Summary
Background
Severe pulmonary hypertension is a usual contraindication to heart transplantation. A few studies have found that sildenafil has a favourable effect on haemodynamic variables in patients with severe left ventricular systolic dysfunction.
Aim
To report our clinical experience of sildenafil in patients with left ventricular systolic dysfunction and severe pulmonary hypertension.
Methods
All patients underwent echocardiography, radionuclide angiography, a cardiopulmonary exercise test and right heart catheterization before and after treatment with sildenafil. All patients were clinically stable and were receiving maximal tolerated doses of recommended drugs.
Results
We included 18 patients, with a mean ± standard deviation age of 47 ± 13 years. After a median of 8.7 months (interquartile range, 4.4–13.5 months) on sildenafil, there was a significant improvement in New York Heart Association classification ( P = 0.02) and mean right ventricular ejection fraction (from 26 ± 7% to 30 ± 9%; P = 0.008), with a decrease in the VE/VCO 2 slope (from 52 ± 11 to 44 ± 11; P = 0.009) and in pulmonary vascular resistance (from 5.3 ± 1.9 Wood units to 3.3 ± 1.8 Wood units; P = 0.01). During follow-up, three patients had urgent heart transplantation, two had non-urgent transplantation and six had left ventricular assist device implantation. All patients with pulmonary vascular resistance < 3 Wood units after sildenafil were alive, compared with four in the other subgroup (44% survival).
Conclusion
In patients with pulmonary hypertension related to left ventricular systolic dysfunction, sildenafil seems to improve cardiac haemodynamics.
Résumé
Contexte
La présence d’une hypertension pulmonaire sévère est une contre-indication habituelle à la transplantation cardiaque. Quelques études ont montré des effets hémodynamiques favorables du sildénafil chez des patients avec une dysfonction systolique sévère du ventricule gauche.
Objectif
De présenter notre expérience du sildénafil chez des patients présentant une dysfonction systolique du ventricule gauche et une hypertension pulmonaire sévère.
Méthodes
Tous les patients ont réalisé avant et après l’introduction de sildénafil une échographie cardiaque, une angiographie ventriculaire isotopique, une épreuve d’effort métabolique et un cathétérisme cardiaque droit. Tous les patients étaient cliniquement stables et tous recevaient un traitement recommandé, aux doses maximales tolérables.
Résultats
Nous avons inclus 18 patients avec une moyenne d’âge de 47 ± 13 ans. Après 8,72 mois (4,4–13,5) sous sildénafil, on a constaté une amélioration significative de la classification NYHA ( p = 0,02) et de la fraction d’éjection du ventricule droit (26 ± 7 % à 30 ± 9 % ; p = 0,008) avec une diminution de la pente de VE/VCO 2 (52 ± 11 à 44 ± 11 ; p = 0,009) et une diminution des résistances vasculaires pulmonaires (RVP) (5,3 ± 1,9 à 3,3 ± 1,8 unités Wood ; p = 0,01). Pendant le suivi, 3 patients ont pu bénéficier d’une transplantation en urgence, 2 d’une transplantation non urgente, 6 de l’implantation d’une assistance monoventriculaire gauche. Tous les patients avec des RVP < 3 unités Wood après sildénafil sont vivants, alors que seuls 4 le sont dans l’autre groupe (44 % de survie).
Conclusion
Le sildénafil semble améliorer les données hémodynamiques chez des patients avec une hypertension pulmonaire sévère secondaire à une dysfonction systolique du ventricule gauche.
Background
Morbimortality remains elevated despite improvements in the therapeutic management of patients with heart failure related to left ventricular systolic dysfunction (LVSD) . Heart transplantation is required in some patients, but the low number of heart donors is a major limiting factor preventing the widespread use of this approach. Because of this limitation, the implantation of a left ventricular assist device (LVAD) as a bridge to transplantation is sometimes required. For some young patients in whom heart transplantation is contraindicated because of non-cardiac comorbidities, a LVAD can be implanted definitively as a destination therapy. Heart transplantation or LVAD implantation are effective therapies, but with a high operative risk. Thus, the selection of candidates for these alternative therapies must be performed carefully. One major contraindication to heart transplantation is the presence of severe pulmonary hypertension . Currently, we do not have effective drugs that have demonstrated a significant effect on post-capillary pulmonary hypertension. Some studies in patients with post-capillary pulmonary hypertension have reported the usefulness of sildenafil, a phosphodiesterase type V inhibitor, extensively prescribed in patients with pulmonary arterial hypertension . We report our clinical experience with sildenafil in patients with LVSD and with severe pulmonary hypertension and elevated pulmonary vascular resistance (PVR).
