Summary
Background
Heart transplantation is the gold-standard treatment for end-stage heart failure. However, the shortage of grafts has led to longer waiting times and increased mortality for candidates without priority.
Aims
To study waiting-list and post-transplant mortality, and their risk factors among patients registered for heart transplantation without initial high emergency procedure.
Methods
All patients registered on the heart transplantation waiting list (2004–2015) without initial high emergency procedure were included. Clinical, biological, echocardiographic and haemodynamic data were collected. Waiting list and 1-year post-transplant survival were analysed with a Kaplan-Meier model.
Results
Of 221 patients enrolled, 168 (76.0%) were men. Mean age was 50.0 ± 12.0 years. Forty-seven patients died on the waiting list, resulting in mortality rates of 11.2 ± 2.7% at 1 year, 31.9 ± 5.4% at 2 years and 49.4 ± 7.1% at 3 years. Median survival was 36.0 ± 4.6 months. In the multivariable analysis, left ventricular ejection fraction < 30% (hazard ratio [HR]: 3.76, 95% confidence interval [CI]: 1.38–10.24; P = 0.010) and severe right ventricular systolic dysfunction (HR: 2.89, 95% CI: 1.41–5.92; P = 0.004) were associated with increased waiting-list mortality. The post-transplant survival rate was 73.1 ± 4.4% at 1 year. Pretransplant severe right ventricular dysfunction and age > 50 years were strong predictors of death after transplantation (HR: 5.38, 95% CI: 1.38–10.24 [ P = 0.020] and HR: 6.16, 95% CI: 1.62–9.32 [ P = 0.0130], respectively).
Conclusions
Mortality among candidates for heart transplantation remains high. Patients at highest risk of waiting-list mortality have to be promoted, but without compromising post-transplant outcomes. For this reason, candidates with severe right ventricular dysfunction are of concern, because, for them, transplantation is hazardous.
Résumé
Contexte
La transplantation cardiaque est le traitement de référence de l’insuffisance cardiaque terminale. La pénurie de greffons entraîne des délais d’attente trop longs et une surmortalité des candidats non prioritaires.
Objectifs
Étudier le pronostic sur liste et en post-transplantation des candidats sans priorité initiale.
Méthodes
De 2004 à 2015, tous les patients inscrits sur liste d’attente sans priorité initiale ont été inclus. Les caractéristiques cliniques, biologiques, échographiques et hémodynamiques ont été recueillies. Nous avons analysé la survie sur liste par la méthode de Kaplan-Meier.
Résultats
Un total de 221 patients ont été étudiés. On retrouvait une majorité d’hommes ( n = 168, 76,0 %). L’âge moyen était de 50,0 ± 12,0 ans. Quarante-sept patients sont décédés sur liste d’attente, soit une mortalité de 11,2 ± 2,7 % à 1 an, 31,9 ± 5,4 % à 2 ans et 49,4 ± 7,1 % à 3 ans. La médiane de survie était de 36,0 ± 4,6 mois. En analyse multivariée, une fraction d’éjection ventriculaire gauche < 30 % (3,76, IC 95 % : 1,38–10,24 ; p = 0,010) et une dysfonction ventriculaire droite sévère (2,89, IC 95 % : 1,41–5,92 ; p = 0,004) étaient indépendamment associés à une surmortalité. La survie post-transplantation était de 73,1 ± 4,4 % à un an. Une dysfonction ventriculaire droite sévère en pré-transplantation (5,38, IC 95 % : 1,38–10,24 ; p = 0,020) et un âge > 50 ans (6,16, IC 95 % : 1,62–9,32 ; p = 0,0130) étaient des facteurs prédictifs de décès post-greffe.
Conclusions
La mortalité sur liste d’attente transplantation cardiaque demeure élevée. Les candidats les plus à risque de décès sur liste doivent être favorisés sans compromettre leur survie post-transplantation. Les patients avec dysfonction ventriculaire droite sévère ne semblent pas tirer de bénéfice de la transplantation.
Background
Heart failure is the third major cause of cardiovascular death, after ischaemic stroke and myocardial infarction . In France, 2.3% of the population have heart failure, leading to more than 20,000 deaths each year . The prognosis is worse for patients with end-stage heart failure, refractory to optimal medical and instrumental therapy . In this case, the gold-standard treatment is cardiac transplantation , which significantly improves survival and quality of life . Since the first cardiac transplant, performed in South Africa in 1967 by Christiaan Barnard, 11,837 grafts have been realised in France. However, the number of transplants has failed to progress since the early 2000s because, whereas the number of candidates is increasing, the number of donors remains limited. In 2013, 410 transplantations were performed in France, whereas 870 patients were registered on the waiting list, resulting in one potential graft for every 2.1 candidates. This shortage is compounded by the success of road safety awareness programmes, and by the frequent opposition to donation by donors’ families, reducing the pool of potential grafts. The main consequence of this graft shortage is an increase in time on the waiting list, leading to a deterioration in the haemodynamic status of candidates, compromising pre- and post-transplant outcomes .
