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

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 management of grown-up congenital heart disease 2010

Beneficial effects of losartan in a Marfan mouse model Combi met 4 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. 7

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

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

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!!!

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

Results

Aortic root dilatation rate (n=145)

Beneficial effect of losartan in all subgroups 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) 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%) Aortic dissection - Type A - Type B 2 (2%) Cardiovascular mortality Combined endpoint 11 (9%)

Dilatation rate of the aortic arch after prophylactic AOR replacement

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 endpoints European Heart Journal doi: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. 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.

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

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 J Timmermans M Kempers M van den Berg P van Tintelen

Backup slides

Inclusion COMPARE trial

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

Systolic blood pressure and aortic root dilatation rate

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

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.

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.

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