Risk Reduction and Right Heart Reverse Remodeling by Upfront Triple Combination Therapy in PAH

Quick Takes

  • Symptomatology and outcome in pulmonary arterial hypertension (PAH) are largely determined by right heart remodeling in response to increased afterload.
  • Right heart remodeling and its reverse are functions of increase/reduction in pulmonary vascular resistance (PVR).
  • Triple combination therapy including parenteral prostanoids can achieve right heart reverse remodeling, allowing long-term survival.

Background
The symptomatology and outcome in PAH are largely determined by right heart remodeling in response to increased afterload.1,2 Therefore, right ventricle (RV) dilatation leads to right-sided heart failure, and its reversal would be expected to improve symptoms and prognosis in PAH. Evidence that this can be achieved by current therapies is scarce. In fact, even though some modality imaging such as echocardiography and magnetic resonance are widely used in daily practice, their use is not uniform across expert centers, and RV imaging data are not reported in PAH clinical trials. As a consequence, the risk stratification models do not include these features.

The study summarized here evaluated the effects of a triple upfront combination including parenteral prostacyclins on RV function and outcomes in patients with severe PAH.

Methods

The study design is reported in Table 1.

Table 1: Study Characteristics

Design
  • Two centers (Monaldi Hospital in Naples and La Sapienza University in Rome, Italy)
  • Retrospective
Inclusion criteria
  • 21 consecutive incident (newly diagnosed) PAH patients (2014-2018)
  • Advanced disease (high risk score)
Treatment (triple upfront therapy)
  • Ambrisentan 5 mg daily, uptitrated to 10 mg at week 8
  • Tadalafil 20 mg daily, uptitrated to 40 mg at week 4
  • Subcutaneous treprostinil (continuous infusion) from 2 ng/kg/min; dose increased by 2 ng/kg/min every 8 to 12 h
Follow-up
  • Simplified REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management) risk score at baseline and every 3 months
  • Clinical examination, World Health Organization (WHO) functional class, 6-minute walk distance, N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, and echocardiography at baseline and every 3 months
  • Right heart catheterization at baseline, after 3 months, and after 12 ± 4 months of treatment

The zero level at right heart catheterization was set at the midthoracic level. Wedge pressure was obtained at end-expiration, and cardiac output was measured by thermodilution using an average of at least three measurements.

The features considered at echocardiography were right atrial area, RV end-diastolic area, RV end-systolic area, RV fractional area change, left ventricular (LV) eccentricity index, and standard M-mode, two-dimensional, and Doppler images obtained in accordance with the American Society of Echocardiography guidelines.

Subcutaneous treprostinil was administered using a portable infusion pump (CADD-MS 3 Ambulatory Infusion Pump [Smiths Medical ASD, Inc.; Minneapolis, MN]) initiated at 2 ng/kg/min with the dose increased by 2 ng/kg/min every 8 to 12 h. After 5 days and once a treprostinil dose of 10 ng/kg/min had been reached, the patients were discharged. Treprostinil was further uptitrated by 2 ng/ kg/min every week depending on patient's tolerance. The treprostinil dose at the end of follow-up was 45 ± 17 ng/kg/min (range of 26-92 ng/kg/min). No patient discontinued oral or subcutaneous combination therapy because of side effects. The matched historical cohort for comparative purposes comprised 31 treatment-naïve patients with non-reversible idiopathic PAH receiving oral monotherapy:

  • Bosentan: n = 12 (39%)
  • Ambrisentan: n = 6 (19%)
  • Sildenafil: n = 8 (26%)
  • Tadalafil: n = 5 (16%)

Results

  • WHO functional class. At baseline, patients were in WHO functional Class III (57%) and Class IV (43%). All patients improved their WHO functional class at end follow-up, with 19 out of 21 patients (90%) reaching WHO functional Class I or II.
  • 6-minute walk distance. The 6-minute walk distance significantly increased by 273 m (from 158 ± 130 to 431 ± 66 m; p < 0.001).
  • NT-proBNP. NT-proBNP levels significantly decreased from 3379 ± 1921 to 498 ± 223 pg/mL; p < 0.001).
  • Hemodynamics. Improvement of all parameters at end follow-up:
    • Right atrial pressure: 62% decrease (-8 mmHg)
    • Mean pulmonary arterial pressure: 30% decrease (-18 mmHg)
    • PVR: 69% decrease (-10.9 Wood units)
    • Cardiac index: 94% increase (1.7 l/min/m2)
  • Echocardiography. Improvement of RV function and structure:
    • Right atrial area decreased by 28% (-8 cm2)
    • RV end-diastolic and end-systolic areas decreased by 29% (-8 cm2) and 43% (-9 cm2), respectively
    • RV fractional area change increased by 63% (+13%)
    • LV eccentricity index decreased by 20% (-0.3)
  • REVEAL risk score. All patients had a REVEAL risk score ≥9 at baseline. At end follow-up, the REVEAL risk score was reduced in all patients; 17 of 21 patients (81%) reached the low-risk status.
  • Interesting findings:
    • All patients were alive at end follow-up.
    • There were no significant correlations between changes in right heart dimensions or RV systolic function and changes in the REVEAL risk score.
    • Significant correlation was found between right heart dimensions/RV systolic function and PVR decrease (p < 0.001). Changes in RV end-diastolic area and RV fractional area change were observed as a function of percent decrease in PVR.

