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ISHLT in Nizza - What's Hot, What's New for Transplant Cardiologists in 2015

Marco Masetti, MD
Luciano Potena, MD, PhD

University of Bologna
Bologna, Italy

The 34th ISHLT Meeting and Scientific Sessions, held from April 15th to 18th, gathered the largest audience ever for an ISHLT European venue. Besides the charming Promenade des Anglais, the freshness of the seafood at Café de Turin, and the Italian taste of the old downtown, what is going to remain in the heart of the many cardiologists crowding the Acropolis conference Center?

This year, congress dealt with many of the current needs and doubts of a physician working in the field of heart failure and heart transplantation, identifying four major topics of novelty: 1) utilization of hearts from DCD donors; 2) optimization of LVAD use, indications and outcomes; 3) intriguing insights into the use of mTOR inhibitors; 4) novel approaches to monitor for rejection and digging into the AMR conundrum.

A still heart, resuscitated, warm perfused, reconditioned, and successfully transplanted. The breathtaking reports from Sidney and Cambridge discussed in a pre-meeting symposium and in a concurrent session, presented two different techniques, both based on the cardiac organ care system (OCS), allowing successful heart transplants from DCD donors. The phases of minimization of organ damage during withdrawal, organ preservation and assessment of heart function before implantation were presented and discussed, as well as related ethical issues and ex vivo assessment of their function. This is probably the foremost important novelty showed at the meeting in the heart transplantation field. Despite the rise of the machines to mechanically assist circulation is epidemiologically overcoming transplantation, Peter MacDonald and Steven Tsui groups brought us back to a crucial task of our mission of taking care of patients with severely failing heart: improve organ utilization and quality of donors. Their techniques not only allows safe utilization of organs from a rising category of donors, those with circulatory death, but also shed light on the need to improve in everyday practice the under-use of many organs from brain dead donors. If a still heart may resuscitate and work in a severely ill heart failure patient, couldn't we recover and use some of the many beating hearts currently feared too risky to be taken?

Besides the annual INTERMACS registry report, showing constant improvement of outcomes in patients bridged to transplant, but also treated with a LVAD as destination therapy, several studies have reported novel insights regarding the use, indications, management and results of LVAD therapy. A study from Grimm et al, it appeared that bridge to transplant with a VAD > 1 year doesn't confer an increased risk of mortality. One of the most relevant news is ENDURANCE trial, a non-inferiority prospective randomized study comparing safety and efficacy of HVAD pump vs Heartmate-II pump (2:1 randomization) among 447 patients within NYHA IIIb and IV ineligible for transplantation. The primary endpoint was disabling stroke-free survival (Modified Rankin Score ?4) at two years, defined as alive on the originally-implanted device, transplanted or explanted due to patient recovery. HVAD system achieved the non-inferiority endpoint, showing a higher rate of strokes but a lower rate of device malfunctions requiring exchange or transplant compared to Heartmate-II. HVAD system appeared to improve quality of life and 6-minutes walking test; sintering of the inflow cannula in HVAD resulted in a marked reduction in pump thrombosis, comparable to the one of Heartmate-II; multivariate analysis confirmed the previously-observed link between neurological events and mean arterial pressure, as elevated blood pressure was the strongest predictor of neurologic events. Thus, the results of a second destination therapy cohort, designed to confirm observations from ENDURANCE, that sites adhering to more regular monitoring and management of patient blood pressure witnessed a notably lower incidence of neurological events, are waited. Results from a subgroup analysis of REVOLVE registry confirmed the excellent outcomes on the HVAD device at 2 years. A study from Maltais et al showed a comparable neurological risk between the HMII and the HVAD devices in a contemporary cohort of patients bridged to transplantation, remaining advanced age the primary determinant of neurological events.

The issue of the comparison between medical therapy and LVAD implantation in ambulatory patients with advanced heart failure not inotropic dependent was investigated for the first time in the multicenter non randomized ROADMAP study, assessing the effect of Heartmate-II pump compared to optimal medical management; the results indicated that the HeartMate II enhanced long-term outcomes (1-year survival 80% vs 64%)Regarding myocardial recovery, RESTAGE-HF study, a prospective multicenter trial on myocardial recovery in LVAD patients suggested that a standardized regime of optimal pharmacological therapy combined with LVAD unloading and regular testing of underlying myocardial function may result in a higher rate of explantation and remission from Stage D heart failure.

A specific focus on the importance of renal issues has been made throughout LVAD or transplant candidates and transplanted patients. In particular, some contributions showed the importance of a careful assessment of renal function prior to LVAD implantation, including albuminuria detection, as a possible risk factor for subsequent right ventricular failure. The difficult interplay between heart and kidney function has been the topic of a Wednesday's concurrent symposium, focused on the role played by venous congestion in determining renal failure and in contributing to the worsening of heart insufficiency, and in concurrent sessions, reporting renal sparing strategies by minimization or avoidance of calcineurin inhibitors in heart transplanted patients by the SCHEDULE and MANDELA trials.

The three years outcomes of the SCHEDULE study have been reported in several abstracts dealing with primary and secondary endpoints. This study compared an immunosuppressive strategy based everolimus and MMF with cyclosporine withdrawal at month 1-2 after heart transplant with a standard MMF-CyA arm. The three years results confirmed maintenance of the good kidney function data achieved at year 1 in the CyA free arm, despite some cross-overs mainly related to the increased number of biopsy detected cellular rejections. In addition, patients in the everolimus-MMF arm showed less CAV progression at three years as compared to the control arm. Similar outcomes were reported in the German MANDELA trial, in which two everolimus arms were compared: one with complete CNI withdrawal at month 3 after transplant, the other with CNI (either TAC or CyA) minimization. The primary endpoint was renal function at one year. The novelty of this study was the association in de novo heart recipients of everolimus with TAC. Similarly to SCHEDULE the CNI-free regimen was associated with better renal function but more cellular rejection.

Antibody mediated rejection and non-invasive diagnosis of rejection were the two other main transplant topics at the meeting. Unfortunately, except for further confirmatory data about the prognostic and diagnostic role of donor-specific antibodies, and of the pAMR grading, no big news on evidences on treatments efficacy and safety were available. As stated in the pre-meeting symposium on B-cells, AMR still seems a big elephant examined by many blind researchers, all telling the truth, but none of them really aware of the big picture behind.

On the other hand, promising results on the side of non-invasive diagnosis for rejection have been brought by the CARGO II study investigators presenting several retrospective analyses on donor-derived cell-free DNA. This biomarker appears to identify biopsy-proven rejection with good accuracy, when used alone, and with excellent predictive ability when combined with the allomap scores. Despite limitations due to retrospective design and lack of prognostic correlation, this approach suggest a roadmap to identify an optimal approach for non-invasive diagnosis of rejection: the combination of immune-monitoring with a sensitive and specific marker for graft damage may lead to significant improvement of post-transplant management and reduction of unnecessary invasive procedures.

It has overall been a very exciting meeting, cutting edge, and also a meeting in which the changing of the era in the spirit and composition of our society was clearly touchable. New challenges are upcoming, as well as new excitement. The machine for the next meeting is already moving. See you in Washington and remember to submit your proposals for symposia!! ■

Disclosure Statement: The authors have no conflicts of interest to disclose.

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