1. Effect of losartan on aortic dilatation rate in adult patients with Marfan syndrome
Maarten Groenink
R Franken, AW den Hartog, T Radonic, V de Waard, AM Spijkerboer, AH Zwinderman, BJM Mulder
J Timmermans
AJHA Scholte
MP van den Berg

2. Disclosures
No conflict of interest
No disclosures

3. Marfan syndrome : aortic complications
Connective tissue disorder
Fibrillin-1 defect
Structural dysfunction of media
Regulatory dysfunction (TGF- β)
Aortic dilatation => aortic dissection and sudden death

4. Marfan syndrome : clinical management
Surgical (prophylactic) - Aortic root mm I C - Beyond the aortic root > 50 mm IIa C
Pharmacological - β blockers - Losartan ?
Lifestyle
ESC Guidelines for the management
of grown-up congenital heart disease 2010

5. Beneficial effects of losartan in a Marfan mouse model
Combi met 4
Habashi et al. Science Apr 7;312(5770):

6. Primary aim of the COMPARE study
To assess the effect of losartan in addition to standard of care on aortic dilatation rate at any aortic level in adult patients with Marfan syndrome
Design : multicentre, open-label, randomised controlled trial with blinded assessments

7. Methods Enrollment: January 2008 - December 2010
All (4) Dutch university Marfan screening centres
National database of adults with congenital heart disease (CONCOR)
Randomisation:
Losartan 100 mg vs. no losartan,
Previously prescribed medication was continued
MRI scan at inclusion and after 3 years of follow-up
Trials Jan 12;11:3. doi: / 7

8. Predefined endpoints Primary endpoint:
Aortic dilatation rate at any predefined aortic level in 3 years
Secondary endpoints : - Cardiovascular mortality
- Prophylactic aortic surgery
- Aortic dissection

9. Inclusion criteria
Marfan syndrome according to the Ghent criteria of 1996
Age ≥ 18 years
Aortic root diameter < 50 mm
No aortic dissection
Maximal 1 vascular prosthesis

10. Intention to treat analysis
259 not meeting inclusion criteria
305 declined participation
Randomisation
Intention to treat analysis

11. Baseline characteristics (n=233)
Controls (n=117)
Losartan (n=116)
Gender (female)
62 (53%)
47 (41%)
Age (years)
38.3 ± 13.4
36.8 ± 12.3
β-blocker therapy
82 (70%)
87 (75%)
SBP (mmHg)
125 ± 13
124 ± 14
Aortic root surgery
36 (31%)
27 (23%)
Hier vertellen over de novo dissectie!!!

12. Baseline aortic measurements (mm)
Controls (n=117)
Losartan (n=116)
Aortic root
43.7 ± 4.8
44.8 ± 5.6
Ascending aorta
28.1 ± 3.9
28.0 ± 3.6
Aortic arch
24.4 ± 3.3
23.6 ± 2.8
Descending aorta
proximal
23.9 ± 3.6
23.7 ± 3.7
diaphragm
21.2 ± 3.5
20.3 ± 2.5
abdominal
16.2 ± 3.4
16.4 ± 3.9

13. Results

14. Aortic root dilatation rate (n=145)

15. Beneficial effect of losartan in all subgroups
Age ≤ 40 (92)
> 40 (53)
Sex M (72)
F (73)
FBN (117)
- (25)
β – blocker + (107)
- (38)
MAP (mmHg) ≤ 90 (75)
> 90 (66)
AOR (mm) ≤ 45 (89)
> 45 (56)
Losartan effective

16. No differences in aortic dilatation rate beyond the aortic root
(mm/3 years)
Controls (n=105)
Losartan (n=113)
Ascending aorta
0.85 ± 1.23
0.78 ± 1.32
Aortic arch
0.61 ± 1.35
0.52 ± 1.37
Descending aorta
proximal
0.72 ± 1.40
0.54 ± 1.40
diaphragm
0.43 ± 1.13
0.31 ± 1.13
abdominal
0.37 ± 1.12
0.51 ± 2.18

17. No differences in clinical endpoints
Controls
(n=117)
Losartan
(n=116)
Aortic root surgery
8 (7%)
10 (9%)
Distal aortic surgery
1 (1%)
Aortic dissection
- Type A
- Type B
2 (2%)
Cardiovascular mortality
Combined endpoint
11 (9%)

