Summary
Background
The relationship between pulmonary arterial hypertension-specific drug therapy (PAH-SDT) and mortality in Eisenmenger syndrome (ES) is controversial.
Aims
To investigate outcomes in patients with ES, and their relationship with PAH-SDT.
Methods
Retrospective, observational, nationwide, multicentre cohort study.
Results
We included 340 patients with ES: genetic syndrome ( n = 119; 35.3%); pretricuspid defect ( n = 75; 22.1%). Overall, 276 (81.2%) patients received PAH-SDT: monotherapy (endothelin receptor antagonist [ERA] or phosphodiesterase 5 inhibitor [PDE5I]) 46.7%; dual therapy (ERA + PDE5I) 40.9%; triple therapy (ERA + PDE5I + prostanoid) 9.1%. Median PAH-SDT duration was 5.5 years [3.0–9.1 years]. Events (death, lung or heart-lung transplantation) occurred in 95 (27.9%) patients at a median age of 40.5 years [29.4–47.6]. The cumulative occurrence of events was 16.7% [95% confidence interval 12.8–21.6%] and 46.4% [95% confidence interval 38.2–55.4%] at age 40 and 60 years, respectively. With age at evaluation or time since PAH diagnosis as time scales, cumulative occurrence of events was lower in patients taking one or two PAH-SDTs ( P = 0.0001 and P = 0.004, respectively), with the largest differences in the post-tricuspid defect subgroup ( P < 0.001 and P < 0.02, respectively) versus patients without PAH-SDT. By multivariable Cox analysis, with time since PAH diagnosis as time scale, New York Heart Association/World Health Organization functional class III/IV, lower peripheral arterial oxygen saturation and pretricuspid defect were associated with a higher risk of events ( P = 0.002, P = 0.01 and P = 0.04, respectively), and one or two PAH-SDTs with a lower risk of events ( P = 0.009).
Conclusions
Outcomes are poor in ES, but seem better with PAH-SDT. ES with pretricuspid defects has worse outcomes despite the delayed disease onset.
Résumé
Contexte
L’intérêt du traitement médical spécifique (TMS) de l’hypertension artérielle pulmonaire (HTAP) dans le syndrome d’Eisenmenger (SE) est controversé.
Objectifs
Étudier le pronostic à long terme des patients ayant un SE et la relation avec le TMS.
Méthodes
Une cohorte observationnelle longitudinale multicentrique rétrospective historique française de 340 SE a été constituée.
Résultats
Le shunt était prétricuspide dans 75 cas (22,1 %). Au total, 276 (81,2 %) patients étaient sous TMS (monothérapie 46,7 % ; bi-thérapie 40,9 % ; tri-thérapie 9,1 %). La durée médiane de TMS était de 5,5 ans [3,0–9,1]. Un événement clinique majeur (ECM : décès, transplantation cardiopulmonaire ou bipulmonaire) a été observé dans 95 (27,9 %) cas à un âge médian de 40,5 [29,4–47,6] ans. La survenue cumulée d’un ECM était de 16,7 % [IC 95 % 12,8–21,6 %] et 46,4 % [IC 95 % 38,2–55,4 %] à l’âge de 40 et 60 ans. Avec l’âge ou le délai depuis le premier examen comme échelle temporelle, la survenue cumulée des ECM était moindre chez les patients sous un ou deux TMS ( p = 0,0001 et p = 0,004), en particulier chez les patients avec un shunt post-tricuspide ( p < 0,001 et p < 0,02) comparée aux patients sans TMS. Une analyse multivariée de Cox avec le délai depuis le diagnostic de l’HTAP comme échelle temporelle a montré qu’une classe fonctionnelle III ou IV de la NYHA/WHO, une saturation périphérique en oxygène basse (en variable continue), un shunt pré-tricuspide et l’absence de TMS étaient associés à un risque augmenté d’ECM ( p = 0,002 ; p = 0,01 ; p = 0,04 and p = 0,009, respectivement).
Conclusions
Le TMS dans le SE semble associé à un meilleur pronostic. Néanmoins, même avec un traitement médical palliatif, le pronostic du SE reste altéré. Les patients avec un shunt prétricuspide ont un profil clinique et un pronostic plus sombre malgré une survenue plus tardive de l’HTAP.
Background
Eisenmenger syndrome (ES) develops when pulmonary arterial hypertension (PAH) caused by an unrepaired congenital left-to-right shunt becomes sufficiently severe to reverse the direction of the shunt, resulting in cyanosis . ES is present in 3.5–12.0% of adults with congenital heart disease (CHD) .