Methods
Study population
We included in this analysis all patients admitted to our department between 2007 and 2013 for a possible listing for heart transplantation. All patients had chronic heart failure related to LVSD and were receiving maximal tolerated doses of recommended drugs. For angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and beta-blockers, we determined the percentage of maximal recommended doses of the different drugs, based on the most recent European guidelines . Patients underwent echocardiography, radionuclide angiography, a cardiopulmonary exercise test and right heart catheterization.
Haemodynamic measurements
Right heart catheterization was performed under local anaesthesia, either by the brachial or the femoral vein, using a Swan-Ganz catheter. All measurements were obtained at steady state with the patient in a supine position. Mean pulmonary artery pressure (mPAP) and pulmonary artery wedge pressure (PAWP) were calculated by the computer as the integrated mean of the curves. Mixed central venous blood gas was sampled from the pulmonary artery. Cardiac output was determined as the mean of three to seven separate measurements by the thermodilution technique. PVR, cardiac index, transpulmonary gradient (mPAP–PAWP) and diastolic pressure gradient (diastolic pulmonary pressure – PAWP) were calculated using standard formulae. After baseline measurements, in case of elevated PVR (> 3 Wood units [WU]), dobutamine infusion was started at a dose of 10 γ/kg/min over 10 minutes and increased up to 40 γ/kg/min in case of insufficient response, and a complete new haemodynamic evaluation was performed.
Other measurements
Echocardiography was performed with a Vivid E9 (GE Medical Systems, Wauwatosa, WI, USA) with the determination of standard and Doppler variables according to the recommendations of the American Society of Echocardiography . Left ventricular filling pressure was estimated by the sonographer (normal or increased), as recommended by the American Society of Echocardiography . Equilibrium radionuclide angiography was performed at rest in the supine position for the determination of left ventricular ejection fraction and right ventricular ejection fraction, using an ECAM camera (Siemens, Erlangen, Germany), after the injection of 740 MBq of technetium-99 m. The data for gas exchange during the cardiopulmonary exercise test were collected on a breath-by-breath basis using a computerized system (Vmax; SensorMedics, Yorba Linda, CA, USA). Peak oxygen consumption was defined as the highest average value during 20 seconds, obtained during the last minute of exercise. The predicted value of maximal oxygen consumption was calculated using Wasserman’s equation. B-type natriuretic peptide concentration was measured with the Advia Centaur BNP assay (Bayer Healthcare LLC, Tarrytown, NY, USA), and with the Triage BNP assay (Biosite Diagnostics, Inc., San Diego, CA, USA) for the historical cohort.
Committee decision
The decision to add patients to the waiting list for heart transplantation or to propose an LVAD implantation in young patients (≤ 65 years) with contraindication to heart transplantation was made by a committee that included cardiologists, surgeons and anaesthesiologists, all of whom were experts in heart failure. This committee estimated the operative risk for each patient and decided to introduce sildenafil when the risk was estimated to be excessive because of at least the presence of persistent post-capillary pulmonary hypertension, defined as mPAP ≥ 25 mmHg, PAWP > 15 mmHg and PVR > 3 WU, without reversibility despite an inotropic challenge with dobutamine (PVR ≥ 3 WU or mPAP ≥ 35 mmHg with a transpulmonary gradient ≥ 12 mmHg). Sildenafil was started at a dose of 20 mg three times daily. Doses were increased in case of non-functional improvement and a new cardiac evaluation was performed six months after the last increase in sildenafil dose.
Statistical analysis
Results are expressed as means ± standard deviations or as medians with interquartile ranges for variables that were not normally distributed. Discrete variables were compared using the Chi 2 test, with a Fisher’s exact test if necessary. Comparisons between quantitative variables were made using the non-parametric Wilcoxon test for repeated measures and the Mann–Whitney test. A value of P ≤ 0.05 was considered statistically significant. Statistics were performed with SPSS software, version 15.0 (SPSS Inc., Chicago, IL, USA).
Results
From January 2007 to December 2013, 268 patients were admitted for possible inclusion on the waiting list for heart transplantation. The patient flow chart is presented in Fig. 1 . From these 268 patients, we included in this open-label study, 18 patients suitable for either heart transplantation or LVAD implantation, with elevated PVR and a high estimated operative risk. Baseline characteristics are presented in Table 1 . The mean age of the study population was 47 ± 13 years, there were three women, one patient had chronic atrial fibrillation and four patients had diabetes mellitus. LVSD was related to ischaemic cardiopathy in 10 patients, five patients had dilated cardiomyopathy, one had anthracycline-induced cardiopathy, one had a valvular heart disease and the last patient had a congenital cardiopathy (neonatal myocardial infarction). Five patients had complete left bundle branch block with resynchronization therapy; 17 had an implantable defibrillator. The treatment of the study population is summarized in Table 1 . All patients received maximal tolerated doses of renin inhibitors (ramipril, 7.1 ± 3.3 mg/day [ n = 7]; perindopril, 8.3 ± 2 mg/day [ n = 8]) and beta-blockers (bisoprolol, 9.2 ± 3.7 mg/day [ n = 15]; nebivolol, 7.5 ± 3.5 mg/day [ n = 2]), 16 received mineralocorticoid receptor antagonists, which were introduced after the first right heart catheterization in four patients, and 10 received oral anticoagulants. All patients received diuretics. Doses of diuretics were increased after sildenafil therapy (furosemide, 100 [60–250] mg/day vs 160 [120–375] mg/day; P = 0.04), whereas doses of other drugs remained stable. For sildenafil, two patients received 180 mg/day, seven patients received 120 mg/day and the other patients received 60 mg/day.
