1. Rome, 15th December 2015 Valeria Maida Medical Affairs
Understanding SURVET
Rome, 15th December 2015
Valeria Maida
Medical Affairs

3. 2005
2006
2007
2008

4. Patient demographics Russia Poland Czech Republic Slovakia Italy
205 (33%)
Poland
166 (27%)
Czech Republic
81 (13%)
Slovakia
43 (7%)
Italy
67 (11%)
Romania
53 (9%)
Andreozzi Circulation 2015

5. Primary efficacy endpoint Primary safety endpoint
The population included adult patients with first-ever unprovoked VTE who had completed 3–12 months of VKA therapy
SURVET was a multicentre, randomised, double-blind, parallel-group, placebo-controlled trial in adult patients with first-ever unprovoked VTE
Sulodexide
500 LSU orally twice daily
+ compression therapy
Primary efficacy endpoint
Confirmed recurrence of VTE*
Primary safety endpoint
Major or clinically relevant non-major bleeding†
Patients aged ≥18 years with first-ever unprovoked VTE who had completed oral anticoagulation therapy
RANDOMISATION
n=308
Placebo
twice daily
+ compression therapy
n=309
3–12 months
1–12
weeks
2 years
DVT = Deep Vein Thrombosis LSU = Lipasemic Units PE = Pulmonary Embolism VTE = Venous Thromboembolism
* The primary efficacy outcome was symptomatic, objectively confirmed recurrence of VTE, defined as the composite of deep vein thrombosis (DVT) objectively confirmed by compression ultrasonography, or non-fatal or fatal pulmonary embolism (PE) objectively confirmed by computed tomography or lung scanning.1
† The principal safety outcome was major or clinically relevant non-major bleeding.1 An overt bleeding event was defined as major if fatal, or occurred in a critical location, or required a transfusion of ≥2 units of whole blood or red cells.1 Clinically relevant non-major bleeding was defined as overt bleeding that did not meet the criteria for major bleeding but was associated with the need for medical intervention, contact with a physician, or interruption of the study drug or with discomfort or impairment of activities of daily life.1
Andreozzi Circulation 2015

6. VTE: a definition

7. VTE: a definition

8. Nothing can be said about efficacy in PE
Treatment groups were well balanced with respect to baseline characteristics
Baseline characteristics
Characteristic
Sulodexide (n=307)
Placebo (n=308)
Age, years±SD
55.7±14.1
55.9±14.4
Male, n (%)
175 (57)
155 (50)
Index event
DVT, n (%)
284 (92)
PE, n (%)
23 (8)
24 (8)
Sample was calculated to detect differences in VTE
Nothing can be said about efficacy in PE
Andreozzi Circulation 2015

9. Primary efficacy endpoint Primary safety endpoint
The population included adult patients with first-ever unprovoked VTE who had completed 3–12 months of VKA therapy
SURVET was a multicentre, randomised, double-blind, parallel-group, placebo-controlled trial in adult patients with first-ever unprovoked VTE
Sulodexide
500 LSU orally twice daily
+ compression therapy
Primary efficacy endpoint
Confirmed recurrence of VTE*
Primary safety endpoint
Major or clinically relevant non-major bleeding†
Patients aged ≥18 years with first-ever unprovoked VTE who had completed oral anticoagulation therapy
RANDOMISATION
n=308
Placebo
twice daily
+ compression therapy
n=309
3–12 months
1–12
weeks
2 years
DVT = Deep Vein Thrombosis LSU = Lipasemic Units PE = Pulmonary Embolism VTE = Venous Thromboembolism
* The primary efficacy outcome was symptomatic, objectively confirmed recurrence of VTE, defined as the composite of deep vein thrombosis (DVT) objectively confirmed by compression ultrasonography, or non-fatal or fatal pulmonary embolism (PE) objectively confirmed by computed tomography or lung scanning.1
† The principal safety outcome was major or clinically relevant non-major bleeding.1 An overt bleeding event was defined as major if fatal, or occurred in a critical location, or required a transfusion of ≥2 units of whole blood or red cells.1 Clinically relevant non-major bleeding was defined as overt bleeding that did not meet the criteria for major bleeding but was associated with the need for medical intervention, contact with a physician, or interruption of the study drug or with discomfort or impairment of activities of daily life.1
Andreozzi Circulation 2015

