The GRAFT Study: Evaluation of Graft Function, Rejection and Cardiac Allograft Vasculopathy in First Heart Transplant Recipients.

Heart Transplant Recipients Clinical Trial

Official title:

The GRAFT Study: Evaluation of Graft Function, Rejection and Cardiac Allograft Vasculopathy in First Heart Transplant Recipients.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02077764
• Other study ID #: Sagsnr. 1-10-72-153-13
• Secondary ID: The GRAFT study:
• Status: Completed
• Phase: N/A
• First received: February 28, 2014
• Last updated: April 13, 2016
• Start date: September 2013
• Est. completion date: January 2016

Study information

• Verified date: April 2016
• Source: Aarhus University Hospital Skejby
• Contact: n/a
• Is FDA regulated: No
• Health authority: Denmark: The Central Denmark Region Committees on Health Research EthicsDenmark: Danish Dataprotection Agency
• Study type: Observational [Patient Registry]

Clinical Trial Summary

Objective:

• To assess the relationship between coronary allograft vasculopathy (CAV) and graft function, and to evaluate non-invasive methods for CAV diagnosis.

• To assess left ventricular (LV) and right ventricular (RV) function in the acute phase and serially during the first year after transplantation.

• To evaluate the impact of acute and repetitive rejection on the longitudinal myocardial function Hypothesis

1. Timing of development and degree of CAV can be measured non-invasively combining myocardial longitudinal deformation (by advanced echocardiography) and coronary flow velocity reserve (CFVR) (by echocardiography and PET). This combination of methods can detect CAV before it is angiographically visual and gives supplementary information of the impact on myocardial graft function.

2. Longitudinal deformation, 3D echocardiography, cardiac magnetic resonance imaging (CMRI) and PET can be used for RV and LV myocardial function assessment and represent more valid markers of the function than standard echocardiography in heart transplant (HTX) patients.

3. Myocardial longitudinal deformation is a better marker of acute rejections than conventional ejection fraction (EF).

Background The most frequent heart related death causes after HTX are CAV, acute graft failure and rejection.

CAV is characterized by diffuse concentric intima thickening involving both epicardial vessels and the coronary microvascular system. In our clinical approach HTX-patients are followed with annual CAG and standard echocardiography with estimation of LV systolic function by EF. Standard echocardiography has not proven benefit in the diagnosis of CAV. CAG often misses CAV in early phases.

In various cardiac diseases it is well known that ischemia and fibrosis often affect the endocardial longitudinal oriented layers. Longitudinal deformation by advanced echocardiography has shown to be better markers for systolic function in HTX patients compared to standard EF. Longitudinal LV systolic function is dependent of endocardial perfusion. CFVR represents the capacity of the coronary circulation to dilate due to metabolic demands and has been shown to correlate with longitudinal deformation in myocardial infarction. CFVR measurements in HTX patients with advanced echocardiography and PET scan have shown a significant correlation to CAV.

RV failure is an early, potentially fatal, complication to HTX. The function and change over time of RV have not been fully studied using modern echocardiographic techniques or assessment by CMRI.

Acute rejection is an inflammatory response often diagnosed by routine biopsies (gold standard). These are expensive, time consuming and inconvenient for the patient. The role of conventional echocardiography has not yet found a significant role in the diagnostics of acute rejections and furthermore how repeated rejections influence on graft function is not well described.

Study 1 A cross sectional study consisting of 50 stabile HTX patients. These will be selected with 25 patients with no or light CAV and 25 patients with moderate or severe CAV.

Severity of CAV will be evaluated by:

• CAG

• CFVR measurement by advanced echocardiography and PET.

Graft function will be evaluated by:

• Advanced echocardiography at rest end during bicycle exercise.

• CMRI including assessment of LV and RV EF, strain and mass.

• During rest and bicycle exercise echocardiography simultaneously right heart catheterization are performed for hemodynamic measurement

Study 2 A prospective cohort study with 20-25 newly transplanted patients over a period of 12 months.

LV and RV function will be measured by:

• Advanced echocardiography

• CFVR measurement (echocardiography and PET)

• CMRI for LV and RV EF, strain and mass

• Right heart catheterization

Study 3 Prospective examination of correlation between graft function, CAV and rejection. Information of former episodes of acute rejection is collected retrospective. Study objectives are all living HTX patients (approx. 200) in the period of 2011-2013.

Advanced echocardiography (including longitudinal deformation), biopsies (rejection evaluation) and CAG (CAV evaluation).

Description:

Objective

1. To assess the relationship between myocardial perfusion, coronary anatomy and longitudinal myocardial function in heart transplanted (HTX) patients with and without coronary allograft vasculopathy (CAV).

