Strategies To Prevent Cardiac Allograft Vasculopathy Related Events in Heart Transplant Recipients

NCT01305395 | Withdrawn DMC

• 1 other identifier: 1007M85473
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

1. 1.Early initiation of sirolimus will prevent or delay the development of intimal thickening and subsequent graft failure.
2. 2.Treatment guided by the development of cardiac allograft vasculopathy (CAV) on intravascular ultrasound (IVUS) will be more effective in delaying progression of CAV compared to treatment guided by angiography.
3. 3.Prevention of the development and progression of intimal thickness on IVUS will prevent the development of heart failure, graft dysfunction, and cardiovascular death related to CAV.
4. 4.Small artery elasticity predicts progression of cardiac allograft vasculopathy and is modified by sirolimus
5. 5.Patients who have no progression of CAV will have favorable improvement in biomarkers and endothelial cells compared to patients who have progression of CAV

Conditions

Cardiac Allograft Vasculopathy

Keywords

Cardiac Allograft Vasculopathy in Heart Transplant

Outcome Measures

Primary Outcomes (1)

• 1. Change in maximal intimal thickness

  1, 2, 3 and 4 years

Secondary Outcomes (6)

• Mean maximal intima thickness

  1, 2, 3, and 4 years

• Percent atheroma volume

  1,2,3 and 4 years

• Death from CAV, death from any cause, myocardial infarction, need for percutaneous coronary intervention (PCI), number of hospitalizations, infection rates, evidence of restrictive physiology, arrhythmic event related to CAV or pulmonary hypertension

  at 4 years.

• Change in small artery elasticity

  At 1, 2, 3, and 4 years

• Change in endothelial progenitor cell count

  At 1 and 2 years

Study Arms (5)

Early Intervention Arm

EXPERIMENTAL

Initiate sirolimus within 6 months of heart transplant

Drug: Sirolimus

Late Intervention Arm: Group 2A

EXPERIMENTAL

Initiate sirolimus after CAV is diagnosed by angiogram

Drug: Sirolimus

Retrospective Arm: Angiogram group

EXPERIMENTAL

Start sirolimus after CAV diagnosed is by angiogram

Drug: Sirolimus

Late Intervention Arm: Group 2B

EXPERIMENTAL

Start sirolimus after CAV is diagnosed by IVUS

Drug: Sirolimus

Retrospective Arm: Intravascular Ultrasound

EXPERIMENTAL

Sirolimus after CAV is diagnosed by IVUS

Drug: Sirolimus

Interventions

Sirolimus DRUG

Will initiate sirolimus within 6 months of heart transplant

Also known as: Rapamycin

Early Intervention Arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• For Prospective Arm:
• years or older
• Successful orthotropic heart transplant within 6 months of enrollment
• For Retrospective Arm:
• years or older
• Successful orthotropic heart transplant within 6 months to 3 years of enrolment
• Less than moderate CAV by angiogram or IVUS

You may not qualify if:

• For Prospective Arm:
• Greater than minimal baseline coronary disease
• Chronic kidney disease with creatinine \>2mg/dl
• Baseline (1 month) ejection fraction \< 50%
• IV contrast allergy
• Rejection within 3 months of enrollment
• Sensitivity to sirolimus or its derivatives
• Prior sirolimus use
• For Retrospective Arm:
• Significant baseline (one month) coronary artery disease (\>50% in one or more vessels by angiogram or MIT \>0.5 by IVUS)
• Chronic kidney disease with creatinine \>2mg/dl
• Baseline (1 month) ejection fraction \< 50%
• IV contrast allergy
• Rejection within 3 months prior to enrollment
• Sensitivity to sirolimus or its derivatives

Sponsors & Collaborators

• University of Minnesota: lead

Study Sites (1)

Cardiology Division, University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Related Publications (13)

• Christie JD, Edwards LB, Aurora P, Dobbels F, Kirk R, Rahmel AO, Stehlik J, Taylor DO, Kucheryavaya AY, Hertz MI. The Registry of the International Society for Heart and Lung Transplantation: Twenty-sixth Official Adult Lung and Heart-Lung Transplantation Report-2009. J Heart Lung Transplant. 2009 Oct;28(10):1031-49. doi: 10.1016/j.healun.2009.08.004. No abstract available.

  PMID: 19782285 BACKGROUND

• Rahmani M, Cruz RP, Granville DJ, McManus BM. Allograft vasculopathy versus atherosclerosis. Circ Res. 2006 Oct 13;99(8):801-15. doi: 10.1161/01.RES.0000246086.93555.f3.

  PMID: 17038650 BACKGROUND

• Weis M, von Scheidt W. Cardiac allograft vasculopathy: a review. Circulation. 1997 Sep 16;96(6):2069-77. doi: 10.1161/01.cir.96.6.2069.