10. Hypercoagulable State
Trauma
Surgery of lower extremities
Thrombophilia…..
VTE: Virchow’s Triad
Hypercoagulable State
Circulatory Stasis
Vascular Wall Injury
Trauma or sugery
Atherosclerosis
Venepuncture…..
Immobility or paralysis
Venous insufficiency
Obesity or pregnancy

11. Cumulative r-VTE incidence
r-DVT Epidemiology
After 6 months
3.7%
After 1 year
with transitory risk factors
7.8%
6.7%
Cumulative r-VTE incidence
in patients without transitory
risk factors
After 2 years %
After 5 years
24.6%
After 8 years
30.3%
Agnelli J Thromb Thrombolys 2008; van Gogh’ Investigators NEJM 2007

12. r-VTE: EPIDEMIOLOGY Patients who present
with thrombotic episodes of unknown origin have a more
than two-fold higher risk of recurrences than that
observed in patients with temporary risk factors
The risk of recurrence increased with age
both in the entire cohort and in the subgroup of patients with unprovoked VTE
Prandoni Haematologica 2007

13. Provoked and unprovoked VTE: stratification
Distribution of VTE patients
All VTE patients
All VTE patients
Provoked
Unprovoked
Extended Anticoagulation
Recent surgery
Pregnancy
Immobilization
Trauma
Idiopathic
More VTE episodes
Serious thrombophilia
APS PE
Pulmonary hypertension
25%
50%
25%
low risk (surgery)
medium risk (non surgery)
high risk
very high risk

14. Primary efficacy endpoint Primary safety endpoint
The population included adult patients with first-ever unprovoked VTE who had completed 3–12 months of VKA therapy
SURVET was a multicentre, randomised, double-blind, parallel-group, placebo-controlled trial in adult patients with first-ever unprovoked VTE
Sulodexide
500 LSU orally twice daily
+ compression therapy
Primary efficacy endpoint
Confirmed recurrence of VTE*
Primary safety endpoint
Major or clinically relevant non-major bleeding†
Patients aged ≥18 years with first-ever unprovoked VTE who had completed oral anticoagulation therapy
RANDOMISATION
n=308
Placebo
twice daily
+ compression therapy
n=309
3–12 months
1–12
weeks
2 years
DVT = Deep Vein Thrombosis LSU = Lipasemic Units PE = Pulmonary Embolism VTE = Venous Thromboembolism
* The primary efficacy outcome was symptomatic, objectively confirmed recurrence of VTE, defined as the composite of deep vein thrombosis (DVT) objectively confirmed by compression ultrasonography, or non-fatal or fatal pulmonary embolism (PE) objectively confirmed by computed tomography or lung scanning.1
† The principal safety outcome was major or clinically relevant non-major bleeding.1 An overt bleeding event was defined as major if fatal, or occurred in a critical location, or required a transfusion of ≥2 units of whole blood or red cells.1 Clinically relevant non-major bleeding was defined as overt bleeding that did not meet the criteria for major bleeding but was associated with the need for medical intervention, contact with a physician, or interruption of the study drug or with discomfort or impairment of activities of daily life.1
Andreozzi Circulation 2015

15. VTE: Treatment a long time ago… present time ACUTE TREATMENT
fondaparinux
LMWH
up to 7 days
up to 3 months
LMWH
VKA
VKA
NOAC

16. First approval r-DVT approval
October 2010
April 2014
August 2011
July 2011
February 2012
September 2008
January 2013
December 2012
August 2014
May 2011
June 2014
Boehringer Ingelheim
Janssen (US), Bayer
Pfizer (US), BMS
January 2015
July 2015
July 2015
DaichiiSankyo

17. r-DVT: stopping anticoagulation
3 months of anticoagulant treatment resulted in a similar risk of recurrence after treatment was stopped to a longer duration of treatment and that shortening treatment to 1.0 or 1.5 months doubled recurrence rates.
The risk of recurrence after stopping treatment is about double when venous thromboembolism is unprovoked compared with if it is provoked by a temporary risk factor
Boutitie BMJ 2011