2. Evaluation of systolic and diastolic capacity during exercise in HTX patients with and without CAV.

3. Evaluation of non-invasive methods for CAV diagnosis.

4. To assess left ventricular (LV) and right ventricular (RV) function in the acute phase and during follow-up (5 times) the first year after transplantation and furthermore to compare advanced echocardiographic evaluation of graft function with cardiac magnetic resonance imaging (CMRI), right heart catheterization, and positron emission tomography (PET).

5. Finally, to evaluate the impact of acute and repetitive rejection on myocardial graft function measured by standard 2D echocardiography and advanced echocardiography with analysis of longitudinal myocardial function.

Hypothesis

1. Timing of development and degree of CAV can be measured non-invasively combining myocardial longitudinal deformation measurement by advanced echocardiography and coronary flow velocity reserve (CFVR) by echocardiography and PET. This combination of methods can detect CAV before it is angiographic visual and gives supplementary information of the impact on myocardial graft function. This setup might be more appropriate in evaluation of the myocardial graft function and CAV than standard echocardiography and coronary angiography (CAG). Optical coherence tomography (OCT) can detect CAV in early phases and gives supplementary characterization of the plaque.

2. Modern non-invasive methods (longitudinal deformation, 3D echocardiography, CMRI and PET) can be used in RV and LV myocardial function assessment and represents more valid markers of the function than standard echocardiography in HTX patients.

3. During exercise patients with CAV will show impaired longitudinal myocardial deformation and restrictive filling with significant increasing LV and RV filling pressures.

4. Myocardial longitudinal deformation is a better marker of acute rejections than conventional ejection fraction (EF). After an episode of severe acute rejection the graft function will improve, but instances of repetitive rejections will lead to impaired longitudinal systolic function with preserved LV EF.

Background Mean survival after HTX at our center is 15.6 years. Complications remain frequent and serious. In the first postoperative year the main causes of death are graft failure, rejections and infection. At long term follow up main causes of death are CAV and malignancies.

CAV is characterized by diffuse concentric intima thickening involving both epicardial vessels and the coronary microvascular system. After 10 years more than 50% of patients shows angiographic signs of CAV.

In our clinical approach HTX-patients are followed with annual CAG and standard echocardiography with estimation of LV systolic function by EF. EF is often within normal range even though CAV lesions are evident by CAG, suggesting that LV EF is an inappropriate parameter for detecting impaired myocardial function in CAV. Symptoms of graft dysfunction first present themself with severe CAV. Studies have shown that CAG often misses CAV in early phases. OCT is a novel intravascular imaging modality with excellent spatial resolution. It has been used in a few small cross sectional studies with HTX patients and seems like a promising tool for detecting CAV and gives supplementary characterization of the plaque.

In various cardiac diseases it is well known that ischemia and fibrosis often affect the endocardial longitudinal oriented layers leading to abnormal systolic function of both LV and RV. Longitudinal deformation by tissue Doppler and strain analysis has shown to be better markers for systolic function in HTX patients compared to standard measurements such as LV EF. Longitudinal LV systolic function is dependent of endocardial perfusion. CFVR represents the capacity of the coronary circulation to dilate, due to increased myocardial metabolic demands and is expressed by the difference between the hyperaemic and resting flow. CFVR has been shown to correlate with the degree of decreased longitudinal deformation in myocardial infarction. CFVR measurements in HTX patients with color Doppler echocardiography and PET scan have shown a significant correlation to CAV.

RV failure is an early, potentially fatal, complication to HTX. Standard echocardiographic measurement does not seem to reflect the overall RV systolic performance and clinical status of the patient. Prior studies have found impaired RV function after HTX, but most studies of RV function were not performed with simultaneous right heart catheterization or assessment of RV EF by CMRI (golden standard). Overall the function and change over time of RV have not been fully studied using modern echocardiographic techniques or assessment by CMRI.

Acute rejection is an inflammatory response most frequently in the first 6 months after HTX. Two thirds experience rejection episodes within first year.

Rejections are often asymptomatic and associated with poor outcome, including development of CAV. Patients are followed with routine biopsies (gold standard), but these are expensive, time consuming and inconvenient for the patient. The role of conventional echocardiography has not yet found a significant role in the diagnostics of acute rejections and furthermore how repeated rejections influence on graft function is not well described.

Study objective, design and methods Study 1 Design: A cross sectional study consisting of 50 stabile HTX patients. These will be selected with 25 patients with no or light CAV and 25 patients with moderate or severe CAV. 25 matched controls.

Methods:

Severity of CAV will be evaluated by:

• CAG supplied with OCT.

• CFVR measurement by echocardiography with adenosine induced hyperemia.

• CFVR measurement with H215O-PET.

