effect of losartan on aortic dilatation rate in adult patients with marfan syndrome
DESCRIPTION
Effect of losartan on aortic dilatation rate in adult patients with Marfan syndrome. R Franken, AW den Hartog, T Radonic, V de Waard, AM Spijkerboer, AH Zwinderman, BJM Mulder J Timmermans AJHA Scholte MP van den Berg. Maarten Groenink. Disclosures. No conflict of interest No disclosures. - PowerPoint PPT PresentationTRANSCRIPT
Effect of losartan on aortic dilatation rate in adult patients with Marfan syndrome
R Franken, AW den Hartog, T Radonic, V de Waard, AM Spijkerboer, AH Zwinderman, BJM Mulder
J Timmermans
AJHA Scholte
MP van den Berg
Maarten Groenink
Disclosures
• No conflict of interest
• No disclosures
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
Marfan syndrome : clinical management
• Surgical (prophylactic)- Aortic root 46-50 mm I C- Beyond the aortic root > 50 mm IIa C
• Pharmacological- β blockers- Losartan ?
• Lifestyle ESC Guidelines for the managementof grown-up congenital heart disease 2010
Beneficial effects of losartan in a Marfan mouse model
Habashi et al. Science. 2006 Apr 7;312(5770):117-21. Habashi et al. Science. 2006 Apr 7;312(5770):117-21.
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
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. 2010 Jan 12;11:3. doi: 10.1186/1745-6215-11-3.
Predefined endpoints
Primary endpoint: Aortic dilatation rate at any predefined aortic level in 3 years
Secondary endpoints :- Cardiovascular mortality
- Prophylactic aortic surgery
- Aortic dissection
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
Randomisation
Intention to treat analysis
Screening 797 patients
116 losartan 117 control
564 not eligible
113 105
259 not meeting inclusion criteria305 declined participation
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%)
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
Baseline aortic measurements (mm)
Results
Aortic root dilatation rate (n=145)
Control Losartan0.0
0.5
1.0
1.5
2.0p = 0.014
(mm
/3 y
ears
)
(n=67) (n=78)
Age ≤ 40 (92) > 40 (53)
Sex M (72)F (73)
FBN-1 + (117) - (25)
β – blocker +(107)
- (38)MAP (mmHg) ≤ 90 (75)
> 90 (66)AOR (mm) ≤ 45 (89)
> 45 (56)
Beneficial effect of losartan in all subgroups
Losartan effective
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
No differences in clinical endpoints
Controls
(n=117)
Losartan
(n=116)
Aortic root surgery 8 (7%) 10 (9%)
Distal aortic surgery 1 (1%) 0
Aortic dissection
- Type A 0 0
- Type B 2 (2%) 0
Cardiovascular mortality 0 0
Combined endpoint 11 (9%) 10 (9%)
Dilatation rate of the aortic arch after prophylactic AOR replacement
Control (n=31) Losartan (n=26)0.0
0.5
1.0
1.5 p = 0.033
(mm
/3 y
ears
)
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
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 endpointsEuropean Heart Journaldoi:10.1093/eurheartj/eht334
Study limitations
• Open label
• Target inclusion not achieved
• Longer FU needed for clinical endpoints
• Subanalyses on relatively small groups
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. Losartan vs β-blocker 1–55 291 ∆ AoR Echo
Fr: Detaint et al. Losartan vs placebo ≥ 10 300 ∆ AoR Echo
Be: Moberg et al. Losartan vs placebo ≥ 10 490 ∆ Any level
Echo + MRI
UK: Mullen et al. Irbesartan vs placebo 6-40 490 ∆ AoR Echo
SP: Forteza et al. Losartan vs β-blocker 5-60 150 ∆ AoR Echo + MRI
UK: Creager et al. Losartan vs β-blocker ≥ 25 50 ∆ AoR Echo
Can: Sandor et al. Losartan vs β-blocker ≥ 10 300 ∆ AoR Echo
Conclusions
• 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
Recommendations for clinical practice
In adult patients with Marfan syndrome,
unoperated and after elective aortic root surgery,
losartan therapy should be advised
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
M van den Berg
P van Tintelen
J Timmermans
M Kempers
Backup slides
Inclusion COMPARE trial
0 6 12 18 24 30 360
50
100
150
200
250
300
350
months since study take-off
pat
ien
ts in
clu
ded
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; 330:1335-1341
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
0 mg 50 mg 100 mg 0.0
0.5
1.0
1.5
Ao
rtic
ro
ot
dila
tati
on
rat
e (m
m/3
year
)
Systolic blood pressure and aortic root dilatation rate
-5 0 5 10
100
120
140
160
180
Aortic Root Dilatation Rate (mm/3year)
Sys
tolic
Blo
od
Pre
ssu
re (
mm
Hg
)
R = 0.004
P = 0.967
Change in systolic blood pressure and aortic root dilatation rate
-5 0 5 10
-40
-20
0
20 Losartan
Controls
Aortic Root Dilatation Rate (mm/ 3years)
Ch
ang
e in
Sys
tolic
Blo
od
Pre
ssu
re (
mm
Hg
)
Losartan:
R = 0.058
P = 0.630
Controls
R = 0.001
P = 0.993
233 patients underwent randomisation
Patients from all four participating Marfan screening clinics and CONCOR assessed 797 patients for screening
564 Were not eligible 334 Did not meet protocol criteria 89 More than 1 aortic graft 56 Prior aortic dissection 72 Already using ACEi or ARB 22 Mental retardation 20 Pregnancy 253 Declined participation 142 Miscellaneous reasons 69 Refused medical treatment 42 Logistic reasons 52 Did not respond
233 patients underwent randomisation
116 in Losartan group 117 in Control group
Follow up not performed due to 1 Non cardiovascular death 2 Refused participation
17 patients prematurely discontinued losartan treatment due to 14 dizziness or low blood pressure 1 renal dysfunction 1 extreme fatigue 1 angioedema
1 patient started losartan therapy during study
113 in intention-to-treat analysis 105 in intention-to-treat analysis
Follow up not performed due to 2 Type B aortic dissection 10 Refused participation
Aortic root replacement*27 replacements prior to study10 replacements during study
78 patients for aortic root analysis 67 patients for aortic root analysis
Aortic root replacement**36 replacements prior to study 8 replacements during study
Prophylactic aortic root replacement
Bentall David
Predefined endpoints
Primary endpoint: Aortic dilatation rate at any predefined aortic level in 3 years
Secondary endpoints :- Cardiovascular mortality
- Prophylactic aortic surgery
- Aortic dissection