10. Anticoagulation after VTE
Cancer patients
LMWH for 6 months
Complete remission +
no additional risk factors
Active cancer ±
additional risk factors
Chemotherapy
Interventions
Stop anticoagulation
Stable disease
Patient‘s preference
LMWH
Oral anticoagulants
11. Take home!
•
•
•
Considerable risk of recurrent VTE after stopping anticoagulation
Cancer patients are at high risk of recurrent VTE and bleeding
Provoked VTE low risk (~3%/yr)
13. Take home!
•
•
•
•
Considerable risk of recurrent VTE after stopping anticoagulation
Cancer patients are at high risk of recurrent VTE and bleeding
Provoked VTE low risk (~3%/yr)
Unprovoked VTE high risk (up to 15%/yr)
15. Bleeding during anticoagulation for VTE
Time period of AC
Initial 3 months
> 3 months
Major bleeding
(%, 95% CI)
2.06
2.74
(2.04-2.08)
(2.71-2.77)/yr
Intracranial bleeding
(%, 95% CI)
1.48
0.65
(1.40–1.56)
(0.63–0.68)/yr
Case fatality rate after 3 mo 9.1% (95% CI 2.5–21.7%)
Linkins, Ann Intern Med 2003
16. Take home!
•
•
•
•
•
•
Considerable risk of recurrent VTE after stopping anticoagulation
Cancer patients are at high risk of recurrent VTE and bleeding
Provoked VTE low risk (~3%/yr)
Unprovoked VTE high risk (up to 15%/yr)
Low recurrence risk during anticoagulation
Risk of bleeding
18. Recurrence risk after VTE
Duration of anticoagulation
6
12
18 months
Boutitie, BMJ 2011
19. Take home!
•
•
•
•
•
•
•
Considerable risk of recurrent VTE after stopping anticoagulation
Cancer patients are at high risk of recurrent VTE and bleeding
Provoked VTE low risk (~3%/yr)
Unprovoked VTE high risk (up to 15%/yr)
Low recurrence risk during anticoagulation
Risk of bleeding
Recurrence risk increases as soon as anticoagulation is stopped
regardless of previous duration
20. Take home!
•
•
•
•
•
•
•
•
•
Considerable risk of recurrent VTE after stopping anticoagulation
Cancer patients are at high risk of recurrent VTE and bleeding
Provoked VTE low risk (~3%/yr)
Unprovoked VTE high risk (up to 15%/yr)
Low recurrence risk during anticoagulation
Risk of bleeding
Recurrence risk increases as soon as anticoagulation is stopped
regardless of previous duration
The case/fatality rate of recurrence is low (<5%)
The case/fatality rate of severe bleeding while on anticoagulants is
high (~10%)
21. Management of patients with unprovoked VTE
• Identifying patients with low recurrence risk
– Thrombophilia screening
22. Risk factors of recurrence
HR
95% CI
Laboratory abnormality
Any vs. none
1.4
0.9 - 2.3
Men vs. women
2.7
1.8 - 4.2
Idiopathic vs. provoked
1.9
1.2 - 2.9
Christiansen, JAMA 2005
23. Risk factors (RF) in 158 pts with a second VTE
24%
35%
40%
no RF
1 RF
2 RF
3 RF
4 RF
factor V Leiden, factor II G20210A, HHC, high factor VIII or IX
Kyrle & Eichinger, Lancet 2010
24. Management of patients with unprovoked VTE
• Identifying patients with low recurrence risk
– Thrombophilia screening
– Residual vein thrombosis
25. Management of patients with unprovoked VTE
• Identifying patients with low recurrence risk
– Thrombophilia screening
– Residual vein thrombosis
– D-Dimer
– Prediction models
26. Nomogram to predict recurrence:
Eichinger, Circulation 2010
Vienna Prediction Model
27. Management of patients with unprovoked VTE
•
Identifying patients with low recurrence risk
•
Alternative antithrombotic concepts
28. Direct oral anticoagulants
EINSTEINext
AMPLIFYext
RESONATE
RE-MEDY
Einstein Inv.
