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