Clinical trial NCT06656065: IMR-Heart Trasplant Study
Official title: Index Microvascular Resistance (IMR)-guided Management of Heart Transplantation (IMR-Heart Transplant Study)
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Heart Transplant Rejection
Microvascular Resistance
Keywords: Heart Trasplant
Acute cellular rejection
IMR
Endomyocardial biopsy
Lead sponsor: Hospital Miguel Servet
Sponsor class: OTHER
Collaborators: name: Central University Hospital of Asturias
name: University Hospital La Fe, Valencia
name: University Hospital Virgen de la Arrixaca, Murcia
name: University Hospital 12 Octubre, Madrid
name: University Hospital Reina Sofia, Cordoba
name: Bellvitge University Hospital
name: University Hospital Virgen del Rocio, Sevilla
First posted: 2024-10-24
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Heart trasplant patients that have signed informed consent and meet all inclusion and exclusion criteria for undergoing IMR assessment.

Brief summary: Endomyocardial biopsy (EMB) is the gold standard method to guide post-heart trasplant (HT) patients, as it represents the best tool to identify rejection in orthotopic HT. However, it is frequently repeated during the first year, with some variations depending on each center protocol and it is potentially associated with serious complications.Several studies have presented the association between acute allograft rejection, micro-vasculopathy and cardiac allograft epicardial vasculopathy (CAV). Index of microvascular resistance (IMR) measured early after HT has been significantly associated with the risk of acute cellular rejection (ACR). The aim of this study will be to evaluate if the use of IMR early after HT may improve the patients care after HT, by reducing the number of EMB.

Detailed description: Acute allograft rejection (ACR) is an important cause of mortality and re-transplantation in heart transplant (HT) patients, particularly during the first year. Endomyocardial biopsy (EMB) is the "gold standard" to guide post- HT treatment. EMB is repeatedly performed during the first year and is associated with complications that, despite infrequent, can be potentially serious. In order to avoid the inconveniences of EMB, non-invasive techniques have been studied to detect rejection. However, none of these techniques has been able to replace EMB. Index of microvascular resistance (IMR) is a specific physiological parameter to measure microvascular function. An increased index of microvascular resistance (IMR) measured early after HT has been associated with ACR, a higher all-cause mortality and adverse cardiac events regardless of epicardial vasculopathy. According to available data, no study has evaluated IMR impact on post-HT management (number of EMBs performed). The aim of this study will be to evaluate if the use of IMR early after HT may improve the patients care after HT, by reducing the number of EMB.

The IMR-HT study is a multicenter, prospective observational study that will include post-HT stable patients undergoing coronary physiological assessment in the first two months and one year. Assessment of IMR, coronary flow reserve (CFR) and fractional flow reserve (FFR) will be performed using the standard thermodilution technique. The left anterior descending coronary artery will be evaluated in all patients. Circumflex or right coronary artery could be additionally evaluated at operator's discretion. An intracoronary pressure and temperature sensor-tipped guidewire (Pressure Wire TM X guide- wire 0.014', Abbott, IL, USA) will be used to perform the measurements. The tip pressure sensor will be advanced into the mid-to-distal portion of the evaluated vessel. Baseline aortic pressure (Pa) and distal intracoronary pressure (Pd) will be obtained to calculate the resting index Pd/Pa. To measure the mean transit time (Tmn) under basal conditions, intracoronary administration of 3 mL of room-temperature saline will be manually injected three times in succession (3 mL/s). Then maximal hyperemia will be induced using adenosine iv (140 to 180 mg/kg/min) and three additional intracoronary room temperature saline boluses of 3 ml will be administered to determine the mean transit time at hyperemia (Tmnh). Finally, fractional flow reserve (FFR), coronary flow reserve (CFR) and IMR will be calculated using the software Coroventis Coroflow (Coroventis Abbott, Uppsala, Sweden).

Depending on IMR values obtained in the first two months, clinical status and the other complementary tests the physician could be able to modify the number of biopsies established in each center protocol. If the IMR is less than 15: the number of biopsies could be reduced or kept the same. No immunosuppressive therapy changes would be made. If the IMR is 15 or greater: the number of biopsies would be performed as usual per protocol, immunosuppressive therapy could be intensified or maintained the same.

Clinical conditions, laboratory findings and clinical events will be assessed at one month and one year. Data will be included in an online database specifically designed for the study on platform REDCap (Research Electronic Data Capture).Each center will specify the number of annual biopsies performed based on IMR values obtained between the first two months after HT.

A number will be assigned to each patient; their identity will not be disclosed in any case. All shared information will be anonymized. The principal investigator at each center will be responsible for keeping the data anonymized.Data will be processed in accordance with the protection legislation in force (Spanish Personal Data Protection and Guarantee of Digital Rights Act 3/2018, and Regulation (EU) 2016/679).

The study primary end point will be the number of EMB performed at one year. Other secondary endpoints include the association between IMR and mortality, ACR, cardiac failure, re-trasplantation and cardiac allograft vasculopathy. Patients will be followed for up to 5 years.

Eligibility criteria: Inclusion Criteria:

* Heart transplant patients \>18 years.
* Patients who have received and signed informed consent.