NEJM 2010
Patients, n
Study drug
Control
Agnelli
NEJM 2012
1197
2486
1343
2856
Rivaroxaban
Apixaban
Dabigatran
Dabigatran
1 x 20 mg
2 x 5 mg
2 x 2.5 mg
2 x 150 mg
2 x 150 mg
Placebo
Placebo
Placebo
Warfarin
Schulman
NEJM 2013
Schulman
NEJM 2013
29. EINSTEINext - secondary prevention of VTE
Recurrent VTE and related death
EINSTEIN Investigators, N Engl J Med 2010
30. AMPLIFYext - secondary prevention of VTE
Recurrent VTE and related death
Agnelli, N Eng J Med 2013
31. RESONATE - secondary prevention of VTE
Recurrent VTE and related death
Schulman, N Eng J Med 2013
32. REMEDY - secondary prevention of VTE
Recurrent VTE and related death
Schulman, N Eng J Med 2013
35. Anticoagulation after venous thrombosis
stop: bleeding risk
recurrence risk
distal DVT
provoked* VTE
3 months
unprovoked VTE
long term
alternative: rivaroxaban
aspirin
* Surgery, trauma, immobilisation, pregnancy/puerperium, female hormone intake, long haul travel
9th
ACCP Consensus Conference on Antithrombotic Therapy; Kearon, Chest 2012
AWMF online, 6/2010
Notes de l'éditeur
But is this 10% recurrence rate true for every patient? It is not and if we look closer we will see that the recurrence rates may be quite different between patients. I show you here rec. rates from our own study cohort, AUREC. There are patients with a very low rec. In grey and some with a high in orange. Who are these patients and how can we differentiate them.
But is this 10% recurrence rate true for every patient? It is not and if we look closer we will see that the recurrence rates may be quite different between patients. I show you here rec. rates from our own study cohort, AUREC. There are patients with a very low rec. In grey and some with a high in orange. Who are these patients and how can we differentiate them.
First, there is one simple approach by just looking at the location of the thrombotic event. Patients with isolated distal DVT have a low rec. Rate, whereas the risk is considerably higher among those with PE or prox. DVT and is about 25% after 5 years.
We also know that patients who had their VTE in association with a temporary risk factor have a low rec. risk which is around 3% per year in this meta analysis. Very consistent over the diff. studies.
Patients with cancer are of particular concern in case of venous thrombosis. They do have aa high risk of recurrence. Even when they are treated with VKA theire recurrence risk is 3-fold higher than in non cancer pat. With thrombosis. In addition, their bleeding risk during VKA doubles that of the non cancer population
This was the reason for interventional trials evluating the effect of LMWH heparin in cancer patients with VT. Based on lower recurrence rates at comparable safety LMWH is now recommended for 3-6 months in cancer pat with DVT or PE. No data from controlled trials on anticoagulation beyond 6 months are available. And this is now my personal approach.
In contrast patients with a first unprovoked VTE have a considerably higher risk of rec. Again data from our own study, which show that about 30% of the patients which means almost every third patient will have a recurrent event within 5 years after disc. Of anticoag.
The fate of patients who either stop or continue anticoagulation is nicely summarized in this illustration which I have taken from one of the large studies with the new direct anticoagulants. We can defer many aspects of VTE treatment just from this single graph and learn a lot just by looking at it. In this study all patients where treated with anticoagulants for about 6 months and were then randomized into one group who continued anticoagulation the dotted line and in another who stopped anticoagulation, the straight line. The Kaplan Meier plot shows the recurrent rates of VTE over time. Let‘s first concentrate on the dotted line. What we see here is that patients will start to have recurrent episodes of VTE as soon as anticoagulation ist stopped. The risk of recurrence is about 10% during the first year. This number is very consistent in all trials.
However, AC comes at a price and this is bleeding. Unfortunately, there are not many data on the bleeding risk during AC in VTE patients. Most data come from AFIB patients and cannot necessarily be extrapolated to VTE patients. If we look at recent data from trials with new direct AC we see that the risk of major bleeding in the compartor group who received LMWH followed by VKA ranges between 1.2 – 1.9%.
The fate of patients who either stop or continue anticoagulation is nicely summarized in this illustration which I have taken from one of the large studies with the new direct anticoagulants. We can defer many aspects of VTE treatment just from this single graph and learn a lot just by looking at it. In this study all patients where treated with anticoagulants for about 6 months and were then randomized into one group who continued anticoagulation the dotted line and in another who stopped anticoagulation, the straight line. The Kaplan Meier plot shows the recurrent rates of VTE over time. Let‘s first concentrate on the dotted line. What we see here is that patients will start to have recurrent episodes of VTE as soon as anticoagulation ist stopped. The risk of recurrence is about 10% during the first year. This number is very consistent in all trials.
This graph shows the recurrence rates after different durations of AC. If you shorten treatment duration the risk of rec. doubles during the first year as shown by the blue line and thus 3 months ins the minimum. However, if you extend AC to 3,6 or 12 months and longer rec. rates are similar after stopping. Thus, you have to decide between stopping after 3 months in patients with a low rec. risk or to cont. indefinitely in those at high risk.
There are 2 important consequences of recurrent venous thromboembolism.
