Table 1. Characteristics of included studies.
| Study | n | Length (weeks) |
Baseline therapy (%) | Intervention | Female (%) | NYHA (%) | PH |
HF type (mean EF±SD) | Outcomes | |
|---|---|---|---|---|---|---|---|---|---|---|
| Phosphodiesterase-5 inhibitors | ||||||||||
| Lewis, 2007 [12] | 34 | 12 | ACE-1/ARB (83), Diuretics (100), BB (97), MRA (53), Digitalis (68), ICD (86), CRT (29) | Sildenafil 25 to 75 mg TID | 15 | II (53) III (38) IV (9) |
100% P: 33±3 T: 30±2 (mPAP) |
HFrEF (<40%) P: 20±2 T: 19±2 |
Primary: VO2 max Secondary: 6MWD, hemodynamics, QOL, biomarkers | |
| Guazzi, 2007 [11] | 46 | 26 | IECA (80), ARB (17), Furosemide (67), BB (65), MRA (52), Digitalis (26) | Sildenafil 50 mg BID | 0 | II III |
N/A P: 32±3 T: 34±3 (sPAP) |
HFrEF (<45%) P: 32±3 T: 31±3 |
VO2max, brachial artery FMD, ergoreflex, QOL | |
| Guazzi, Jan 2011 [25] | 45 | 52 | ACE-I (87), ARB (24), BB (84), MRA (42), Digitalis (11), CRT (38) | Sildenafil 50 mg TID | 0 | II (42) III (58) |
N/A P: 38±3 T: 38±6 (sPAP) |
HFrEF (<40%) P: 30±4 T: 30±3 |
Acute sildenafil response, cardiac dimension, echocardiographic parameters, NT-proBNP, CPET, QOL | |
| Guazzi, July 2011 [24] | 44 | 52 | ACE-1/ARB (95), Diuretics (77), BB (82), Digitalis (11) | Sildenafil 50 mg TID | 20 | N/A | 100% P: 36±5 T: 39±5 (mPAP) |
HFpEF (>50%) P: 60±6 T: 60±4 |
Hemodynamics, pulmonary function evaluations, echocardiographic parameters, QOL | |
| Guazzi,2012 [23] | 32 | 52 | ACE-I(75), ARB (25), BB (78), MRA (50), Digitalis (9), CRT (53) | Sildenafil 50 mg TID | 0 | III (91) IV (9) |
100% P: 34±3 T: 35±4 (mPAP) |
HFrEF (<45%) P: 28±7 T: 29±8 |
EOB, hemodynamics, VO2 max, QOL | |
| Amin, 2013 [26] | 106 | 12 | ACE-I/ARB (94), Diuretics (99), BB (95), MRA (64), Digitalis (27), CRT (7), ICD (9) | Sildenafil 50 mg 3 times a week | 26 | II (53) III (47) |
N/A | HFrEF (<35%) |
Primary: mean BP and 6MWD Secondary: hospitalization, survival |
|
| Redfield, 2013 [32] | 216 | 24 | ACE-I\ARB (70), Diuretics (86), BB (76), MRA (11) | Sildenafil 60 mg TID | 48 | II (47) III (53) |
N/A P: 43±15 T: 41±14 (sPAP) |
HFpEF (>50%) P: 60±7 T: 60±7 |
Primary: changes in VO2max at 24 weeks Secondary: composite clinical status score (death, hospitalization, MLHFQ), 6MWD at 12 and 24 weeks, peak sildenafil levels and PCGM at 12 and 24 weeks, left ventricular structure, vascular function, PASP, biomarkers, safety |
|
| Kim, 2015 [33] | 41 | 12 | ACE-I/ARB (100), Diuretics (100), BB (85), MRA (37), CRT/ICD (7) | Udenafil 100 mg BID | 32 | II (76) III (24) |
N/A P: 43±12 T: 41±9 (sPAP) |
HFrEF (<40%) P: 29±7 T: 30±6 |
Primary: change in VO2max at 12 weeks Secondary: changes in ventilatory efficiency, LVEF, E/e', LAVI, PASP, NYHA FC at 12 weeks, changes in BNP at 4 and 12 weeks |
|
| Hoendermis, 2015 [34] | 52 | 12 | ACE-I/ARB (75), Diuretics (90), BB (87), MRA (35) | Sildenafil 60 mg TID | 71 | II (21) III (79) |
100% P: 35±7 T: 35±10 (mPAP) |
HFpEF (>45%) P: 58±4 T: 58±4 |
Primary: mPAP Secondary: PAWP, CO, VO2max |
|
