Table 1.

Main trials on cardiac drugs in ACHD-related heart failure.

Study Design	Subaortic LV Failure	Sub-Pulmonary RV Failure	Subaortic RV Failure	Failing Fontan
RCT or Meta-analysis	Ramipril in ToF (post-hoc analysis of APPROPRIATE study): stabilization of LV and RV function [7]	Losartan in ToF (REDEFINE): no effect on RVEF [9] PAH therapies (Section 3)	Eplerenone: no effect on sRV mass and EF, neurohormonal and collagen turnover biomarkers [15] Losartan [18], valsartan [19]: no effect on sRVEF, exercise capacity, and NT-proBNP Ramipril: no changes in sRV volumes and EF [20] Tadalafil (SERVE): no change in sRV volume or sRVEF (results communicated at ESC congress 2022, not yet published) SGLT2i (ongoing studies: NCT05580510)	Bosentan: conflictual effect on peakVO2 and NYHA, no effect on NTproBNP and QoL [35,42] Ambrisentan: improvement of peak VO2 [43] Macitentan (not yet published) Udenafil (FUEL): no improvement in peak VO2 [36] Sildenafil: conflictual results on peak VO2 [44,45]; no change in pressure-volume loop [46]; increase in cardiac index [47] Iloprost: improvement of peak VO2 [48] Meta-analysis [34]: significant improvements in hemodynamics, functional class, and 6 min walk distance but no changes in mortality or NT-proBNP Enalapril in asymptomatic patients: decrease in cardiac index [40] Carvedilol: no change in exercise performance and mild increase in NT-proBNP level [41]
Open label trial	No data	No data	Eplerenone: no effect on collagen biomarkers, 6MWD, or QoL [16]	Bosentan: no changes in saturations of oxygen, exercise performance, and QoL [38]; improvement of 6MWD and MRI-derived resting cardiac output [49] Sildenafil: improvement of peak VO2 [50]
Prospective observational studies	Guideline-directed medical therapy would improve LVEF [3]		Β-blockers may improve NYHA, QoL, +/− sRVEF [12] ACEi or ARBs: no association with a reduced HF incidence or mortality [22] ARNI: conflicting data but seem to be associated with improvement of NT-proBNP level, sRV function, NYHA, 6MWD, and QoL [24,25,26,27,28] SGLT2 i: one clinical case with functional and echocardiographic improvement [51]	PAH therapy: improvement of NYHA functional class in patients with PAH therapies [37]
Recommendations	Diuretics, ACE inhibitors, ARBs, angiotensin receptor/neprilysin inhibitors, mineralocorticoid receptor antagonists, βblockers, and SGLT2i should be used	Losartan should not be prescribed routinely in ToF to prevent the progression of RV dysfunction and RV HF	No evidence for eplerenone, ACEi, ARBs, βblockers, sacubitril/valsartan effects in sRV Valsartan or sacubitril/valsartan should be considered in symptomatic patients No data yet on SGLT2i use	Considering PAH therapy in selected Fontan patients with elevated PVR (>2 indexed Wood units) in the absence of high ventricular end diastolic pressure Avoiding βblockers and ACEi specifically in patients without systolic ventricular dysfunction and increased end-diastolic ventricular pressure No data yet on ARNI and SGLT2i use

6MWD, 6 min walk distance; ACE, angiotensin converting enzyme; ARBs, angiotensin II receptor blockers; ARNI, angiotensin receptor-neprilysin inhibitor; EF, ejection fraction; HF, HF; LV, left ventricle; NT-proBNP, N-terminal pro b-type natriuretic peptide; NYHA, New York Heart Association; PAH, pulmonary arterial hypertension; PVR, pulmonary vascular resistance; QoL, quality of life; RCT, randomized clinical trial; RV, right ventricle; SGLTi, sodium-glucose cotransporter 2 inhibitor; sRV, systemic right ventricle; ToF, tetralogy of Fallot.