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Effect of losartan on aortic dilatation rate in adult patients with Marfan syndrome

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.

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Effect of losartan on aortic dilatation rate in adult patients with Marfan syndrome

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  1. 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

  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 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

  5. Beneficial effects of losartan in a Marfan mouse model Habashi et al. Science. 2006 Apr 7;312(5770):117-21.

  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. 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 Methods Trials. 2010 Jan 12;11:3. doi: 10.1186/1745-6215-11-3.

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

  11. Baseline characteristics (n=233)

  12. Baseline aortic measurements (mm)

  13. Results

  14. Aortic root dilatation rate (n=145) (n=67) (n=78)

  15. 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

  16. No differences in aortic dilatation rate beyond the aortic root

  17. No differences in clinical endpoints

  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

  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:10.1093/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

  23. 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

  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; 330:1335-1341

  29. Aortic root dilatation rate and losartan dose

  30. Systolic blood pressure and aortic root dilatation rate R = 0.004 P = 0.967

  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. Prophylactic aortic root replacement Bentall David

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

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