| Variables | Historical cohort | Before sildenafil | After sildenafil | P | P (historical vs before sildenafil) |
|---|---|---|---|---|---|
| NYHA class | |||||
| II | 4 | 3 | 10 | 0.02 | 0.73 |
| III | 12 | 14 | 8 | ||
| IV | 2 | 1 | 0 | ||
| Heart rate (beats/min) | 76 ± 13 | 70 ± 10 | 73 ± 11 | 0.21 | 0.06 |
| Systolic blood pressure (mmHg) | 93 ± 12 | 99 ± 15 | 95 ± 12 | 0.34 | 0.82 |
| Diastolic blood pressure (mmHg) | 61 ± 6 | 66 ± 10 | 60 ± 10 | 0.03 | 0.40 |
| ACE inhibitor | 13 | 15 | 13 | ||
| ARB | 5 | 3 | 5 | ||
| ACE inhibitor/ARB (% of maximal doses) | 71 ± 30 | 78.5 ± 30 | 85.4 ± 25.8 | 0.37 | 0.36 |
| Beta-blocker (% of maximal doses) | 61 ± 30 | 88 ± 38 | 75 ± 28 | 0.25 | 0.055 |
| Spironolactone | 11 | 6 | 10 | ||
| Spironolactone (mg/day) | 25 (0–25) | 25 (25–25) | 25 (12.5–25) | 0.32 | 0.61 |
| Eplerenone | – | 7 | 6 | ||
| Eplerenone (mg/day) | – | 25 (25–50) | 50 (25–50) | 0.32 | |
| Furosemide (mg/day) | 80 (60–500) | 100 (60–250) | 160 (120–375) | 0.04 | 0.87 |
| LVEF (%) | 24 ± 10 | 24 ± 8 | 26 ± 7 | 0.1 | 0.70 |
| RVEF (%) | 29 ± 9 | 26 ± 7 | 30 ± 9 | 0.008 | 0.32 |
| LVEDD (mm) | 71 ± 9 | 66 ± 12 | 67 ± 12 | 0.62 | 0.21 |
| LVEDV (mL) | 245 ± 130 | 208 ± 92 | 214 ± 90 | 0.65 | 0.41 |
| Left atrial diameter (mm) | 47 ± 9 | 47 ± 7 | 48 ± 10 | 0.28 | 0.96 |
| Left atrial surface (cm 2 ) | 28 ± 10 | 30 ± 9 | 32 ± 11 | 0.33 | 0.73 |
| E/A | 2.3 ± 0.91 | 3.1 ± 1.2 | 3.1 ± 0.98 | 0.75 | 0.02 |
| Mitral deceleration time (s) | 120 ± 19 | 122 ± 39 | 128 ± 34 | 0.41 | 0.46 |
| E/e’ | 13.4 ± 5.2 | 22 ± 9 | 22 ± 11 | 0.87 | 0.004 |
| Right atrial surface (cm 2 ) | 23 ± 9 | 24 ± 7 | 24 ± 8 | 0.87 | 0.51 |
| TAPSE (mm) | 16.2 ± 4 | 16.2 ± 4.5 | 16.4 ± 4.3 | 0.94 | 0.89 |
| RVTiDS (cm/s) | 6.8 ± 1.44 | 9.5 ± 2.5 | 9.7 ± 2.6 | 0.53 | 0.002 |
| Peak VO 2 (mL/min/kg) | 11.6 ± 3 | 11.5 ± 3.8 | 12.4 ± 3.7 | 0.28 | 0.77 |
| Peak VO 2 (%) | 39 ± 13 | 39 ± 14 | 43 ± 16 | 0.08 | 0.95 |
| Peak RER | 1.18 ± 0.11 | 1.27 ± 0.12 | 1.26 ± 0.12 | 0.87 | 0.10 |
| VE/VCO 2 slope | 48 ± 10 | 52 ± 11 | 44 ± 10 | 0.009 | 0.63 |
| BNP (pg/mL) a | 490 (290–1011) | 877 (315–1397) | 559 (270–1380) | 0.22 | – |
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