IMR-Heart Trasplant Study

Official title

Index Microvascular Resistance (IMR) in Heart Transplant Patients

Overview

Acute allograft rejection (AAR) is an important cause of morbi-mortality in heart transplant (HT) patients, particularly during the first year. Endomyocardial biopsy (EMB) is the "gold standard" to guide post- heart transplantation treatment. However, it is associated with complications that can be potentially serious. The index of microvascular resistance (IMR) is a specific physiological parameter used to assess microvascular function. Invasive coronary assessment has been shown to be both feasible and safe. Detection of coronary microvascular dysfunction (MCD) by IMR may help to identify high risk HT patients. In fact, an increased IMR measured early after HT has been associated with AAR, higher all-cause mortality and adverse cardiac events. A high IMR value early after HT may identify patients at higher risk who require increased surveillance or adjustments in immunosuppressive therapy. Conversely, a low IMR value may support reducing the number of EMBs. Our aim is to evaluate IMR in heart transplant patients within the first year. Changes in management after knowing IMR values and prognostic implications of IMR in a long term follow up will also be assessed.

Detailed description

The IMR-HT study is a multicenter, prospective observational study that will include post-HT stable patients undergoing coronary physiological assessment in the first three 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).

Changes in HT patient management (number of EMBs, immunosuppressive therapy modifications) after knowing IMR values will also be assessed.

Based on previously published clinical data on IMR in heart transplant patients, a post-HT management algorithm is proposed:

* IMR \< 15: The frequency of biopsies could be reduced or maintained as per protocol. No changes to immunosuppressive therapy would be required. * IMR ≥ 15: Biopsies would be performed at the standard frequency according to protocol. Immunosuppressive therapy could be intensified or maintained the same.

Of note, given the observational characteristics of the study, clinical management decisions will be made at the discretion of the treating physician, taking into account the patient's clinical condition and other complementary tests.

Both groups (IMR\<15 vs IMR≥15) will be compared in terms of cardiac events occurrence.

Clinical conditions, laboratory findings and clinical events will be assessed at one month and one year. Follow up will be extended for up to five years. Data will be included in an online database specifically designed for the study on platform REDCap (Research Electronic Data Capture).

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).

Our aim will be to assess IMR values in heart transplant patients within one year and evaluate changes in management after knowing of IMR values. We believe it is important to move forward in AAR surveillance and reduce the number of endomyocardial biopsies. In addition to assessing their diagnostic capabilities, IMR should also be assessed based on clinical outcomes. Therefore, we are convinced the results of this trial will be very important for our HT patient population.

Primary outcome measures

• IMR values in the first three months and one year after heart transplant [Time frame: One year]

Secondary outcome measures (7)

• IMR variation between first three months after HT and one year [Time frame: One year]
• Acute cellular rejection [Time frame: One year]
• Cardiac allograft vasculopathy [Time frame: Five years]
• Cardiovascular mortality [Time frame: Five years]
• Heart failure [Time frame: Five years]
• Inmunosupressive therapy [Time frame: Five years]
• EMB performed in each center within the first year [Time frame: One year]

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Spain · 2 centers

• Hospital Universitario de Bellvitge — L'Hospitalet de Llobregat
• Hospital Miguel Servet — Zaragoza

Publications

• 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. PMID 34474597
• 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. PMID 30987835
• 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. PMID 34886963
• 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. PMID 17709643
• 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. PMID 21693299
• 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 the PMID 31548031
• 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, PMID 20643330
• 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 A PMID 26454738

Identifiers

NCT: NCT06656065 · C.I. PI23/242

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