New strategies have emerged in France to resolve this concerning phenomenon. In 2004, a temporary national priority procedure, called “High Emergency 1” (HE1), was added to our graft allocation system, to improve access to transplantation for highly unstable candidates (except those presenting renal failure, with creatinine clearance < 40 mL/min) . HE1 may be required initially (i.e. concomitant to registration on the list) or during follow-up, for a previously registered candidate. These two situations concern very different patients: initial HE1 mainly concerns patients with acute heart failure without a history of heart disease, whereas non-initial HE1 concerns patients with chronic end-stage heart failure, with a worsening clinical status, on the waiting list. Initial HE1 is used increasingly, and has created a skewed effect, favouring graft allocation for unstable hospitalised patients at the expense of ambulatory candidates . As suggested by Leprince, “the decision to transplant a patient with an HE1 will impact not only the patient concerned, but also the waiting time of the other patients on the list, independently of allocation rules”.
In this context, the aim of our study was to analyse heart transplantation waiting-list mortality and post-transplant outcomes among patients registered without initial HE1 procedure, in order to improve our graft allocation strategy.
Methods
Study population
We performed a retrospective single-centre study. From January 2004 to May 2015, all patients aged > 18 years registered on our heart transplantation waiting list were included, including retransplantations and combined transplantations. Each patient underwent complete clinical, biological, echocardiographic and haemodynamic evaluation to determine status, and to search for any contraindications to transplantation.
The indications and contraindications for heart transplantation were consistent with current international guidelines . January 2004 marks the time when the HE1 procedure was put into use. Patients who had benefited from an initial HE1 procedure (i.e. < 8 days after registration) were excluded. Patients who were delisted for clinical improvement or deterioration were excluded from the survival analysis.
Data collected
Age, sex, body mass index, aetiology of cardiac disease, history of cardiac surgery, diabetes, peripheral artery disease, prophylactic defibrillator, beta-blockers, New York Heart Association status, Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) status, blood group, sensitisation (human leukocyte antigen [HLA] antibodies), creatinine, total bilirubin, B-type natriuretic peptide (BNP), left ventricular ejection fraction (LVEF), maximal oxygen consumption (VO 2max ) and results of right catheterisation were collected at the time of registration with the “Cristal registry” of the French Biomedicine Agency, and from medical records.
Right ventricular function was assessed using echocardiographic data, when available, such as tricuspid annular plane systolic excursion (TAPSE), S wave in tissular Doppler imaging and right ventricular (RV) diameters. However, as it was performed routinely, we considered subjective visual evaluation of RV systolic function as the most relevant variable for defining severe dysfunction .
Outcome
The primary outcome was mortality while on the heart transplantation waiting list. Secondary outcomes were related to candidate outcome on the waiting list (such as rehospitalisation for congestive heart failure, HE1 procedure > 8 days after registration, implantation of venoarterial extracorporeal membrane oxygenation [ECMO], implantation of a left ventricular assist device [LVAD], delisting because of clinical improvement/deterioration and transplantation) and 1-year post-transplant mortality when patients had been transplanted.
Statistical analysis
Categorical variables are presented as number (%). Quantitative variables are presented as mean ± standard deviation. A survival analysis was conducted to study outcome after registration on the list. For overall mortality, the event assessed was combined all-cause death, and patients were censored at the date of their last follow-up, receipt of transplantation or delisting. The log-rank test was used to compare survival curves. After the univariate analysis was performed, the multiple Cox regression model was used to study the factors independently associated with mortality. A backward stepwise approach, based on the log-likelihood ratio test (threshold for retention: P < 0.05), was used to select the variables from those that were significant in the univariate analysis. All analyses were performed using SPSS Statistics 20.0 software (IBM Corp., Armonk, NY, USA). A degree of significance < 0.05 was considered statistically significant.
Results
Baseline characteristics
From January 2004 to May 2015, 283 patients were registered on the heart transplantation waiting list of La Timone Hospital in Marseille. Sixty-two patients registered in the initial HE1 procedure were excluded. Our analysis is based on data from 221 patients ( Fig. 1 ).