18. from 3 months to indefinite
VTE: Treatment
a long time ago…
present time
ACUTE TREATMENT
fondaparinux
LMWH
fondaparinux
LMWH
up to 7 days
up to 3 months
LMWH
VKA
VKA
VKA
NOAC
EXTENDED TREATMENT
from 3 months to indefinite
VKA
VKA
NOAC
NOAC
aspirin
aspirin
aspirin

19. DURATION OF ANTICOAGULATION
CRITERIA FOR SHORT AC
AFTER 1ST VTE
post major surgery (< 3 mo.)
post bed resting
post major trauma (< 3 mo.)
post plasters or immobilization (< 3 mo.)
High bleeding risk
CRITERIA FOR
EXTENDED AC
more documented VTE episodes
Active cancer
Serious thrombophilia
Antiphospholipid syndrome PE
Pulmonary Hypertension
Other indications for AC
NYHA 3 or 4

20. Provoked and unprovoked VTE: stratification
Distribution of VTE patients
All VTE patients
Provoked
Recent surgery
Pregnancy
Immobilization
Trauma
25%
Extended Anticoagulation
More VTE episodes
Serious thrombophilia
APS PE
Pulmonary hypertension
low risk (surgery)
medium risk (non surgery)
very high risk
All VTE patients
Provoked
Recent surgery
Pregnancy
Immobilization
Trauma
25%
Unprovoked
Idiopathic
50%
Extended Anticoagulation
More VTE episodes
Serious thrombophilia
APS
PE (with shock or life-threatening)
Pulmonary hypertension
low risk (surgery)
medium risk (non surgery)
high risk
very high risk

21. ACCP Guidelines do not specify the duration of extended anticoagulant therapy in patients with first-ever unprovoked VTE1
Recommended therapy:1
Parenteral anticoagulation with LMWH or fondaparinux for ≥5 days and until INR ≥2.0 for ≥24 hours
VKA therapy started on same day
Recommended duration of therapy:1
3 months of anticoagulant therapy in patients with high bleeding risk
Extended anticoagulant therapy (for >3 months) in patients with low or moderate bleeding risk
After 3 months of treatment, patients with unprovoked VTE should be evaluated for the risk-benefit ratio of extended therapy1
2012
ACCP = American College of Chest Physicians INR = International Normalised Ratio LMWH = Low Molecular Weight Heparin VKA = Vitamin K Antagonist VTE = Venous Thromboembolism
1. Kearon C, et al. Chest. 2012;141(Suppl. 2):e419S-94S.

22. r-VTE: WHO IS AT RISK?
Fahrni VascHealthRiskManag 2015

23. D-Dimer
D-dimer is a fibrin degradation product (or FDP), a small protein fragment present in the blood after a blood clot is degraded by fibrinolysis. It is so named because it contains two crosslinked D fragments of the fibrin protein.
D-dimers are not normally present in human blood plasma, except when the coagulation system has been activated
An abnormal D-Dimer at one month following discontinuation of anticoagulation after DVT treatment is an independent risk factor for recurrent DVT.

24. D-DIMER AND r-VTE
Cumulative probability of recurrence according to normal (≤500 ng/ml) or abnormal D-dimer results obtained 3 months after anti-coagulation was stopped
HR=2.45
Palareti T&H 2002

25. Dulcis results in young and elderly patients who did not resume AC
D-DIMER AND r-VTE
Dulcis results in young and elderly patients who did not resume AC
<= 70 y
> 70 y p
Negative DD
recurrences
2.1%
8.9%
0.0008
Positive DD
14.3%
12.5% ns
Palareti Blood 2014

26. D-Dimer: SANVAL REGISTRY RESULTS
% of subjects with increased D-dimer
p<0.05
Available pts
199 control
198 sdx
182 control
178 control
189 sdx
Errichi Angiol 2004

27. r-VTE AND RISK OF BLEEDING
In patients who receive extended anticoagulant therapy, the continuing use of treatment should be reassessed at periodic intervals (eg, annually), patient preference considered, and the choice of anticoagulant regimen reevaluated
Fahrni VascHealthRiskManag 2015

28. 1%–4% per year r-VTE and BLEEDING Incidence of major bleeding
while on anticoagulation
Case fatality rate for bleeding can be higher
than case fatality rate for re-thrombosis
Fahrni VascHealthRiskManag 2015

