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