)
• Douketis J et al.-patient-level meta-analysis of 2554 patients
– Unprovoked VTE Hazard Ratio (HR) 2.2 (1.7-2.8)
– Provoked VTE HR 1.2 (0.6-2.4)
Kyrle P et al. NEJM 2004; McRae S et al. Lancet 2006; Douketis J et al. BMJ 2011
Pregnancy-associated VTE increases risk with future pregnancies
• Pregnancy increases risk of VTE by 4-5 fold
– Risk highest in 3rd trimester and post-partum
– Elevated risk extends to 12 weeks post-partum
• White R et al. Administrative database analysis
– Recurrence risk less with pregnancy-associated VTE than unprovoked VTE within 5 years (5.8% v. 10.4% HR 0.6 [0.4-0.9])
– Pregnancy-associated VTE has a higher recurrence risk higher during subsequent pregnancy than unprovoked (5.7% v. 3.5% RR 1.7 [1.0-2.8])
• Anticoagulant prophylaxis is essential during subsequent pregnancies
Heit J et al. Ann Intern Med 2005; Pomp ER et al. J Thromb Haemost 2008; White R et al. Thromb Haemost 2008; Kamel H et al N Engl J Med 2014
Inherited thrombophilia is not a
potent risk factor for recurrent VTEStudy Subjects Follow
up
(mos.)
Recurrent VTE
Baglin T 2003 570 1st VTE 24 15% vs. 10% (HR 1.5
[0.8-2.8])
Christiansen S
2005
474 1st DVT 87 28 vs. 22 per 1000 pt.-yrs
(HR 1.4 [0.9-2.2])
Prandoni P 2007 1626 1st VTE 50 HR 2.02 [1.52-2.69]
Santamaria M
2005
267 1st DVT 47 HR 1.78 [1.0-3.14]
Ribierio D 2012 378 1st VTE 43 IRR 1.6 [0.5-5.5]
Tosetto A 2012 1785 1st
idiopathic VTE
22 23.4% vs. 20.9%, p=0.4
Baglin T et al. Lancet 2003; Christiansen S JAMA 2005; Prandoni P Haematologica 2007;SantaMaria M Thromb Res 2005; Ribierio D Thromb Res 2012; Tosetto A JTH 2012
Limited evidence supports APS as a
risk factor for recurrent VTE• Systematic review of 6 RCT and 2 OS
• Relative Risk of recurrent VTE 1.41 (0.99-2.36)
• Weaknesses- varied APL testing, timing of testing
• Conclusion- More research needed
Garcia D et al. Blood 2013
Adverse outcomes during VTE
treatment
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1600
1 2 3 4 5 6 7 8 9 10
Ad
vers
e ev
ents
per
10
0,0
00
pt-
mo
s.
Months
Recurrent VTE Major Bleeding
N=41,826
Lecumberri R et al Thromb Haemost 2013
Fatal events during VTE therapy
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350
1 2 3 4 5 6 7 8 9 10
Fat
al e
ven
ts p
er 1
00
,00
0 p
t-m
os.
Months
Fatal VTE Fatal Bleed
N=41,826
Lecumberri R et al Thromb Haemost 2013
Case Fatality rates during VTE
therapy
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10
15
20
25
30
1 2 3 4 5 6 7 8 9 10
Cas
e Fa
talit
y ra
te (
%)
Months
VTE Bleeding
N=41,826
Lecumberri R et al Thromb Haemost 2013
The Natural History of VTE
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0 6 12 36 60 96 120
Rec
urr
ent
VT
E (
%)
Follow Up (months)
Unprovoked Provoked• Observational cohort of
consecutive patients
after 1st VTE
• Duration of AC ≤ 6 mos.
in 83%
• Median follow up – 50
mos. (2-120 mos.)
• Conclusion- Not all
patients with
unprovoked VTE recur
N=1626
Prandoni P et al. Haematologica 2007
D Dimer alone does not identify
low risk patients
• Prospective management study of 410 1st VTE
• D Dimer at 0 and 30 days
• Negative D dimer associated with low risk in women with estrogen-associated VTE
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5.4
00
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4
6
8
10
12
Men (n=180) Women-NoEst (N=81)
Women-Est(N=58)
Rec
urr
ent
VTE
(p
er 1
00
pt.
yrs.
