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Heart Transplantation in 2019 Old and New Frontiers
Is Heart Transplant still the Gold standard?
Dr. Victor Pretorius
Associate Clinical Professor of Surgery
Surgical Director of the Heart Transplant and Circulatory Support Program
UCSD
Cape Town RSA Groote Schuur Hospital OT – 50 years ago
Life defining moment: Christiaan Barnard and the first human heart transplant
Donor Co-location
RSA Laws
• Law simply stated that the patient was dead when declared dead by a physician
The Heroes
Early transplants
Early Survival
Cardiac Allograft Survival in Primates
treated with Cyclosporin-A
Jamieson SW, Burton NA, Oyer PE, Reitz BA, Stinson
EB, Shumway NE.
Lancet 1979, 1:545
CNI – Cyclosporin-A
Fungus Talyplocladium inflatum
Dr Stuart Jamieson
First primates to receive cyclosporin
after heart transplantation - 1978
Immunosuppression
• Clinical trials have been paramount to the success of heart transplantation
• No single validated immunosuppression regimen
• Immunosuppression should be individualized
• Fine balance between the numerous risks of life long immunosuppression and the risk of rejection
• As new agents are discovered, clinical trials will continue to guide clinicians and benefit patients
DSA and Survival in Transplantation (kidney data)
• Accommodation is the absence of AMR and continued function of a graft, despite the presence of anti-donor antibodies in the circulation.
• The difference between accommodation and antibody mediated rejection appears to be the level of complement activation.
Accommodation
Adapted from Jignesh Patel’s presentation on the DUET cardiac trial.
Disrupting the Complement Cascade
• Eculizumab is a humanized monoclonal antibody that binds to and subsequently prevents activation of complement component C5 by the amplified C3 convertase molecules.
• Eculizumab is approved by the USA Food and Drug X Administration for treating paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (HUS).
Mechanism of Eculizumab
• Eculizumab Protocol:
• Meningococcal vaccine ≥ 2 weeks prior to transplant or gram negative antibiotic prophylaxis
• Methylprednisolone IV, Anti-thymocyte globulin (ATG) 1.5 mg/kg x 5 days followed by IVIG 1 gm/kg x 2 days
• Eculizumab
• Day 0: 1200 mg
• Day 1,7,14,21: 900 mg
• Day 28,42,56: 1200 mg
• Chronic Immunosuppression: tacrolimus, mycophenolate, prednisone
DUET Protocol
Adapted from Jignesh Patel’s presentation on the DUET cardiac trial.
S K: Former Professional Soccer Player 35 years Post Heart Transplant
50 YO male with h/o fulminant myocarditis s/p transplant ~ 35 years ago Multiple admissions with refractory ascites, worsening renal function, hypotension, failure to thrive, cachexia Listed for heart-kidney transplant due to end-stage CAV and ESRD Underwent 2 attempts of desensitization due to high PRA Attempts to de-sensitize patient with plasmapheresis, IVIG, and bortezomib were unsuccessful
• 12/10/18 PRA 97%
• 1/2/19 PRA 97%
• 1/22/19 97%
• 2/14/19 99% (dilute 97%)
• 3/4/19 98% (dilute 97%)
Prospective flow cytometry crossmatch revealed positive B-cell but negative T-cell (majority of HLA anti-bodies were class II). The patient proceeded to heart-kidney transplant using the DUET protocol.
HLA/Crossmatch Report
Normal graft function and hemodynamics; + DSA 1 month after transplant that cleared
thereafter; no episodes of rejection at 3 months.
Indications and Contra indications to Heart transplant
ORGAN
Transplants
Reported from
7/1/14 through
6/30/2015
Total
Transplants
Reported
through
6/30/2015
Heart 4,334 126,905
Heart-
Lung 48 4,614
Lung 3,651 58,043
ISHLT 2016 Total Transplants
190,000
J Heart Lung Transplant 2016;35: 1149-1205
European Journal of Cardio-Thoracic Surgery, Volume 55, Issue Supplement_1, June 2019, Pages i38–i48, https://doi.org/10.1093/ejcts/ezz107
The content of this slide may be subject to copyright: please see the slide notes for details.
Figure 3: Kaplan–Meier survival in adult heart transplant recipients
by era (transplants: January 1982–June 2015). ...
Adult Heart Transplants by Diagnosis
MCS Bridge to Transplant - April 1969
Generations of VADs
Old vs. New
35
European Journal of Cardio-Thoracic Surgery, Volume 55, Issue Supplement_1, June 2019, Pages i38–i48, https://doi.org/10.1093/ejcts/ezz107
Parametric survival curve and associated hazard function with 70%
confidence limit for survival after durable MCS
European Journal of Cardio-Thoracic Surgery, Volume 55, Issue Supplement_1, June 2019, Pages i38–i48, https://doi.org/10.1093/ejcts/ezz107
Figure 4: Survival rates in trials and registry reports of heart
transplantation and chronic mechanical circulatory ...