29. All VTE patients RISK OF BLEEDING
High
History of major bleeding events
Known inherited bleeding disorder
Platelet count < mmc
Need for double antiplatelet therapy
Portal hypertension (bleeding esophageal varices)
Known cerebral alterations in the elderly (amyloidosis, micro-bleeds)
Moderate
History of clinically relevant non-major bleeding
Treatment with an antiplatelet drug
Platelet count < mmc
Low
Negative history for bleeding
No bleeding during previous AC treatment
No associated pro-hemorrhagic drugs
There are few data assessing outcomes in patients with different risks of bleeding, and there is a lack of well-validated tools for stratifying risk of bleeding in patients with VTE
Kearon Chest 2012

30. Primary efficacy endpoint Primary safety endpoint
The population included adult patients with first-ever unprovoked VTE who had completed 3–12 months of VKA therapy
SURVET was a multicentre, randomised, double-blind, parallel-group, placebo-controlled trial in adult patients with first-ever unprovoked VTE1
Sulodexide
500 LSU orally twice daily
+ compression therapy
Primary efficacy endpoint
Confirmed recurrence of VTE*
Primary safety endpoint
Major or clinically relevant non-major bleeding†
Patients aged ≥18 years with first-ever unprovoked VTE who had completed oral anticoagulation therapy
RANDOMISATION
n=308
Placebo
twice daily
+ compression therapy
n=309
3–12 months
1–12
weeks
2 years
Adapted from Andreozzi et al
DVT = Deep Vein Thrombosis LSU = Lipasemic Units PE = Pulmonary Embolism VTE = Venous Thromboembolism
* The primary efficacy outcome was symptomatic, objectively confirmed recurrence of VTE, defined as the composite of deep vein thrombosis (DVT) objectively confirmed by compression ultrasonography, or non-fatal or fatal pulmonary embolism (PE) objectively confirmed by computed tomography or lung scanning.1
† The principal safety outcome was major or clinically relevant non-major bleeding.1 An overt bleeding event was defined as major if fatal, or occurred in a critical location, or required a transfusion of ≥2 units of whole blood or red cells.1 Clinically relevant non-major bleeding was defined as overt bleeding that did not meet the criteria for major bleeding but was associated with the need for medical intervention, contact with a physician, or interruption of the study drug or with discomfort or impairment of activities of daily life.1
Andreozzi Circulation 2015

31. Sulodexide 500 LSU orally twice daily demonstrated half the risk of recurrent VTE vs placebo1
Statistically significant reduction in risk of recurrent VTE vs placebo1 Recurrent VTE occurred in 15 (4.9%) patients treated with sulodexide compared with 30 (9.7%) patients treated with placebo (HR: 0.49; 95% CI: 0.27– 0.92; p=0.02)1*†
Cumulative risk of recurrent VTE in patients assigned to sulodexide (n=307) or placebo (n=308)1*
Sulodexide
Placebo
CI = Confidence Interval; DVT = Deep Vein Thrombosis; HR = Hazard Ratio; LSU = Lipasemic Units; PE = Pulmonary Embolism; VKA = Vitamin K Antagonist; VTE = Venous Thromboembolism
* The analysis adjusted for age, sex, index event, country, duration of exposure to VKA, and delay from end of VKA treatment and randomisation, confirmed that sulodexide treatment reduced the risk of recurrence (adjusted HR: 0.45; 95% CI: 0.24–0.84; p=0.01).1 No association was found between recurrent VTE and length of exposure to VKA (HR: 0.79; 95% CI: 0.41–1.53; p=0.48).1
† Of the 15 episodes of recurrent VTE with sulodexide, 12 (75%) were DVT and 3 (25%) were PE.1 Of the 30 episodes in the placebo group, 24 (80%) were DVT and 6 (20%) were PE.1
Andreozzi Circulation 2015

32. Cumulative r-VTE incidence
r-DVT Epidemiology
After 6 months
3.7%
After 1 year
with transitory risk factors
7.8%
6.7%
After 2 years %
After 5 years
24.6%
After 8 years
30.3%
Cumulative r-VTE incidence
in patients without transitory
risk factors
After 6 months
3.7%
After 1 year
with transitory risk factors
7.8%
6.7%
After 5 years
24.6%
After 8 years
30.3%
Agnelli J Thromb Thrombolys 2008; van Gogh’ Investigators NEJM 2007

