Table 1
Clinical and pathobiological characteristics of pulmonary arterial hypertension (PAH) and pulmonary hypertension (PH) due to left heart diseases. ACE: angiotensin converting enzyme; ARB: angiotensin receptor antagonist; ARNI: angiotensin receptor neprilysin inhibitor; ERA: endothelin receptor antagonist; F: female; HF: heart failure; HFpEF: heart failure with preserved ejection fraction; HFrEF: heart failure with reduced ejection fraction; LA: left atrium; LBBB: left bundle branch block; LHF: left heart failure; LV: left ventricle; M: male; MRA: mineral-corticoid receptor antagonist; PAWP: pulmonary artery wedge pressure; PDE5: phosphodiesterase-5; PVOD: pulmonary veno-occlusive disease; RA: right atrium; RBBB: right bundle branch block; RHF: right heart failure; RV: right ventricle; sGC: soluble guanylate cyclase; SGLT2: sodium-glucose cotransporter 2; TR: tricuspid regurgitation; VCO2: CO2 output; VE: ventilation; VO2: oxygen uptake.
| GROUP 1 PH (PAH) | GROUP 2 PH (PH-LHD) | |
|---|---|---|
Pathobiology
|
|
|
Phenotype/demographic
|
|
|
Clinical
|
|
|
| Therapy |
|
|
Table 2
Design and main results of randomized clinical trials exploring pulmonary arterial hypertension (PAH)-specific drugs in pulmonary hypertension (PH) due to left heart diseases.33,34,35,36,37,38,39,40,41,42 6MWD: 6-minute walk distance; BNP: B-type natriuretic peptide; CI: cardiac index; CO: cardiac output; CPET: cardiopulmonary exercise test; DPG: diastolic pulmonary gradient; EOB: exercise oscillatory breathing; HF: heart failure; HFpEF: heart failure with preserved ejection fraction; HFrEF: heart failure with reduced ejection fraction; LV: left ventricle; mPAP: mean pulmonary artery pressure; NYHA: New York Heart Association (functional class); PAWP: pulmonary artery wedge pressure; PVR: pulmonary vascular resistance; QoL: quality of life; RAP: right atrial pressure; RHC: right heart catheterization; RV: right ventricle; sPAP: systolic pulmonary artery pressure; VO2: oxygen uptake; WU: Wood units
| STUDY | TARGET PATIENTS | DRUG (N) | END POINTS | RESULTS |
|---|---|---|---|---|
| FIRST33 | Severe HFrEF (LVEF < 25%) NYHA IIIB/IV Congestive HF (PAWP > 15, CI < 2.2) | Epoprostenol (237) vs conventional medical therapy (234) | Primary: death; major event (death, need
for mechanical ventilation, inotropic drugs, mechanical circulatory
support) Secondary: 6MWD, QoL, clinical status at 3 months | Early termination due to increased mortality for HF in treatment group |
| Lewis GD et al.34 | HFrEF (LVEF < 40%) NYHA II-IV PH (mPAP > 25 mm Hg at RHC) | Sildenafil (17) vs placebo (17), for 12 weeks | Primary: VO2
peak Secondary: 6MWD, PVR | Increase peak VO2, improved 6MWD, decrease PVR in treatment group |
| Guazzi M, et al.35 | HFpEF (LVEF > 50%) NYHA II-IV PH (sPAP > 40 mm Hg at echo) | Sildenafil (22) vs placebo (22), for 1 year | Primary: pulmonary hemodynamics; RV
function (TAPSE) Secondary: QoL | Significant reduction in RAP, mPAP, PAWP and PVR; improvement in RV function, CI and QoL |
| Guazzi M, et al.36 | HFrEF (LVEF < 45%) PH (mPAP 25–35 mm Hg at RHC) EOB at CPET | Sildenafil (16) vs placebo (16) for 1 year | Respiratory pattern during
CPET Pulmonary hemodynamics | Significant EOB reversal in treatment
group Significant reduction in pulmonary pressure and PVR, and increase in CO in treatment group |
| Hoendermis ES, et al.37 | HFpEF (LVEF ≥ 45%) PH (mPAP > 25, PAWP > 15 mm Hg) | Sildenafil (26) vs placebo (26), for 12 weeks | Change in mPAP, PAWP, CO and peak VO2 | No significant differences |