)
(95% CI2.5 to 10.2%)
Kearon C et al. Ann Intern Med 2015
(95% CI 6.7% to 13.7%
(95%CI 0 to 3.0%
How can we identify low and high risk patient with idiopathic VTE?
Prospective cohort study of
929 patients with idiopathic
VTE
Enrolled at 4 centers between July 1992 and August 2008 prior to DC of warfarin after at least 3 months of therapy
Information on laboratory and clinical variables associated with VTE were collected at time of discontinuation of AC
Multivariate analysis used to develop clinical prediction rule for recurrent VTE
Results Risk Factors for Recurrent VTE
Pulmonary embolism vs. distal DVT HR 2.8 (1.4-6.2)
Male gender HR 2.0 (1.3-3.2)
Peak thrombin generation HR1.4 (1.2-1.7)
D dimer HR 1.3 (1.1-1.7)
Median F/U -43.3 months (14.7-78.5 mos.)
Eichinger S, et al. Circulation. 2010
Risk Stratification for Recurrent VTE: The Vienna Risk Prediction Model
Eichinger S, et al. Circulation. 2010
Version 2: https://cemsiis.meduniwien.ac.at/en/kb/science-research/software/clinical-
software/recurrent-vte/#calc-params
Risk Stratification for Recurrent VTE: The Vienna Risk Prediction Model
Eichinger S, et al. Circulation. 2010
How do we identify the low risk patient with idiopathic VTE?
Prospective cohort study of
665 patients with idiopathic
VTE
Enrolled at 12 centers, 4 countries prior to DC of warfarin after 5-7 months of therapy
Information of 76 laboratory and clinical variables associated with VTE collected
Multivariate analysis used to develop clinical prediction rule for recurrent VTE
Results Recurrent VTE
Annual Risk 9.3% (7.7-11.3%)
- Men 13.7% (10.8-17%)
- Women 5.5% (3.7-7.8%)
•F/U population 600/665 (90%)•Mean F/U -18 months (1-47 mos)
Rodger MA, et al. CMAJ. 2008
Clinical Prediction Rule for Recurrent VTE in Women
Mo
del
Variable
Annual Risk of Recurrent VTE
Sensitivity Specificity NPV Low-risk High-risk% Low-riskby Model
1• Hyperpigmentation, edema and redness• Body mass index > 30 kg/m2
• Age > 65 years0.89 0.37 0.97 1.6% 7.9% 34.7%
2• Hyperpigmentation, edema and redness• D-Dimer > 250 µg/L• Body mass index > 30 kg/m2
0.88 0.38 0.97 2.3% 10.4% 35.5%
3
• Hyperpigmentation, edema and redness• D-Dimer > 250 µg/L• Body mass index > 30 kg/m2• Age > 65 years
0.88 0.57 0.98 1.6% 14.1% 52.2%
4
• Hyperpigmentation, edema and redness• D-Dimer > 250 µg/L• Body mass index > 30 kg/m2• Previous secondary VTE
0.76 0.65 0.96 2.9% 14.8% 38.7%
5
• Hyperpigmentation, edema and redness• D-Dimer > 250 µg/L• Body mass index > 30 kg/m2• Previous secondary VTE• Age > 65 years
0.88 0.56 0.98 1.7% 13.8% 51.4%
Model 3 final - due to smallest annual risk of recurrent VTE in low-risk group, highest NVP, >10% risk recurrence in high-risk group, highest low-risk excluded proportion; most parsimonious and easy to remember and apply in clinical setting. NVP = negative predictive value
Rodger MA, et al. CMAJ. 2008
Validation of the HERDOO2 Rule
• Prospective Cohort study of 2785 pts.