18. Dilatation rate of the aortic arch after prophylactic AOR replacement

19. No differences in dilatation rate of the descending aorta after aortic root replacement
Outcome (mm/3years)
Controls (n=31)
Losartan (n=26)
P-value
- proximal
1.00 ± 1.25
0.50 ± 1.70
0.249
- diaphragm
0.48 ± 1.37
0.41 ± 1.04
0.376
- abdominal
0.16 ± 1.37
0.71 ± 3.02
0.348

20. Summary Marfan patients on losartan demonstrated:
a significantly lower aortic root dilatation rate
no significant differences in aortic dilatation rate beyond the aortic root in the total study population
after aortic root replacement, a significantly lower dilatation rate of the aortic arch
no significant differences in clinical endpoints
European Heart Journal
doi: /eurheartj/eht334

21. Study limitations Open label Target inclusion not achieved
Longer FU needed for clinical endpoints
Subanalyses on relatively small groups

22. Ongoing RCT investigating losartan in MFS
Study
Design
Age N
Endpoint
Modality
US:Lacro et al.
Losartan vs β-blocker
0.5–25
604
∆ AoR
Echo
IT:Gambarin et al.
1–55
291
Fr: Detaint et al.
Losartan vs placebo
≥ 10
300
Be: Moberg et al.
490
∆ Any level
Echo + MRI
UK: Mullen et al.
Irbesartan vs placebo
6-40
SP: Forteza et al.
5-60
150
UK: Creager et al.
≥ 25 50
Can: Sandor et al.

23. Conclusions Reduces aortic root dilatation rate
Addition of losartan to standard of care (betablockers) in adults with Marfan syndrome:
Reduces aortic root dilatation rate
After aortic root replacement:
Reduces aortic arch dilatation rate
In conclusion, losartan has a prominent but highly variable effect on TGF-beta plasma levels in marfan syndrome. Responders to losartan therapy are marfan patients with dominant negative fibrillin one mutations, severe aortic dilatation and high baseline TGF-beta levels in plasma. 23

24. Recommendations for clinical practice
In adult patients with Marfan syndrome,
unoperated and after elective aortic root surgery,
losartan therapy should be advised

25. Thank you R Franken AW den Hartog T Radonic P de Witte V de Waard
AM Spijkerboer
HA Marquering
AH Zwinderman
BJM Mulder
AJHA Scholte
Y Hilhorst-Hofstee
J Timmermans
M Kempers
M van den Berg
P van Tintelen

26. Backup slides

27. Inclusion COMPARE trial

28. Current medicinal therapy
β-blocker therapy:
Reducing inotropy / bloodpressure
Reducing chronotropy
Reduction of aortic root dilatation rate
Shores et al. N ENGL J MED 1994; 330:

29. Aortic root dilatation rate and losartan dose
Outcome (mm/3years)
Losartan < 100 mg (n=40)
Losartan 100 mg (n=38)
P-value
Aortic root dilatation rate
0.89 ± 1.74
0.72 ± 1.00
0.627

30. Systolic blood pressure and aortic root dilatation rate

31. Change in systolic blood pressure and aortic root dilatation rate
Losartan:
R = 0.058
P = 0.630
Controls
R = 0.001
P = 0.993

32. At baseline TGF-beta levels were significantly higher in marfan patients than in healthy controls, what we expected from literature and pathophysiology. We than devided the Marfan patients in two groups based on their TGF-beta level. The patients with high TGF-beta levels, are the patients with TGF-beta levels more than the mean plus two standard deviations above from healty controls.

33. At baseline TGF-beta levels were significantly higher in marfan patients than in healthy controls, what we expected from literature and pathophysiology. We than devided the Marfan patients in two groups based on their TGF-beta level. The patients with high TGF-beta levels, are the patients with TGF-beta levels more than the mean plus two standard deviations above from healty controls.

34. Prophylactic aortic root replacement
Bentall
David

35. Predefined endpoints Primary endpoint:
Aortic dilatation rate at any predefined aortic level in 3 years
Secondary endpoints : - Cardiovascular mortality
- Prophylactic aortic surgery
- Aortic dissection