PAH-specific drug therapies (PAH-SDTs) are mainly designed to induce vasodilation and diminish pulmonary microvascular remodelling . Moderate beneficial effects of PAH-SDTs on New York Heart Association/World Health Organization functional class (NYHA/WHO FC) have been reported in patients with ES . The PAH-SDT bosentan, a dual endothelin receptor antagonist (ERA), is approved in Europe for patients who are NYHA/WHO FC III or IV . Evidence supporting the use of other PAH-SDTs in ES is scanter . Indeed, survival is better in ES than in idiopathic PAH, and the long-term effects of PAH-SDTs on hard outcomes, such as death and lung transplantation, remain unclear .
We conducted a large, multicentre, retrospective, cohort study of patients with ES to assess the relationships linking PAH-SDT to death and lung transplantation.
Methods
This retrospective, longitudinal, cohort study included all patients with ES followed in French tertiary care centres (university hospitals, the M3C Network for Complex CHD, the French Community of CHD Specialists [filiale de cardiologie pédiatrique et congénitale de la Société française de cardiologie] and the French referral centre for severe pulmonary hypertension). This study was compliant with the requirements of the Commission nationale de l’informatique et des libertés, and all patients provided informed consent to participate .
ES was defined as PAH (as demonstrated by right-heart catheterization, showing a mean pulmonary pressure of ≥ 25 mmHg, a normal pulmonary capillary wedge pressure of ≤ 15 mmHg and pulmonary vascular resistance > 3 Wood units) in the presence of a large, non-restrictive, intracardiac or extracardiac shunt, according to the Nice classification . Patients with other patterns of PAH associated with CHD were not included: PAH with coincidental small cardiac defect or patent foramen ovale, or correctable or non-correctable prevalent systemic-to-pulmonary shunt; patients who had previously undergone corrective surgery or interventions and did not present with an unrestrictive residual shunt; patients with Glenn-type physiology; and those with segmental pulmonary hypertension (e.g. pulmonary atresia with ventricular septal defects). The diagnosis of CHD was based on echocardiography and/or cardiac catheterization findings.
For each patient, the following data were retrieved from the medical files: age; sex; cardiac and extracardiac diagnoses, including genetic syndromes; NYHA/WHO FC; resting peripheral arterial oxygen saturation (SaO 2 ), 6-minute walking test results; and medications (PAH-SDTs, heart-failure medications, oral anticoagulation and aspirin). For each patient on PAH-SDTs, we collected clinical data for three time points: PAH diagnosis; PAH-SDT initiation; and most recent evaluation. For each patient without PAH-SDT, there were only two data-collection time points: PAH diagnosis; and most recent evaluation. Data for the earliest time point were not collected when the PAH diagnosis data were unclear.
Follow-up data were obtained from the medical files and by telephone calls to patients, relatives, general practitioners and/or cardiologists. The following clinical events were recorded: heart failure; severe infection; arrhythmias; stroke; haemoptysis; other bleeding events; lung or heart-lung transplantation; and death. Selection for transplantation was based on an assessment of each individual patient during a multidisciplinary discussion that focused on functional class and right-heart-failure variables .
Statistical methods
Statistical analyses were performed using Stata ® 11.2 software (StataCorp, College Station, TX, USA). Data are described as mean ± standard deviation for normally distributed variables, median [interquartile range] for skewed continuous variables and number (%) for categorical variables. Categorical variables were compared with the χ 2 statistic or Fisher’s exact statistic. Comparisons of continuous variables were done with Student’s t test for independent samples, if its basic assumptions were satisfied (Shapiro-Wilks and Levene tests), and the Wilcoxon-Mann-Whitney U test otherwise. When continuous variables were distributed among more than two groups, the Kruskal-Wallis test was applied. Within-patient comparisons of continuous variables at different time points were made with the Wilcoxon matched-pairs signed-rank test. In patients taking PAH-SDT, changes in clinical variables from PAH-SDT initiation to the most recent evaluation were assessed, regardless of the number of drugs. Reported P- values are two-sided. P -values < 0.05 were considered statistically significant.