Graft function will be evaluated by:

• 2D and 3D echocardiography (including longitudinal deformation and tissue Doppler)

• Diastolic (and systolic) stress test: Bicycle exercise with simultaneously echocardiography and right heart catheterization.

Blood samples are taken for analysis of myocardial fibrosis markers, CRP, TNT and NT-proBNP.

Study 2 Design: A prospective cohort study with 20 newly transplanted patients over a period of 12 months.

Methods: LV and RV function shall be measured by:

• 2D and 3D echocardiography (including longitudinal deformation, tissue Doppler, CFVR, LV and RV EF),

• CMRI for LV and RV EF, strain and mass

• Right heart catheterization

• H215O-PET at baseline and after 3 month in the assessment of RV function

• Coronary angiography after 3 and 12 month will be supplied with OCT for early signs of CAV development.

Biopsies are performed according to routine protocol after transplantation. Blood samples for analysis of myocardial fibrosis markers, CRP, TNT and NT-proBNP.

Study 3 Design: Prospective examination of correlation between graft function, CAV and rejection. Information of former episodes of acute rejection is collected retrospective. Study objectives are all living HTX patients (approx. 200) in the period of 2011-2013.

Methods: Advanced echocardiography (including longitudinal deformation and tissue Doppler), biopsies (rejection evaluation) and CAG (CAV evaluation).

Publication Plan:

Positive as well as negative result from study 1-3 will be published. We aim at publishing study 1-3 in peer review international, scientific journals. Study 3 is expected to be published in 2014 and study 1 and 2 in 2016. MD, PhD student Tor Skibsted Clemmensen will draft the manuscripts and be 1st author hereof.

Ethical considerations Adenosine, used for CFVR measurement and PET, often causes mild facial flushing, chest discomfort and dyspnoea. After suspended infusion symptoms last less than one minute since half time is below 10 seconds.

Right heart catheterisation is part of the standard protocol after HTX. Only patients in study 1 might be subjected to more catheterisations than normally. Complications are rare with experienced operators.

The radiation dose of H215O-PET is 2-2,5 mSv, approximately the same as one year background radiation. Patients in study 1 will be subjected to one examination, patients in study 2 two examinations.

No additional CAG are made in the studies. OCT examination is considered very safe with a risk of complication <0,5%.

The investigators are convinced that the possible risks are outweighed by the expected benefits from this study and no study-related examinations will be conducted until informed consent form has been signed.

Regional Scientific Ethical Committee of Central Denmark has approve the studies.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 65
• Est. completion date: January 2016
• Est. primary completion date: January 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 100 Years

Eligibility

Inclusion Criteria:

• Age 18-100

• Informed and signed consent

Exclusion Criteria:

• - Coronary stenosis within the first 3 mounts after HTX (donor transmitted coronary atherosclerosis).

• Severe asthma or COLD with FEV1 < 50%

• 2° or 3° AV block

• Pregnancy

• S-creatinine >200 µmol/l

• Allergy towards the contrast agent

Study Design

Observational Model: Case Control, Time Perspective: Cross-Sectional

Related Conditions & MeSH terms

• Heart Transplant Recipients
• Vascular Diseases

Intervention

Procedure:
• OCT and coronary angiography

• Right heart cat.

Radiation:
• PET

Procedure:
• Echocardiography

• exercise test

Other:
• blood samples

Locations

Country	Name	City	State
Denmark	Aarhus University Hospital, Skejby	Aarhus	Aarhus N

Sponsors (1)

Lead Sponsor	Collaborator
Aarhus University Hospital Skejby

Country where clinical trial is conducted

Denmark, 

References & Publications (11)

Clemmensen TS, Munk K, Tram EM, Ilkjær LB, Severinsen IK, Eiskjær H. Twenty years' experience at the Heart Transplant Center, Aarhus University Hospital, Skejby, Denmark. Scand Cardiovasc J. 2013 Dec;47(6):322-8. doi: 10.3109/14017431.2013.845688. Epub 2013 Oct 16. — View Citation

D'Andrea A, Riegler L, Nunziata L, Scarafile R, Gravino R, Salerno G, Amarelli C, Maiello C, Limongelli G, Di Salvo G, Caso P, Bossone E, Calabrò R, Pacileo G, Russo MG. Right heart morphology and function in heart transplantation recipients. J Cardiovasc Med (Hagerstown). 2013 Sep;14(9):648-58. doi: 10.2459/JCM.0b013e32835ec634. — View Citation

Fyfe DA, Mahle WT, Kanter KR, Wu G, Vincent RN, Ketchum DL. Reduction of tricuspid annular doppler tissue velocities in pediatric heart transplant patients. J Heart Lung Transplant. 2003 May;22(5):553-9. — View Citation