  PMID: 9323100 BACKGROUND

• Johnson DE, Alderman EL, Schroeder JS, Gao SZ, Hunt S, DeCampli WM, Stinson E, Billingham M. Transplant coronary artery disease: histopathologic correlations with angiographic morphology. J Am Coll Cardiol. 1991 Feb;17(2):449-57. doi: 10.1016/s0735-1097(10)80114-7.

  PMID: 1991903 BACKGROUND

• Rickenbacher PR, Pinto FJ, Chenzbraun A, Botas J, Lewis NP, Alderman EL, Valantine HA, Hunt SA, Schroeder JS, Popp RL, et al. Incidence and severity of transplant coronary artery disease early and up to 15 years after transplantation as detected by intravascular ultrasound. J Am Coll Cardiol. 1995 Jan;25(1):171-7. doi: 10.1016/0735-1097(94)00323-i.

  PMID: 7798497 BACKGROUND

• Costello JM, Wax DF, Binns HJ, Backer CL, Mavroudis C, Pahl E. A comparison of intravascular ultrasound with coronary angiography for evaluation of transplant coronary disease in pediatric heart transplant recipients. J Heart Lung Transplant. 2003 Jan;22(1):44-9. doi: 10.1016/s1053-2498(02)00484-9.

  PMID: 12531412 BACKGROUND

• Sharples LD, Jackson CH, Parameshwar J, Wallwork J, Large SR. Diagnostic accuracy of coronary angiography and risk factors for post-heart-transplant cardiac allograft vasculopathy. Transplantation. 2003 Aug 27;76(4):679-82. doi: 10.1097/01.TP.0000071200.37399.1D.

  PMID: 12973108 BACKGROUND

• Kobashigawa JA, Tobis JM, Starling RC, Tuzcu EM, Smith AL, Valantine HA, Yeung AC, Mehra MR, Anzai H, Oeser BT, Abeywickrama KH, Murphy J, Cretin N. Multicenter intravascular ultrasound validation study among heart transplant recipients: outcomes after five years. J Am Coll Cardiol. 2005 May 3;45(9):1532-7. doi: 10.1016/j.jacc.2005.02.035.

  PMID: 15862430 BACKGROUND

• Tuzcu EM, Kapadia SR, Sachar R, Ziada KM, Crowe TD, Feng J, Magyar WA, Hobbs RE, Starling RC, Young JB, McCarthy P, Nissen SE. Intravascular ultrasound evidence of angiographically silent progression in coronary atherosclerosis predicts long-term morbidity and mortality after cardiac transplantation. J Am Coll Cardiol. 2005 May 3;45(9):1538-42. doi: 10.1016/j.jacc.2004.12.076.

  PMID: 15862431 BACKGROUND

• Mancini D, Pinney S, Burkhoff D, LaManca J, Itescu S, Burke E, Edwards N, Oz M, Marks AR. Use of rapamycin slows progression of cardiac transplantation vasculopathy. Circulation. 2003 Jul 8;108(1):48-53. doi: 10.1161/01.CIR.0000070421.38604.2B. Epub 2003 May 12.

  PMID: 12742978 BACKGROUND

• Keogh A, Richardson M, Ruygrok P, Spratt P, Galbraith A, O'Driscoll G, Macdonald P, Esmore D, Muller D, Faddy S. Sirolimus in de novo heart transplant recipients reduces acute rejection and prevents coronary artery disease at 2 years: a randomized clinical trial. Circulation. 2004 Oct 26;110(17):2694-700. doi: 10.1161/01.CIR.0000136812.90177.94. Epub 2004 Jul 19.

  PMID: 15262845 BACKGROUND

• Raichlin E, Bae JH, Khalpey Z, Edwards BS, Kremers WK, Clavell AL, Rodeheffer RJ, Frantz RP, Rihal C, Lerman A, Kushwaha SS. Conversion to sirolimus as primary immunosuppression attenuates the progression of allograft vasculopathy after cardiac transplantation. Circulation. 2007 Dec 4;116(23):2726-33. doi: 10.1161/CIRCULATIONAHA.107.692996. Epub 2007 Nov 19.

  PMID: 18025531 BACKGROUND

• Raichlin E, Prasad A, Kremers WK, Edwards BS, Rihal CS, Lerman A, Kushwaha SS. Sirolimus as primary immunosuppression is associated with improved coronary vasomotor function compared with calcineurin inhibitors in stable cardiac transplant recipients. Eur Heart J. 2009 Jun;30(11):1356-63. doi: 10.1093/eurheartj/ehp123. Epub 2009 Apr 21.

  PMID: 19383734 BACKGROUND

MeSH Terms

Interventions

Sirolimus

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Study Officials

• Monica M Colvin-Adams, MD, MS

  University of Minnesota

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 25, 2011
• First Posted: February 28, 2011
• Study Start: November 1, 2010
• Primary Completion: January 1, 2015
• Study Completion: January 1, 2015
• Last Updated: January 24, 2017

Record last verified: 2017-01

Locations

US (1)