| Bermejo, 2017 [15] | 200 | 24 | ACE-I (39), ARB (21), Diuretics (87), BB (48), MRA (42), Digitalis (42), CCB (17) | Sildenafil 40 mg TID | 77 | I (8) II (48) III (42) (WHO) |
100% P: 40±9 T: 38±7 (mPAP) |
N/A |
Primary: composite clinical score (death, HF hospitalisation with diuretics IV, WHO FC, patient’s global assessment) Secondary: Adjusted composite score, all-cause mortality, cardiac mortality, HF hospitalisations, changes in 6MWD, WHO FC, BNP, PASP, stroke volume at 6 months |
|
| Endothelin receptor antagonist | ||||||||||
| Arnand, 2004 [27] | 642 | 24 | ACE-I/ARB (93), Diuretics (91), BB (75), MRA (40) Digitalis (46) |
Darusentan 10, 25, 50, 100 or 300 mg DIE | 18 | II (20) III (79) IV (1) |
N/A | HFrEF (<35%) P: 27±12 T: 26±11 |
Primary: LVESV Secondary: Changes in LVEF, neurohumoral measures, 6MWD, QOL, NYHA class, global assessment, composite clinical status |
|
| Packer, 2005 [28] | 370 | 26 | ACE-I (89), ARB (12), BB (24), Diuretics (100), MRA (14), Digitalis (74) | Bosentan 500 mg BID | 23 | III (69) IV (31) |
N\A | HFrEF (<35%) P: 23± 7 T: 24±6 |
Primary: clinical status Secondary: combined risk of all-cause mortality and worsening HF |
|
| Kaluski, 2008 [29] | 94 | 20 | ACE-I/ARB (99) Furosemid (99) Thiazide diuretic (23), BB (95) MRA (31) |
Bosentan 125 mg BID | 29 | III (83) IV (17) |
100% P: 49±9 T: 52±10 (sPAP) |
HFrEF (<35%) |
Primary: PASP Secondary: CI Exploratory: others echocardiographic parameters |
|
| Zile, 2014 [30] | 192 | 24 | ACE-I/ARB (80), Diuretics (77), BB (64) | Sitaxsentan 100 mg DIE | 63 | II (56) III (44) |
N/A | HFpEF (>50%) P: 60±13 T: 61±12 |
Primary: Changes in TET Secondary: E/e', LVMI, proportion of subjects achieving improvement, no change or worsening in TET, QOL, NYHA, safety |
|
| Koller, 2016 [31] | 20 | 12 | ACE-I (45), ARB (40), BB (65) Furosemid (80), Thiazide diuretics (45) |
Bosentan 125 mg BID | 45 | II III |
100% P: 66±17 T: 61±17 (sPAP) |
HFpEF (>50%) P: 65±7 T: 56±5 |
Primary: 6MWD at 12 weeks Secondary: 6MWD at 24 weeks and NT-proBNP, NYHA, echocardiographic parameters of RV, QOL at 12 and 24 weeks |
|
| Packer, 2017 [21] | 1613 | 36 | ACE-I /ARB (96), BB (51), Loop diuretics (95), MRA (26), Digitalis (58), Nitrates (44), Hydralazine (2), ICD (7) | Bosentan 125 mg BID | 26 | IIIb (91) IV (9) |
N/A | HFrEF (<35%) P: 25±6 T: 25±7 |
Primary: hierarchical clinical composite, all-cause mortality, hospitalization for HF Secondary: all cause mortality |
|
| Vachiery, 2018 [16] | 63 | 12 | ACE-I /ARB (64), BB (68), Loop diuretics (94), MRA (41), Thiazide diuretics (25), CCB (29) | Macitentan 10 mg DIE | 65 | II (24) III (72) |
100% P: 47±11 T: 46±10 (mPAP) |
Both N/A |
Primary: composite of significant fluid retention or worsening in NYHA Exploratory: haemodynamic and echocardiographic parameters, NT-proBNP, 6MWD, HF related hospitalisations |
|
| Soluble guanylate cyclase stimulators | ||||||||||
| Bonderman, 2013 [37] | 201 | 16 | ACE-I (71), ARB (28), Furosemide (94), Thiazide diuretics (16), BB (93), MRA (76), CD (60) | Riociguat 0.5,1 or 2 mg TID | 14 | II (60) III (38) IV (2) |
100% P: 40±1 T: 37±2 (mPAP) |