Goland S, Siegel RJ, Burton K, De Robertis MA, Rafique A, Schwarz E, Zivari K, Mirocha J, Trento A, Czer LS. Changes in left and right ventricular function of donor hearts during the first year after heart transplantation. Heart. 2011 Oct;97(20):1681-6. doi: 10.1136/hrt.2010.220871. Epub 2011 May 17. — View Citation

Khandhar SJ, Yamamoto H, Teuteberg JJ, Shullo MA, Bezerra HG, Costa MA, Selzer F, Lee JS, Marroquin OC, McNamara DM, Mulukutla SR, Toma C. Optical coherence tomography for characterization of cardiac allograft vasculopathy after heart transplantation (OCTCAV study). J Heart Lung Transplant. 2013 Jun;32(6):596-602. doi: 10.1016/j.healun.2013.02.005. Epub 2013 Mar 15. — View Citation

Løgstrup BB, Høfsten DE, Christophersen TB, Møller JE, Bøtker HE, Pellikka PA, Egstrup K. Correlation between left ventricular global and regional longitudinal systolic strain and impaired microcirculation in patients with acute myocardial infarction. Echocardiography. 2012 Nov;29(10):1181-90. doi: 10.1111/j.1540-8175.2012.01784.x. Epub 2012 Aug 3. — View Citation

Sipahi I, Starling RC. Cardiac allograft vasculopathy: an update. Heart Fail Clin. 2007 Jan;3(1):87-95. — View Citation

Stehlik J, Edwards LB, Kucheryavaya AY, Benden C, Christie JD, Dipchand AI, Dobbels F, Kirk R, Rahmel AO, Hertz MI; International Society of Heart and Lung Transplantation. The Registry of the International Society for Heart and Lung Transplantation: 29th official adult heart transplant report--2012. J Heart Lung Transplant. 2012 Oct;31(10):1052-64. doi: 10.1016/j.healun.2012.08.002. — View Citation

Syeda B, Höfer P, Pichler P, Vertesich M, Bergler-Klein J, Roedler S, Mahr S, Goliasch G, Zuckermann A, Binder T. Two-dimensional speckle-tracking strain echocardiography in long-term heart transplant patients: a study comparing deformation parameters and ejection fraction derived from echocardiography and multislice computed tomography. Eur J Echocardiogr. 2011 Jul;12(7):490-6. doi: 10.1093/ejechocard/jer064. Epub 2011 Jun 2. — View Citation

Tona F, Osto E, Tarantini G, Gambino A, Cavallin F, Feltrin G, Montisci R, Caforio AL, Gerosa G, Iliceto S. Coronary flow reserve by transthoracic echocardiography predicts epicardial intimal thickening in cardiac allograft vasculopathy. Am J Transplant. 2010 Jul;10(7):1668-76. doi: 10.1111/j.1600-6143.2010.03160.x. — View Citation

Wu YW, Chen YH, Wang SS, Jui HY, Yen RF, Tzen KY, Chen MF, Lee CM. PET assessment of myocardial perfusion reserve inversely correlates with intravascular ultrasound findings in angiographically normal cardiac transplant recipients. J Nucl Med. 2010 Jun;51(6):906-12. doi: 10.2967/jnumed.109.073833. Epub 2010 May 19. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Correlation between Rubidium and H2O PET	Patients will be subjected to tests with bodt tracers to validate rubidium as tracer in a HTX population	May 2014 to January 2016	Yes
Other	3D echocardiography as a tool to diagnose vasculopathy		September 2013 to January 2016	No
Primary	Coronary flow velocity reserve	Assessed by tissue Doppler echocardiography and H215O-PET	September 2013 to January 2016	Yes
Primary	pulmonary capillary wedge pressure	At rest and during exercise	September 2013 to January 2016	Yes
Primary	global longitudinal strain	At rest and during exercise	September 2013 to January 2016	No
Primary	cardiac allograft vasculopathy	Assessed by coronary angiography and optical coherence tomography	September 2013 to January 2016	Yes
Secondary	RV-EF	3D echocardiography	September 2013 to January 2016	No
Secondary	Quality of life	Minnesota quality of life questionnaires	September 2013 to January 2016	No
Secondary	CRP, TNT, Nt-ProBNP and fibrosis markers	Correlation between cardiac allograft vasculopathy and biomarkers	September 2013 to January 2016	No
Secondary	tissue Doppler	Correlation between rejection, vasculopathy and tissue Doppler echocardiography- in rest and during exercise	September 2013 to January 2016	No
Secondary	Cardiac output	At rest and during exercise in a HTX population	September 2013 to January 2016	Yes
Secondary	intima/media radio	Assessed by optical coherence tomography	September 2013 to January 2016	Yes