33. RESULTS: PRIMARY END POINT
Risk of recurrent VTE vs placebo
Adverse event
Treatment
Treatment duration (months)
Risk of recurrent VTE vs comparator
(HR [95% CI])
SURVET1
Sulodexide 24
0.49
[0.27–0.92]
p=0.02
ASPIRE+WARFASA2
Aspirin
24 (48)
0.68
[0.51–0.90]
p=0.008
RE-SONATE3
Dabigatran 6
0.08
[0.02–0.25]
P<0.001
EINSTEIN-EXT4
Rivaroxaban 12
0.18 [0.09–0.39]
p<0.001
AMPLIFY-EXT 25
Apixaban (2.5 mg)
0.19
[0.11–0.33] -
Apixaban (5 mg)
0.20
[0.11–0.34]
CI = Confidence Interval HR = Hazard Ratio LSU = Lipasemic Units VTE = Venous Thromboembolism
1. Andreozzi GM, et al. Circulation. 2015;132: Simes J, et al. Circulation. 2014;130: Schulman S, et al. N Engl J Med. 2013;368(8): The EINSTEIN Investigators. N Engl J Med. 2010:363: Agnelli G, et al. N Engl J Med. 2013;368(8):

34. RESULTS: SECONDARY END POINT
No episodes of major bleeding occurred in either treatment group
Clinically relevant non- major bleeding occurred in 2 patients in each treatment group
(HR: 0.97; 95% CI: 0.14–6.88; p=0.98)
Andreozzi Circulation 2015

35. RESULTS: SECONDARY END POINT
Risk of clinically relevant bleeding vs placebo
Adverse event
Treatment
Treatment duration (months)
Major bleeding events
Risk of clinically relevant bleeding vs comparator
(HR [95% CI])
SURVET1
Sulodexide 24
0.97
[0.14–6.88]
p=0.98
ASPIRE+WARFASA2
Aspirin
24 (48) 8
1.50
[0.72–3.14]
p=0.28
RE-SONATE3
Dabigatran 6 2
2.92 [1.52–5.60]
p=0.001
EINSTEIN-EXT4
Rivaroxaban 12 4
5.19 [2.13–11.7]
p<0.001
AMPLIFY-EXT 25
Apixaban (2.5 mg)
1.20
[0.69–2.10] -
Apixaban (5 mg) 1
1.62
[0.96–2.73]
CI = Confidence Interval HR = Hazard Ratio LSU = Lipasemic Units
1. Andreozzi GM, et al. Circulation. 2015;132: Simes J, et al. Circulation. 2014;130: Schulman S, et al. N Engl J Med. 2013;368(8): The EINSTEIN Investigators. N Engl J Med. 2010:363: Agnelli G, et al. N Engl J Med. 2013;368(8):

36. Sulodexide 500 LSU orally twice daily was well tolerated
Adverse events were similar for patients taking sulodexide or placebo
Overall adverse events1
Adverse event
Sulodexide (n=307)
Placebo (n=308)
Treatment-emergent AEs reported, n
368
397
Patients with ≥1 AE, n (%)*
150 (48.7)
162 (52.4)
≥1 serious AE, n (%)*
25 (8.1)
34 (11.0)
AE resulting in discontinuation, n (%)*
28 (9.1)
42 (13.6)
AE resulting in death, n (%)*
1 (0.3)
4 (1.3)
AE = Adverse Event LSU = Lipasemic Units
* No statistically significant differences for sulodexide vs placebo.1
Andreozzi Circulation 2015

37. Sulodexide 500 LSU orally twice daily was well tolerated
Most frequent adverse events (>5%)
Adverse event
Sulodexide (n=307)
Placebo (n=308)
Pain in extremity, n (%)
15 (4.9)
16 (5.2)
Deep vein thrombosis, n (%)
12 (3.9)
24 (7.8)
Arthralgia, n (%)
13 (4.2)
8 (2.6)
Hypertension, n (%)
10 (3.2)
Oedema peripheral, n (%)
6 (1.9)
Nasopharyngitis, n (%)
11 (3.6)
Respiratory tract infection, viral, n (%)
9 (2.9)
7 (2.3)
LSU = Lipasemic Units
Andreozzi Circulation 2015

38. POST-THROMBOTIC SYNDROME