HFrEF (<40%) P: 27±5 T: 28±9 |
Primary: Changes mPAP Secondary: changes in hemodynamics, echocardiographic parameters Exploratory: composite of incidence of clinical worsening, composite of cardiovascular death and hospitalization, QOL, WHO/NYHA class, 6MWD, NT-proBNP |
|
| Gheorghlade, 2015 [38] | 456 | 12 | ACE-I (61), ARB (23), Diuretics (94), BB (90), MRA (62), ICD (21), CRT-D (7) | Vericiguat 1.25, 2.5, 5 or 10 mg DIE | 20 | I/II (53) III/IV (47) |
N/A | HFrEF (<45%) P: 29±9 T: 30±8 |
Primary: Change in log transformed NT-proBNP Exploratory: changes in LVEF, LVEDV, LVESV), clinical events, BP, HR, biomarker levels |
|
| Pieske, 2016 [39] | 477 | 12 | ACE-I (40), ARB (34), Diuretics (92), BB (80), MRA (37), CCB (36) |
Vericiguat 1.25, 2.5, 5 or 10 mg DIE | 48 | II (55) III/IV (45) |
N/A | HFpEF (>45%) P: 57± 7 T: 58±6 |
Primary: Change in log transformed NT-proBNP, change in left atrial volume Exploratory: KCCQ, EQ-5D, mortality, morbidity, echocardiography at rest, |
|
| Prostanoids | ||||||||||
| Sueta, 1995 [36] | 33 | 12 | ACE-I (85), Diuretics (100), Digoxin (91) | Max tolerated epoprostenol infusion | 12 | III (36) IV (64) |
N/A | HFrEF (<30%) P: 17±7 T: 17±7 |
6MWD, LVEF, NYHA, hemodynamics | |
| Califf, 1997 [35] | 471 | 36 | ACE-I (84), Diuretics (98), BB (0), Digitalis (91) | Max tolerated epoprostenol infusion | 24 | III (41) IV (59) |
N/A P: 40±9 T: 38±10 (mPAP) |
HFrEF (<25%) P: 18±6 T: 17±6 |
Primary: time until death Secondary: clinical events, exercise capacity, QOL, resource use |
|
n; numbers of study, NYHA; New York Heart Association, PH; pulmonary hypertension, LVEF; left ventricular ejection fraction, ACE-I; angiotensin convertor enzyme inhibitor, ARB; angiotensin receptor blocker, BB; beta-blocker MRA; mineralocorticoid receptor antagonist; REF; reduced ejection fraction, LVESV; left ventricular end systolic volume, 6MWD; 6 minute walking distance, QOL; quality of life, 6MWT; 6 meters walking test, HF; heart failure, PASP; pulmonary arterial systolic pressure, CI; cardiac index, PEF; preserved ejection fraction, TET; treadmill exercise time, E/e'; early diastolic mitral inflow velocity to early diastolic mitral annular velocity, LVMI; left ventricular mass index, NT-proBNP; N-terminal prohormone of brain natriuretic peptide, RV; right ventricule, ICD; implantable cardioverter defibrillator, CRT; cardiac resynchronisation therapy, P; placebo, T; treatment, VO2max; peak oxygen uptake, FMD; flow mediated dilatation, CPET; cardiopulmonary exercise testing, EOB; exercise oscillatory breathing, BP; blood pressure, MLHFQ; Minnesota Living With Heart Failure Questionnaire, PCGM; plasma cyclic guanosine phosphate, LAVI; left atrial volume, BNP; brain natriuretic peptide, mPAP; mean pulmonary arterial pressure, PAWP; pulmonary arterial wedge pressure, CO; cardiac output, WHO; World Health Organization, LVEDV; left ventricular end-diastolic volume, LVESV; left ventricular end-systolic volume, HR; hearth rate, CCB; calcium channel blocker, KCCQ; Kansas City Cardiomyopathy Questionnaire, EQ-5D; EuroQol-5 dimension.