Is dapagliflozin, sacubitril (valsartan) and eplerenone safe for patients with congestive heart failure due to valvular heart disease or rheumatic heart disease?

Safety of Dapagliflozin, Sacubitril/Valsartan, and Eplerenone in Heart Failure Due to Valvular or Rheumatic Heart Disease

These medications have not been studied in patients with heart failure specifically caused by valvular or rheumatic heart disease, and their use in this population should be approached with extreme caution or avoided entirely, as major clinical trials explicitly excluded patients with hemodynamically significant valvular disease.

Critical Evidence Gap

The landmark trials establishing the safety and efficacy of these medications systematically excluded patients with significant valvular heart disease:

• PARADIGM-HF (sacubitril/valsartan) excluded patients with hemodynamically significant valvular disease 1
• DAPA-HF (dapagliflozin) excluded patients with primary valvular heart disease 2
• EMPHASIS-HF (eplerenone) excluded patients with significant valvular disease 3

This means there is no high-quality evidence supporting the safety or efficacy of these agents in the specific population you are asking about.

Why This Matters Clinically

Pathophysiologic Differences

Heart failure from valvular or rheumatic disease has fundamentally different hemodynamics compared to ischemic or non-ischemic cardiomyopathy:

• Volume and pressure loading from valvular lesions creates different neurohormonal activation patterns 4
• Rheumatic heart disease often involves multiple valves with complex hemodynamics
• The benefit-to-risk ratio established in non-valvular HFrEF may not translate to valvular etiologies

Specific Safety Concerns

Sacubitril/Valsartan:

• Causes blood pressure reduction that may be poorly tolerated in patients with fixed cardiac output from severe aortic stenosis or mitral stenosis 3, 4
• Hypotension risk is already elevated (11.1% symptomatic hypotension in PARADIGM-HF) in standard HFrEF populations 3
• In valvular disease with fixed stroke volume, blood pressure drops cannot be compensated by increased cardiac output 1

Dapagliflozin:

• While it has minimal direct blood pressure effects (only -1.50 mmHg in low BP patients), it causes natriuresis that could precipitate hypotension in volume-sensitive valvular lesions 3
• The DAPA-HF trial showed 0.3% symptomatic hypotension, but this was in non-valvular HFrEF 3

Eplerenone:

• Risk of hyperkalemia is already present in standard HFrEF (requiring close monitoring) 3
• In patients with rheumatic heart disease who may have renal dysfunction from chronic congestion, this risk is amplified 3

Clinical Decision Algorithm

Step 1: Determine if Valvular Disease is the Primary Cause

• If heart failure is primarily due to valvular or rheumatic disease: Do not initiate these medications outside of expert consultation
• If valvular disease is incidental and HF is from another cause (ischemic, non-ischemic cardiomyopathy): Standard HFrEF guidelines apply 3

Step 2: If Considering Use Despite Lack of Evidence

Only proceed if:

• Patient has severe, refractory symptoms despite optimal conventional therapy
• Valvular lesion has been corrected (surgical or percutaneous intervention) and residual HF persists
• Cardiology or heart failure specialist consultation obtained
• Patient understands off-label use with unknown risk-benefit profile

Step 3: Monitoring Protocol if Initiated

• Blood pressure monitoring: Check BP sitting and standing before each dose escalation 3
• Renal function: Check creatinine and eGFR weekly for first month, then monthly 5
• Electrolytes: Check potassium weekly if using eplerenone, especially with concurrent RAAS blockade 3
• Clinical status: Assess for worsening symptoms, syncope, or presyncope at each visit 5

What the Guidelines Actually Recommend

The 2024 ESC guidelines for chronic coronary syndromes recommend these medications only for HFrEF in general, without specific guidance for valvular etiologies 3. The 2019 ESC diabetes guidelines similarly recommend sacubitril/valsartan and SGLT2 inhibitors for HFrEF without addressing valvular disease 3.

This absence of specific recommendations for valvular heart disease is itself telling—it reflects the lack of evidence in this population.

Bottom Line for Clinical Practice

Do not routinely use dapagliflozin, sacubitril/valsartan, or eplerenone in patients whose heart failure is primarily caused by valvular or rheumatic heart disease. The evidence base does not support their use, and the pathophysiology differs sufficiently that extrapolation from non-valvular HFrEF trials is inappropriate 4, 2.

If the valvular lesion has been corrected and residual cardiomyopathy persists, then these patients may be treated according to standard HFrEF guidelines, as their heart failure is no longer primarily valvular in etiology 3, 1.