Non-MRA Medications for Heart Failure with Reduced Ejection Fraction
For patients with HFrEF who cannot tolerate MRAs, the core guideline-directed medical therapy consists of ARNi (or ACEi/ARB if ARNi unavailable), beta-blockers, and SGLT2 inhibitors, with hydralazine-isosorbide dinitrate added for African American patients who remain symptomatic or considered for other patients intolerant to first-line agents 1.
Step 1: Foundation Therapy (Start Simultaneously or Sequentially)
The 2022 AHA/ACC/HFSA guidelines establish a clear hierarchy when MRAs cannot be used 1:
Primary Agents:
- ARNi (sacubitril/valsartan) - First choice for symptomatic HFrEF patients
- ACEi or ARB - If ARNi not tolerated or available
- Beta-blockers - Essential in virtually every HFrEF patient
- SGLT2 inhibitors - Proven mortality and hospitalization benefit
These medications should be initiated at low doses and titrated to target doses as tolerated, without waiting to achieve target dosing of one before starting another 1.
Step 2: Additional Therapy Based on Patient Characteristics
For African American Patients:
Hydralazine-isosorbide dinitrate combination is strongly recommended for self-identified African American patients with persistent NYHA class III-IV symptoms despite optimal therapy with ACEi/ARB, beta-blockers, and when MRAs cannot be used 1. This combination:
- Reduced mortality in the A-HeFT trial when added to standard therapy
- Provides cost-effective care (<$60,000 per life-year gained)
- Has insufficient data for concomitant use with ARNi
For Non-African American Patients with MRA Intolerance:
Hydralazine-isosorbide dinitrate might be considered in patients unable to tolerate ACEi, ARB, or ARNi due to hypotension, renal insufficiency, or other drug intolerance 1. However, the evidence is weaker in this population:
- Original V-HeFT I trial showed mortality benefit compared to placebo
- No recent trial data in non-African American populations
- Referral to a heart failure specialist is recommended for guidance when first-line agents cannot be used
Important Caveats and Pitfalls
Avoid These Common Errors:
- Do not delay beta-blocker or SGLT2 inhibitor initiation while attempting MRA rechallenge - these provide independent mortality benefit 2
- Do not use hydralazine-isosorbide dinitrate with ARNi - insufficient safety/efficacy data for this combination 1
- Do not assume hydralazine-isosorbide dinitrate equivalence to ACEi/ARB - head-to-head trials showed ACEi superiority in non-African American populations 1
Monitoring Considerations:
When MRAs are avoided due to hyperkalemia or renal insufficiency, these same concerns may limit ACEi/ARB/ARNi dosing. In such cases:
- Prioritize achieving therapeutic doses of beta-blockers and SGLT2 inhibitors first
- Consider lower but still beneficial doses of renin-angiotensin system blockers
- Specialist referral becomes particularly important for complex medication optimization
Resistant Hypertension and Post-MI Remodeling Context
For resistant hypertension specifically, spironolactone remains the MRA with strongest evidence 3, but when contraindicated, the focus shifts to optimizing other antihypertensive classes rather than hydralazine-isosorbide dinitrate, which is primarily a heart failure therapy.
For post-MI left ventricular dysfunction, eplerenone has the most robust evidence 3, but when MRAs are contraindicated, ensuring optimal ACEi/ARB (or ARNi) and beta-blocker therapy takes precedence, as these also reduce post-MI remodeling.