Recommendation 35: We recommend the combination of H-ISDN be considered in addition to standard guideline-directed medical therapy (GDMT) at appropriate doses for black patients with HFrEF and advanced symptoms (Strong Recommendation, Moderate Quality Evidence).

Recommendation 36: We recommend that H-ISDN be considered in patients with HFrEF unable to tolerate an ACE inhibitor, ARB or angiotensin receptor-neprilysin inhibitor (ARNI) because of hyperkalemia or renal dysfunction (Strong Recommendation, Low Quality Evidence).

Values and preferences: There is limited high-quality clinical trial evidence in the modern era from which to base a H-ISDN recommendation without considering the tolerability and adverse effects. Adverse effects related to H-ISDN are frequent, limit up-titration and result in discontinuation in a significant proportion of patients. Every effort should be made to utilizing ACEi/ARB/ARNI therapy including utilizing low dose and/or re-challenging therapy prior to changing to H-ISDN. Practical tips:

• Renal dysfunction warranting a trial of H-ISDN includes those that have a significant change in creatinine from baseline with ACEi/ARB/ARNI that persists despite modification of dose, re-challenge and/or removal of other potentially nephrotoxic agents. It may also be considered in those with a serum creatinine > 220 µmol/L who experience significant worsening in renal function with the use of ACEi/ARB/ARNI therapy, or in a trial of these agents (e.g., potential worsened renal function requiring renal replacement therapy) is thought to outweigh benefits.
• Hyperkalemia warranting a trial of H-ISDN includes those with persistent hyperkalemia (K > 5.5 mmol/L) despite dietary intervention, dosage reduction of ACEi/ARB/ARNI and removal of other agents known to increase potassium levels.
• Nitrates alone may be useful to relieve orthopnea, paroxysmal nocturnal dyspnea, exercise-induced dyspnea or angina in patients when used as tablet, spray or transdermal patch, but continuous (ie. round the clock) use should generally be avoided because most patients will develop tolerance.