Estimated 3-year Overall Survival by Advanced HF Therapy Strategy
0.8949
0.7046
0.2292
• “Cost effectiveness” • Freedom from First Readmission at 1 year by Advanced HF Therapy Strategy
0.42
0.15 0.13
Percentage of days spent in hospital by HF strategy
Adult Heart Transplants: Bridged with MCS
European Journal of Cardio-Thoracic Surgery, Volume 55, Issue Supplement_1, June 2019, Pages i38–i48, https://doi.org/10.1093/ejcts/ezz107
Adult and pediatric heart transplants according to median
donor age by location and year.
Comparing a Heart transplant to a VAD
Organ Donation by Country
India No registry (NGO) 0.08
Reused Heart
Longest implant to donation time of a reused heart allograft of 31 days.
Durand et al. Ann Intern Med. 2018
High Prevalence of HCV Infection among Overdose-Death Donors
Overdose-death donors
Trauma-death donors
Medical-death donors
Only 5% HCV-Viremic Donor Hearts Used for Transplant
Moayedi et al. Circ Heart Fail. 2018
HCV virus
from
HCV+ donor
HCV- recipient
Gasink et al. JAMA. 2006.
McHutchison et al. N Engl J Med. 2009.
Haji et al. J Heart Lung Transplant. 2004.
• Substantial risk of transmission to the recipients
• Low cure rates and poor tolerability with
interferon-based HCV treatment
• Suboptimal post-transplant outcomes
Direct acting antiviral (DAA)
therapy
NEW HCV TREATMENT:
NS5A + Protease inhibitors Elbasivir/grazoprevir
NS5A + NS5B polymerase Ledipasvir/sofosbuvir
inhibitors
Götte et al. Nat Rev Gastroenterol Hepatol. 2016.
Cure rate up to 100%
Examples: Combinations:
51
4/27/2017
First transplant using
HCV-viremic donor
organs
Listing Period 1 Listing Period 2
(4/27/2017 to 10/26/2018) (10/27/2015 to 4/26/2017)
18 months before 18 months after
Study Design
0
50
100
150
200
250
300
Tra
nsp
lan
t R
ate
pe
r 1
00
Pa
tie
nt-
Ye
ars
Period 1 Period 2
Adjusted for the following confounders: - Age at listing
- Gender
- BMI
- Blood groups
- UNOS status at listing
- Pre-transplant labs: Total bilirubin,
albumin
- Pre-transplant studies: LVEF, CVP,
PCWP
- Pre-transplant supports: Inotrope
infusion, IABP, ECMO
168.2
280.0
Transplant Rate by Listing Period
P < 0.01
Our Experience with Post-Transplant HCV Treatment Using DAAs
No. of candidates received
HCV-viremic donor hearts
n=19 (n=16 isolated HTx, n=3 combined
heart + kidney transplant)
Transmission of HCV n=19 (100%)
No. of recipients completed
12-week course of DAA therapy
n=18 (100%)
SVR12 n=18 (100% Cured)
Mortality n=1 (5%)
*Undetectable viral load prior to death
SVR12 = Sustained viral response at 12 weeks after end of DAA therapy
Post-Transplant Outcomes Did Not Differ Significantly Between the 2 Periods
Period 1 (n=71) Median(range)/No. (%)
Period 1 (n=85) Median(range)/No. (%)
p value
Follow-up duration (years) 1.7 (1.3—2.2) 0.5 (0.3—0.8) --
Hospital stay post-transplant
(days)
18.0 (15.0—28.0) 16.0 (14.0—27.0) 0.121
Mortality at 90 days 0 (0) 0 (0) --
Mortality at 1 year 2 (3.8) 0 (0) 1.000
≥2R rejection at 90 days 2 (3.5) 0 (0) 0.497
CAV at 1 year 24 (66.7) 2 (40.0) 0.336
CAV = Cardiac allograft vasculopathy
New Frontier – Adult Congenital
Survival by Diagnosis
Indications for Heart Transplantation for Adult Congenital Heart Disease
• Stage D heart failure refractory to medical therapy, with no expected benefit from surgery or catheter-based intervention
• Low cardiac output state with progressive end-organ dysfunction
• Near sudden death or life-threatening arrhythmias
• Stage C heart failure with reactive pulmonary hypertension, at risk of developing irreversible fixed pulmonary vascular resistance
• Fontan patients with protein losing enteropathy and/or plastic bronchitis
• Progressive cyanosis causing decline in functional capacity
Combined Organ transplants
New Frontier – “Marginal” Hearts for “Marginal” Recipients
”New” Frontier - Immunology
• Regulatory T cells (CD4+) discovered in 2003 • Suppressing an alloresponse
• Tolerance • ABO incompatible pediatric transplantation
• Xenotransplantation • Pig heart survived over 2.5 years in Baboon with excellent echocardiographic
function and no histologic evidence of graft injury or CAV • Mohiuddin MM et al ,SinghAK, CorcoranPC, etal. Chimeric 2C10R4 anti-CD40 antibody therapy is
critical for long-term survival of GTKO. hCD46. hTBM pig-to-primate cardiac xenograft. NatCommun 2016;79. 7:11138
Current Trends at UCSD
30%
40%
50%
60%
70%
80%
90%
100%
0
10
20
30
40
50
60
2011 2012 2013 2014 2015 2016 2017 2018 2019 ytd
UCSD HEART TRANSPLANT 2011-2019
Number of Transplants 1 Year Survival (Percentage)
72
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