Discussion

This main finding of this small, retrospective, study3 is that reverse remodeling of the RV can be achieved in a substantial proportion of patients with severe PAH by treating with triple upfront combination therapy with ambrisentan, tadalafil, and subcutaneous treprostinil.

Although the European Society of Cardiology and European Respiratory Society guideline-derived scores4 and the REVEAL score5 are both indirectly affected by the adequacy of RV function adaptation to afterload, none of them include measurements of RV dimensions and function necessary for a diagnosis of right-sided heart failure.6

Although parenteral prostacyclins are the preferred option for patients in high-risk status, treatment is started with two oral drugs in the majority of low- and intermediate-risk patients.7-9 A more aggressive triple upfront combination of bosentan, sildenafil, and intravenous epoprostenol has shown a beneficial functional improvement effect in a small study of 19 patients with severe idiopathic PAH.10

In this study,2 a triple upfront combination of ambrisentan, tadalafil, and subcutaneous treprostinil in patients with severe idiopathic PAH produced strikingly similar results, with sustained improvement in functional state and exercise capacity (273 m in 6-minute walk distance), a fall in mean pulmonary artery pressure (18 mmHg), and a decrease in PVR (by 69%). This study adds to the previously noted beneficial effects of such a strategy on RV structure and function.

Reversal of right-sided heart dilatation as defined at two-dimensional echocardiography by the combination of decreased right-sided atrial and RV areas and LV eccentricity index is associated with excellent long-term survival and quality of life. Importantly, the data from this study suggest that restoration of RV function requires a minimal reduction in PVR of >50% of the baseline value.

In this study, a triple upfront combination of targeted therapies allowed for right heart reverse remodeling, and right heart reverse remodeling was associated with a REVEAL risk score <6, resulting in excellent survival. However, there was no significant correlation between changes in right heart dimensions and changes in REVEAL risk scores, indirectly supporting the notion of added value of simple echocardiographic imaging of the right side of the heart in PAH risk assessment.11-14

References

  1. Sanz J, Sánchez-Quintana D, Bossone E, Bogaard HJ, Naeije R. Anatomy, Function, and Dysfunction of the Right Ventricle: JACC State-of-the-Art Review. J Am Coll Cardiol 2019;73:1463-82.
  2. Badagliacca R, Vizza CD. Imaging risk in pulmonary arterial hypertension. Eur Respir J 2020;56:2002313. 
  3. D'Alto M, Badagliacca R, Argiento P, et al. Risk Reduction and Right Heart Reverse Remodeling by Upfront Triple Combination Therapy in Pulmonary Arterial Hypertension. Chest 2020;157:376-83. 
  4. Galiè N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009;30:2493-537.
  5. Benza RL, Gomberg-Maitland M, Elliott CG, et al. Predicting Survival in Patients With Pulmonary Arterial Hypertension: The REVEAL Risk Score Calculator 2.0 and Comparison With ESC/ERS-Based Risk Assessment Strategies. Chest 2019;156:323-37.
  6. Badagliacca R, Papa S, Matsubara H, et al. The importance of right ventricular evaluation in risk assessment and therapeutic strategies: Raising the bar in pulmonary arterial hypertension. Int J Cardiol 2020;301:183-9.
  7. Galiè N, Channick RN, Frantz RP, et al. Risk stratification and medical therapy of pulmonary arterial hypertension. Eur Respir J 2019;53:1801889.
  8. Badagliacca R, D'Alto M, Ghio S, et al. Risk Reduction and Hemodynamics with Initial Combination Therapy in Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 2021;203:484-92.
  9. D'Alto M, Badagliacca R, Lo Giudice F, et al. Hemodynamics and risk assessment 2 years after the initiation of upfront ambrisentan‒tadalafil in pulmonary arterial hypertension. J Heart Lung Transplant 2020;39:1389-97.
  10. Sitbon O, Jaïs X, Savale L, et al. Upfront triple combination therapy in pulmonary arterial hypertension: a pilot study. Eur Respir J 2014;43:1691-7.
  11. Badagliacca R, Poscia R, Pezzuto B, et al. Prognostic relevance of right heart reverse remodeling in idiopathic pulmonary arterial hypertension. J Heart Lung Transplant 2017;Oct 2:[Epub ahead of print].
  12. Badagliacca R, Raina A, Ghio S, et al. Influence of various therapeutic strategies on right ventricular morphology, function and hemodynamics in pulmonary arterial hypertension. J Heart Lung Transplant 2018;37:365-75.
  13. Peacock AJ, Crawley S, McLure L, et al. Changes in right ventricular function measured by cardiac magnetic resonance imaging in patients receiving pulmonary arterial hypertension-targeted therapy: the EURO-MR study. Circ Cardiovasc Imaging 2014;7:107-14.
  14. Badagliacca R, Papa S, Manzi G, et al. Usefulness of Adding Echocardiography of the Right Heart to Risk-Assessment Scores in Prostanoid-Treated Pulmonary Arterial Hypertension. JACC Cardiovasc Imaging 2020;13:2054-6. 

Clinical Topics: Dyslipidemia, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Pulmonary Hypertension and Venous Thromboembolism, Lipid Metabolism, Acute Heart Failure, Pulmonary Hypertension, Echocardiography/Ultrasound

Keywords: Hypertension, Pulmonary, Retrospective Studies, Prostaglandins I, Epoprostenol, Quality of Life, Pulmonary Artery, Exercise Tolerance, Dilatation, Phenylpropionates, Echocardiography, Heart Failure, Vascular Resistance, Risk Assessment, Risk Factors, Pharmaceutical Preparations


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