One complication is the development of the post-thrombotic syndrome, or worsening of an preexisting PTS if venous thrombosis occurs in the same leg. The PTS is often associated with serious consequences for patient, such as life-style alterations, loss of work or frequent hospitalizations. It also results in a considerable increase in health costs.
Much more important, 5 to 10 percent of the patients with recurrent thrombosis die from pulmonary embolism. Therfore, prevention of recurrent VTE is of utmost clinical importance.
Because of the high rec. risk of patients with unprovoked VTE all these patients are candidates for long term AC. This is certainly a challenge for both patients and the health care system and attempts have are are been made to identify low risk patients with unprovoked VTE who may safely stop AC.
Screening for laboratory markers of thrombophilia such as FVL has widely been used for that purpose but has been meanwhile been abandoned. The predicitive value of these markers is either none, too weak or unknown to guide duration of AC
Res. Vein thrombosis is used by some to stratify pts according to their rec. Risk. This method is neither standardized nor validated and can thus not be recommended for routine care.
D-Dimer is predictive of rec. risk particularly when it is integrated with prediction models. At present 3 models which integrate clinical factors and D-Dimer have been published.
In serveral studies a posistive association between VTE and clinical outcomes such ascarotid plaques, AMI, death, etcand .has been described. In two studies no association between subclinical atherothrombosis and VTE was observed.
We also have to face the fact that we do not know everything. You see here the distribution of RF of recurrence in 158 patients from our cohort who all had two episodes of VTE. Many had one, or two or even more RF, but in more than a third of the patients no RF was detectable.
Because of the high rec. risk of patients with unprovoked VTE all these patients are candidates for long term AC. This is certainly a challenge for both patients and the health care system and attempts have are are been made to identify low risk patients with unprovoked VTE who may safely stop AC.
Screening for laboratory markers of thrombophilia such as FVL has widely been used for that purpose but has been meanwhile been abandoned. The predicitive value of these markers is either none, too weak or unknown to guide duration of AC
Res. Vein thrombosis is used by some to stratify pts according to their rec. Risk. This method is neither standardized nor validated and can thus not be recommended for routine care.
D-Dimer is predictive of rec. risk particularly when it is integrated with prediction models. At present 3 models which integrate clinical factors and D-Dimer have been published.
Because of the high rec. risk of patients with unprovoked VTE all these patients are candidates for long term AC. This is certainly a challenge for both patients and the health care system and attempts have are are been made to identify low risk patients with unprovoked VTE who may safely stop AC.
Screening for laboratory markers of thrombophilia such as FVL has widely been used for that purpose but has been meanwhile been abandoned. The predicitive value of these markers is either none, too weak or unknown to guide duration of AC
Res. Vein thrombosis is used by some to stratify pts according to their rec. Risk. This method is neither standardized nor validated and can thus not be recommended for routine care.
D-Dimer is predictive of rec. risk particularly when it is integrated with prediction models. At present 3 models which integrate clinical factors and D-Dimer have been published.
I show you our own model, the VPM, which integrates the pt. sex as the rec. risk is lower among women than in men, the location of VTE and the D-Dimer level measured 3 wks after disc. of AC. We provide a webbased calculator and you get an estimate of the rec. risk after 1 and 5 years. This lady for example has a very low rec risk. I have to point out that none of these models have been validated. We and another group from the Netherladns are currently performing a trial to validate the VPM. And once these data are confirmed this model can be used for routine care.
The limiting factor for indefinite ac is the bleeding risk. If we would have antithrombotic drug with no or a negligible bleeding risk. we could avoid much of this discussion.
With these considerations in the back of mind the new direct oral AC have been evaluated for long term AC after VTE regarding risk of rec. and bleeding. 4 studies have been published, 3 in comparison to placebo and one with warfarin.
The drugs are highly effective in preventing rec. As shown here
Similar efficacy is demonstrated with another xa inhib. apixaban
And also with dabigatran. You see now the graph I have enlarged for illustrative purposes.
In comparison to warfarin, dabigatran shows similar efficacy.
However, these drugs are very potnet and there is bleeding during ac treatment. If we look at major and CRNM rates are higher than in patients with placebo. It has to be kept in mind that the number of patients in these trials is too small to adequately assess the bleeding risk and that the observation time was limited to a maximum of two years. In comparison to warfarin, dabigatran showed lower risk of bleeding.
Just recently, also aspirin has been explored in this indication. In a pooled analysis of two trials aspirin reduces the risk of rec. by 32%. Importantly, aspirin also reduces the risk of other major vascular events including MI and CI. No significant increase in bleeding has been shown.