Kaplan–Meier curves of time to major clinical events (MCEs) (i.e. death, heart-lung transplantation and lung transplantation) were plotted using two different time scales: age at last follow-up, with the scale starting at 18 years, as the study was confined to adults; and years since PAH diagnosis. Differences between event-free times for each PAH-SDT and clinical data were assessed using the log-rank test. Patients with pretricuspid defects were divided into two groups according to age at PAH diagnosis. The cut-off value for age was determined by receiver operating characteristic curve analysis. Associations between baseline variables and outcomes were assessed in a Cox proportional hazards model with stepwise backward regression, including all variables associated with MCEs ( P ≤ 0.1) Proportionality of hazards was evaluated by applying a test for correlation between the scaled Schoenfeld residuals and the logarithmic transformation of time. A first model was built using clinical data at PAH diagnosis and age as the time scale. Defect location, PAH-SDT, CHD complexity, sex and genetic syndrome were forced into the model at the start of the regression process. A second model was built using clinical data at PAH diagnosis, and time since PAH diagnosis as the time scale. Defect location, PAH-SDT, CHD complexity, sex and genetic syndrome were also forced into the model at the start of the regression process.
Results
Study population
We included 340 patients at 20 French centres, six to 99 per centre (online-only Appendix 1 ). The percentage of patients taking PAH-SDT ranged across centres from 41.7% to 100.0%. Data at PAH diagnosis were available for 298 (87.6%) patients overall, 73 of 75 (97.3%) with pretricuspid shunt and 225 of 265 (84.9%) with post-tricuspid defects. Table 1 reports the demographic and clinical data in the overall population and in the two subgroups defined by defect location. A post-tricuspid defect (isolated or with another defect) was diagnosed in 265 (77.9%) patients. Fig. 1 reports the distribution of diagnoses. Ventricular septal defect predominated ( n = 102; 30.0%), followed by atrial septal defect ( n = 69; 20.3%), complete atrioventricular septal defect ( n = 66; 19.4%), patent ductus arteriosus ( n = 22; 6.5%), univentricular heart ( n = 16; 4.7%) and ventricular septal defect + patent ductus arteriosus ( n = 13; 3.8%). Other defects were less common.
| Total population | Pretricuspid shunt | Mixed or post-tricuspid shunt | P | |
|---|---|---|---|---|
| ( n = 340) | ( n = 75; 22.1%) | ( n = 265; 77.9%) | ||
| Female sex | 236 (69.4) | 63 (84.0) | 173 (65.3) | 0.002 |
| Genetic syndrome | 119 (35.0) | 2 (2.7) | 117 (44.2) | < 0.0001 |
| First exam (n = 299; 87.4%) | ||||
| Age (years) ( n = 299) | 26.5 [11.9–39.7] | 37.7 [26.7–52.4] | 20.6 [8.4–35.1] | < 0.0001 |
| SaO 2 (%) ( n = 185) | 85 [81–90] | 90 [84–93] | 85 [80–90] | 0.02 |
| 6-minute walking test (m) ( n = 68) | 348 [231–385] | 371 [276–461] | 331 [180–375] | 0.04 |
| NYHA/WHO FC ( n = 231) | 0.04 | |||
| 1 | 27 (11.7) | 4 (7.8) | 23 (12.8) | |
| 2 | 115 (49.8) | 19 (37.3) | 96 (53.3) | |
| 3 | 85 (36.8) | 26 (51.0) | 59 (32.8) | |
| 4 | 4 (1.7) | 2 (3.9) | 2 (1.1) | |
| Last exam (n = 327; 96.2%) | ||||
| Age (years) ( n = 327) | 41.7 [32.0–52.0] | 49.6 [40.0–60.2] | 40.0 [30.1–49.6] | < 0.0001 |
| SaO 2 (%) ( n = 275) | 85 [79–89] | 90 [82–92] | 84 [78–88] | < 0.0001 |
| 6-minute walking test (m) ( n = 166) | 358 [280–446] | 410 [330–483] | 342 [266–432] | 0.01 |
| NYHA/WHO FC ( n = 285) | 0.2 | |||
| 1 | 17 (6.0) | 3 (4.9) | 14 (6.3) | |
| 2 | 140 (49.1) | 25 (41.0) | 115 (51.3) | |
| 3 | 96 (33.7) | 22 (36.1) | 74 (33.0) | |
| 4 | 32 (11.2) | 11 (18.0) | 21 (9.4) | |
| PAH-SDT | 276 (81.2) | 69 (92.0) | 207 (78.1) | 0.007 |
| Single therapy | 129 (39.0) | 24 (32.4) | 105 (40.9) | < 0.0001 |
| Double therapy | 113 (34.1) | 30 (40.5) | 83 (32.3) | |
| Triple therapy | 25 (7.6) | 14 (18.9) | 11 (4.3) | |
| Complications | 194 (57.1) | 46 (61.3) | 148 (55.9) | 0.5 |
| Heart failure | 73 (21.5) | 23 (30.7) | 50 (18.9) | 0.03 |
Comparing the two defect-location subgroups showed a higher proportion of women in the pretricuspid group ( P = 0.002) and patients with genetic syndromes (chiefly Down syndrome, n = 111/117; 94.9%) in the post-tricuspid group ( P < 0.0001) ( Table 1 ). Median age at PAH diagnosis in the pretricuspid group was 37.7 years (range: 3.0–82.7 years). At PAH diagnosis, patients with pretricuspid defects were older ( P < 0.0001), had a higher resting SaO 2 ( P = 0.02) and 6-minute walking test distance ( P = 0.04), and a lower NYHA/WHO FC ( P = 0.04). At last evaluation, resting SaO 2 and 6-minute walking test distance remained higher in the pretricuspid group ( P < 0.0001 and P = 0.01, respectively), which had higher proportions of patients taking oral anticoagulation ( P < 0.0001) and PAH-SDT ( P = 0.007). PAH-SDT was more intensive in the pretricuspid than the post-tricuspid group; thus, 40.5% of patients with pretricuspid defects were taking two drugs, and 18.9% were taking three drugs ( P < 0.0001).