Table 1 summarizes the main characteristics of these 221 patients at the time of registration on the waiting list. The majority were men ( n = 168, 76.0%), 113 of whom had blood group A ( n = 113, 51.1%), and the mean age was 50.0 ± 12.0 years. Fifty (22.6%) patients had at least one anti-HLA antibody, and four (1.8%) were highly sensitised. Five (2.3%) patients were waiting for a multiorgan transplant: heart-kidney ( n = 2); heart-lung ( n = 2); heart-liver ( n = 1). The mean INTERMACS score was 5.3 ± 0.9. The mean LVEF was 26.0 ± 11.6%; 59 (26.7%) patients had an LVEF ≥ 30%. Forty-seven (23.1%) patients had severe RV systolic dysfunction. Severe RV dysfunction was significantly associated with higher total bilirubin concentration (26.4 ± 12.9 vs 19.5 ± 12.8 μmol/L; P = 0.006), higher pulmonary arterial resistance (3.8 ± 6.6 vs 2.3 ± 1.3 UW; P = 0.03), higher right atrial pressure (18.3 ± 3.3 vs 9.6 ± 5.5 mmHg; P = 0.001) and lower VO 2max (11.7 ± 2.9 vs 13.8 ± 4.2 mL/kg/min; P = 0.04). Mean waiting time on list was also higher in patients with severe RV dysfunction (10.9 ± 7.4 vs 9.2 ± 8.5; P = 0.43), without reaching the threshold of significance.
| Overall population ( n = 221) | No severe RV dysfunction ( n = 174) | Severe RV dysfunction ( n = 47) | P | |
|---|---|---|---|---|
| Age (years) | 50.0 ± 12.0 | 49.1 ± 13.6 | 50.4 ± 9.9 | 0.49 |
| Men | 168 (76.0) | 135 (77.6) | 33 (70.2) | |
| Cardiac disease | ||||
| Ischaemic | 85 (38.5) | 74 (42.5) | 11 (23.4) | |
| Other | 136 (61.5) | 100 (57.5) | 36 (76.6) | |
| Previous cardiac surgery | 73 (33.0) | 53 (30.5) | 20 (42.6) | |
| Diabetes | 27 (12.2) | 21 (12.1) | 6 (12.8) | |
| Peripheral artery disease | 14 (6.3) | 12 (6.9) | 2 (4.3) | |
| Defibrillator implanted | 140 (63.3) | 111 (63.8) | 29 (61.7) | |
| Beta-blocker therapy | 105 (47.5) | 82 (47.1) | 23 (48.9) | |
| NYHA class | ||||
| I or II | 10 (4.5) | 9 (5.2) | 1 (2.1) | |
| III or IV | 208 (94.1) | 162 (93.1) | 46 (97.9) | |
| INTERMACS score | ||||
| 3 | 12 (5.4) | 8 (4.6) | 4 (8.5) | |
| 4 | 31 (14.0) | 24 (13.8) | 7 (14.9) | |
| 5 | 69 (31.2) | 50 (28.7) | 19 (40.4) | |
| 6 | 102 (46.1) | 86 (49.4) | 16 (34.0) | |
| 7 | 7 (3.2) | 6 (3.4) | 1 (2.1) | |
| Creatinine concentration (μmol/L) | 115.0 ± 43.8 | 110.8 ± 37.5 | 123.9 ± 51.6 | 0.14 |
| Total bilirubin (μmol/L) | 21.0 ± 12.5 | 19.5 ± 12.8 | 26.4 ± 12.9 | 0.006 |
| BNP (ng/L) | 867.0 ± 1311.0 | 836.8 ± 1495.1 | 902.7 ± 1107.7 | 0.8 |
| Hyperimmunization | 4 (1.8) | 2 (1.1) | 2 (4.3) | |
| LVEF (%) | 26.0 ± 11.6 | 26.5 ± 10.8 | 33.0 ± 13.2 | 0.94 |
| LVEDD (mm) | 64.5 ± 16.3 | 64.6 ± 15.0 | 64.1 ± 15.0 | |
| sPAP (mmHg) | 47 ± 15 | 47.3 ± 15.1 | 45.3 ± 15.1 | |
| Right heart catheterisation | ||||
| PAR (UW) | 2.7 ± 3.4 | 2.3 ± 1.3 | 3.8 ± 6.6 | 0.03 |
| mPAP (mmHg) | 33.0 ± 10.3 | 32.8 ± 10.0 | 33.5 ± 10.6 | 0.25 |
| RAP (mmHg) | 11.9 ± 6.4 | 9.6 ± 5.5 | 18.3 ± 3.3 | 0.001 |
| VO 2max (mL/kg/min) | 13.3 ± 3.7 | 13.8 ± 4.2 | 11.7 ± 2.9 | 0.04 |
| Waiting time on list (months) | 9.2 ± 8.5 | 10.9 ± 7.4 | 0.43 |
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