• Intervention- Low risk -discontinue AC, High risk-clinician discretion
• Outcome- sx VTE
• Conclusion- The HERDOO2 rule can identify women at low risk for recurrence
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High riskoff AC
(N=323)
High riskon AC
(N=1802)
Low riskoff AC
(N=591)
Low riskon AC(N=31)
Rec
urr
ent
sym
pto
mat
ic V
TE (
per
10
0 p
t.-y
rs.)
(95%CI1.1 to 2.3)
(95% CI 1.8 to 4.8)
(95%CI 5.2 to 11.9)
Rodger M et al BMJ 2017
Bleeding risk scores
• Designed to predict bleeding risk of
anticoagulation
• Limitations
– Developed in Afib pts (HEMORR2HAGES, HAS-
BLED,ATRIA) or mixed populations (mOBRI)
– Expert opinion based (ACCP)
– Validation studies found modest predictive value (AUC
0.49-0.66)
• Further investigation needed before routine use
Schoeb M and Fang M J Thromb Thromboly 2013;Scherz N et al. J Thromb Haemost 2013; Riva N Thromb Haemost 2014
AMPLIFY-EXT: Apixaban versus Placebo for extended treatment of VTE
Agnelli G et al. N Engl J Med 2013
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0
0 1 2 3 4 5 6 7 8 9 10 11 12
Recurr
ent
VT
E (
%)
Months
1211109876543210
0
1
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9
10 Placebo
Apixaban 2.5 mg
Apixaban 5 mg
Recurr
ent
VT
E (
%)
Placebo 8.8%
Apix 2.5 mg 1.7%
(RR 0.19; 0.11-0.33)
AMPLIFY-EXT: Low dose apixaban associated with similar bleeding risk compared with placebo
Months
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0 1 2 3 4 5 6 7 8 9 10 11 12
Cum
ula
tive e
vent ra
te (
%)
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0
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9
10 Placebo (N=823)
Apixaban 2.5 mg (N=840)
Apixaban 5 mg (N=811)
Cum
ula
tive e
vent ra
te (
%)
Placebo 2.7% Apix 2.5 mg 3.2% (RR 1.2; 0.69-2.1)
Agnelli G et al. N Engl J Med 2013
Low-dose rivaroxaban for extended treatment of VTE
• DB-RCT of riva (10 mg or 20 mg) v. aspirin for extended treatment after 6-12 mos. Of AC
• Median Follow up 351 days
• Rivaroxaban is associated with fewer recurrent VTE and similar bleeding compared with aspirin
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Recurrent VTE Major Bleed
Ou
tco
mes
(%
)
Aspirin (N=1131) Riva 10 mg (N=1127)
Riva 20 mg (N=1107)
Weitz JI et al. N Engl J Med 2017
VTE and bleeding are low during
extended therapy with DOAC
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Recurrent VTE Major Bleeding Fatal VTE Fatal Bleeding Fatal VTE andBleed
Even
ts p
er 1
00
pt-
yrs.
Placebo (N=3640) Aspirin (N=616) Warfarin (N=1920) DOAC (N=4366)
Wu C et al. Thromb Res 2015
Duration of Therapy for VTE
• Surgical/major trauma associated VTE- at least 3-6 months• Extended prophylaxis for subsequent surgery
• Ambulatory surgery 10-14 days
• Inpatient surgery- 1-3 months
• Estrogen-associated VTE- 3-6 months• Thromboprophylaxis for pregnancy
• Pregnancy-associated VTE- 3-6 months and beyond the post-partum period (6-12 weeks)• Thromboprophylaxis for subsequent pregnancies
• Cancer-associated VTE
• At least 3-6 months and until cancer in remission and therapy is completed
• Medical-illness VTE
• At least 3-6 months
• Unprovoked VTE
• Consider indefinite therapy
• Consider VTE risk stratification
Duration of Therapy for VTE
Summary
• The appropriate duration of therapy depends upon the constellation of VTE risk factors and bleeding risk factors confronting the individual patient
• Multicomponent VTE risk assessment models show promise in identifying patients at elevated risk for recurrence
• Research to identify a bleeding risk assessment tool for VTE patients with acceptable performance characteristics is ongoing
• Low-dose DOAC regimens for extended treatment offer the promise of low risks for VTE and bleeding
Questions ?