PAH-SDT
Table 2 reports the demographic and clinical data in PAH-SDT users and non-users at the last evaluation. Of the 340 patients, (81.2%), 276 took PAH-SDTs. The 64 non-users were younger and predominantly had post-tricuspid or combined defects. The proportion of PAH-SDT users was non-significantly lower in the group with genetic syndromes (76.5%; P = 0.1).
| PAH-SDT | No PAH-SDT | P | |
|---|---|---|---|
| ( n = 276; 81.2%) | ( n = 64; 18.8%) | ||
| Genetic syndrome | 91 (33.0 | 28 (43.8) | 0.07 |
| Pretricuspid shunt | 69 (25.0) | 6 (9.4) | 0.007 |
| First exam (n = 299, 87.4%) | |||
| Age (years) ( n = 299) | 27.8 [12.8–41.0] | 18.6 [7.2–29.7] | 0.02 |
| SaO 2 (%) ( n = 185) | 85 [81–90] | 86 [80–91] | 0.7 |
| 6-minute walking test (m) ( n = 68) | 350 [239–387] | 180 [150–372] | a |
| NYHA/WHO FC ( n = 231) | 0.6 | ||
| 1 | 21 (11.4) | 6 (12.8) | |
| 2 | 88 (47.8) | 27 (57.5) | |
| 3 | 71 (38.6) | 14 (29.8) | |
| 4 | 4 (2.2) | 0 (0.0) | |
| Exam before PAH-SDT initiation (n = 259; 93.8%) | |||
| Age (years) ( n = 259) | 36.7 [27.6–47.0] | ||
| SaO 2 (%) ( n = 196) | 84 [80–89] | ||
| 6-minute walking test (m) ( n = 142) | 330 [230–396] | ||
| NYHA/WHO FC ( n = 209) | |||
| 1 | 6 (2.9) | ||
| 2 | 72 (34.5) | ||
| 3 | 118 (56.5) | ||
| 4 | 13 (6.2) | ||
| Last exam (n = 327; 96.2%) | |||
| Age (years) ( n = 327) | 43.0 [33.0–52.3] | 38.4 [28.9–46.9] | 0.006 |
| SaO 2 (%) ( n = 275) | 85 [80–90] | 83 [74–88] | 0.2 |
| 6-minute walking test (m) ( n = 166) | 364 [285–450] | 315 [228–432] | 0.2 |
| NYHA/WHO FC ( n = 285) | 0.8 | ||
| 1 | 13 (5.6) | 4 (7.7) | |
| 2 | 117 (50.2) | 23 (44.3) | |
| 3 | 77 (33.0) | 19 (36.5) | |
| 4 | 26 (11.2) | 6 (11.5) | |
| Complications | 152 (55.1) | 42 (65.6) | 0.2 |
| Heart failure | 60 (21.7) | 13 (20.3) | 1.0 |
| Severe infectious syndrome | 21 (7.6) | 5 (7.8) | 1.0 |
| Arrhythmias | 43 (15.6) | 10 (15.6) | 1.0 |
| Haemoptysis | 32 (11.6) | 11 (17.2) | 0.2 |
| Stroke | 17 (6.2) | 0 (0.0) | 0.05 |
| Bleeding | 10 (3.6) | 3 (4.7) | 0.7 |
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