| Liu LC, et al.38 | HFpEF (LVEF ≥ 45%) NYHA II-IV PH (mPAP > 25, PAWP > 15 mm Hg) | Sildenafil (26) vs placebo (26), for 12 weeks | Echocardiographic parameters (RV/LV
dimensions and function) CPET, QoL | No significant differences |
| SIOVAC39 | PH (mPAP > 30 mm Hg at
RHC) Left-side valvular replacement or repair 1 year before | Sildenafil (104) vs placebo (96), for 6 months | Primary: composite clinical score (death
or HF + NYHA class + QoL) Secondary: clinical score components, 6MWD, BNP, echocardiography | Significant worsening in clinical status
of patients in sildenafil group (driven by higher risk of
readmission for HF). No differences in sPAP, 6MWD, NYHA class |
| BADDHY40 | HFpEF (LVEF ≥ 50%) PH (mPAP > 25 mm Hg, PAWP > 15 mm Hg at RHC) RV dysfunction (echo) | Bosentan (9) vs placebo (11) for 12 weeks | 6MWD sPAP and RAP estimated by echocardiography | Insignificant trend in increase of 6MWD in placebo group Acute HF event in 3 patients in bosentan group vs 1 patient in placebo group |
| LEPHT41 | HFrEF (LVEF ≤ 40%) NYHA II-IV PH (mPAP ≥ 25 mm Hg at RHC) | Riociguat (132) vs placebo (69), for 16 weeks | Primary: mPAP changes Secondary: hemodynamic parameters Exploratory: clinical worsening, death, HF hospitalization, 6MWD, NYHA class, QoL | No significant changes in
mPAP Significant increase in CI and decrease in PVR in riociguat group. |
| MELODY-142 | HFpEF and HFrEF (LVEF >
35%) NYHA II-IV CpcPH (mPAP ≥ 25, PAWP > 15, DPG ≥ 7, PVR > 3.0 WU) | Macitentan (31) vs placebo (32) for 12 weeks | Primary: safety and tolerability (fluid
retention, worsening NYHA class) Exploratory: changes in hemodynamics, NT-proBNP, 6MWD | More patients in macitentan group than in
placebo group experienced fluid retention No significant differences in any of the exploratory endpoints |
| ACE | Angiotensin converting enzyme |
| ARB | Angiotensin receptor antagonist |
| ARNI | Angiotensin receptor neprilysin inhibitor |
| AT | Anaerobic threshold |
| CI | Cardiac index |
| CO | Cardiac output |
| CpcPH | Combined post- and precapillary pulmonary hypertension |
| CPET | Cardiopulmonary exercise test |
| DPG | Diastolic pulmonary gradient |
| EOB | Exercise oscillatory breathing |
| ERA | Endothelin receptor antagonist |
| iPAH | Idiopathic pulmonary arterial hypertension |
| IpcPH | Isolated postcapillary pulmonary hypertension |
| HF | Heart failure |
| HFpEF | Heart failure with preserved ejection fraction |
| HFrEF | Heart failure with reduced ejection fraction |
| LA | Left atrium |
| LAP | Left atrium pressure |
| LBBB | Left bundle branch block |
| LHD | Left heart disease |
| LV | Left ventricle |
| LVAD | Left ventricle assistance device |
| mPAP | Mean pulmonary artery pressure |
| MRA | Mineral-corticoid receptor antagonist |
| NO | Nitric oxide |
| NT-proBNP | N-terminal pro–brain natriuretic peptide |
| NYHA | New York Heart Association (functional class) |
| PAP | Pulmonary artery pressure |
| PAWP | Pulmonary artery wedge pressure |
| PDE-5 | Phosphodiesterase-5 |
| PH | Pulmonary hypertension |
| PH-LHD | Pulmonary hypertension due to left heart disease |
| PVOD | Pulmonary veno-occlusive disease |
| PVR | Pulmonary vascular resistance |
| QoL | Quality of life |
| RA | Right atrium |
| RBBB | Right bundle branch block |
| RHF | Right heart failure |
| RV | Right ventricle |
| sGC | Soluble guanylate cyclase |
| SGLT2 | Sodium-glucose cotransporter 2 |
| TR | Tricuspid regurgitation |
| VCO2 | CO2 output |
| VHD | Valvular heart disease |
| VO2 | Oxygen uptake |
| VE | Ventilation |
| 6MWD | 6-Minute walking distance |