Exclusion Criteria:

* Patients with hemodynamic instability after HT, including cardiogenic shock or severe coagulopathy.
* Patients with acute cellular rejection before intracoronary physiological assessment.
* Patients with bronchial asthma or bronchopathy with a positive bronchodilation test, which contraindicates the use of adenosine.
* Patients with epicardial coronary lesions with a resting physiological index ≤0.89 or ≤0.80 at hyperemia.
* Patients unlikely to cooperate or with inability or unwillingness to give informed consent.

Primary outcomes:
measure: Number of biopsies performed in each center at one year
timeFrame: One year
Secondary outcomes:
measure: IMR variation between first two months after HT and one year
timeFrame: One year
measure: Acute cellular rejection
timeFrame: One year
measure: Cardiac allograft vasculopathy
timeFrame: Five years
measure: Cardiovascular mortality
timeFrame: Five years
measure: Heart failure
timeFrame: Five years
measure: Inmunosupressive therapy
timeFrame: Five years
Other outcomes:
Locations:
city: L´Hospitalet de Llobregat
country: Spain
facility: Hospital Universitario de Bellvitge
state: Barcelona
city: Zaragoza
country: Spain
facility: Hospital Miguel Servet
Study officials:
References:
citation: Lee JM, Choi KH, Choi JO, Shin D, Park Y, Kim J, Lee SH, Kim D, Yang JH, Cho YH, Sung K, Choi JY, Park M, Kim JS, Park TK, Song YB, Hahn JY, Choi SH, Gwon HC, Oh JK, Jeon ES. Coronary Microcirculatory Dysfunction and Acute Cellular Rejection After Heart Transplantation. Circulation. 2021 Nov 2;144(18):1459-1472. doi: 10.1161/CIRCULATIONAHA.121.056158. Epub 2021 Sep 3.
citation: Okada K, Honda Y, Luikart H, Yock PG, Fitzgerald PJ, Yeung AC, Valantine HA, Khush KK, Fearon WF. Early invasive assessment of the coronary microcirculation predicts subsequent acute rejection after heart transplantation. Int J Cardiol. 2019 Sep 1;290:27-32. doi: 10.1016/j.ijcard.2019.04.018. Epub 2019 Apr 8.
citation: Ahn JM, Zimmermann FM, Gullestad L, Angeras O, Karason K, Russell K, Lunde K, Okada K, Luikart H, Khush KK, Honda Y, Pijls NHJ, Lee SE, Kim JJ, Park SJ, Solberg OG, Fearon WF. Microcirculatory Resistance Predicts Allograft Rejection and Cardiac Events After Heart Transplantation. J Am Coll Cardiol. 2021 Dec 14;78(24):2425-2435. doi: 10.1016/j.jacc.2021.10.009.
citation: Hiemann NE, Wellnhofer E, Knosalla C, Lehmkuhl HB, Stein J, Hetzer R, Meyer R. Prognostic impact of microvasculopathy on survival after heart transplantation: evidence from 9713 endomyocardial biopsies. Circulation. 2007 Sep 11;116(11):1274-82. doi: 10.1161/CIRCULATIONAHA.106.647149. Epub 2007 Aug 20.
citation: Saraiva F, Matos V, Goncalves L, Antunes M, Providencia LA. Complications of endomyocardial biopsy in heart transplant patients: a retrospective study of 2117 consecutive procedures. Transplant Proc. 2011 Jun;43(5):1908-12. doi: 10.1016/j.transproceed.2011.03.010.
citation: Khush KK, Cherikh WS, Chambers DC, Harhay MO, Hayes D Jr, Hsich E, Meiser B, Potena L, Robinson A, Rossano JW, Sadavarte A, Singh TP, Zuckermann A, Stehlik J; International Society for Heart and Lung Transplantation. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-sixth adult heart transplantation report - 2019; focus theme: Donor and recipient size match. J Heart Lung Transplant. 2019 Oct;38(10):1056-1066. doi: 10.1016/j.healun.2019.08.004. Epub 2019 Aug 10. No abstract available.
citation: Costanzo MR, Dipchand A, Starling R, Anderson A, Chan M, Desai S, Fedson S, Fisher P, Gonzales-Stawinski G, Martinelli L, McGiffin D, Smith J, Taylor D, Meiser B, Webber S, Baran D, Carboni M, Dengler T, Feldman D, Frigerio M, Kfoury A, Kim D, Kobashigawa J, Shullo M, Stehlik J, Teuteberg J, Uber P, Zuckermann A, Hunt S, Burch M, Bhat G, Canter C, Chinnock R, Crespo-Leiro M, Delgado R, Dobbels F, Grady K, Kao W, Lamour J, Parry G, Patel J, Pini D, Towbin J, Wolfel G, Delgado D, Eisen H, Goldberg L, Hosenpud J, Johnson M, Keogh A, Lewis C, O'Connell J, Rogers J, Ross H, Russell S, Vanhaecke J; International Society of Heart and Lung Transplantation Guidelines. The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2010 Aug;29(8):914-56. doi: 10.1016/j.healun.2010.05.034. No abstract available.
citation: Lund LH, Edwards LB, Kucheryavaya AY, Benden C, Dipchand AI, Goldfarb S, Levvey BJ, Meiser B, Rossano JW, Yusen RD, Stehlik J. The Registry of the International Society for Heart and Lung Transplantation: Thirty-second Official Adult Heart Transplantation Report--2015; Focus Theme: Early Graft Failure. J Heart Lung Transplant. 2015 Oct;34(10):1244-54. doi: 10.1016/j.healun.2015.08.003. Epub 2015 Aug 28. No abstract available.