In a patient with an active hemorrhagic bleed who is already receiving sacubitril‑valsartan (Entresto), should spironolactone be held and when can it be safely restarted?

Management of Spironolactone in a Patient with Hemorrhagic Bleeding on Sacubitril/Valsartan

Immediately discontinue spironolactone when active hemorrhagic bleeding occurs, and restart it 48–72 hours after documented hemostasis is achieved, provided the patient is hemodynamically stable, has no ongoing transfusion requirements, and has stable renal function with potassium <5.5 mmol/L. 1, 2

Immediate Management During Active Bleeding

Discontinuation Protocol

• Stop spironolactone immediately upon diagnosis of major hemorrhagic bleeding, defined as bleeding at a critical site, hemodynamic instability, or hemoglobin drop ≥2 g/dL. 1
• Continue sacubitril/valsartan unless the patient is hemodynamically unstable or in shock; hypotension from bleeding is not an absolute contraindication to continuing neurohormonal blockade once volume resuscitation begins. 1
• Do not administer reversal agents for spironolactone, as none exist; focus on supportive care, volume resuscitation, and local hemostatic measures. 1

Monitoring During Acute Phase

• Check serum potassium and creatinine immediately and daily during the bleeding episode, as the combination of sacubitril/valsartan and spironolactone increases risk of hyperkalemia and acute kidney injury. 1, 3
• Monitor hemoglobin every 6–12 hours until stable for at least 24 hours without transfusion. 1, 2
• Assess volume status carefully before restarting any guideline-directed medical therapy (GDMT), as patients may be volume-depleted post-bleeding, which increases hypotension risk when resuming sacubitril/valsartan or adding spironolactone. 1

Criteria for Restarting Spironolactone

Required Conditions (All Must Be Met)

• Hemodynamic stability: No vasopressor requirement, systolic blood pressure ≥90 mmHg, and no orthostatic symptoms. 1, 2
• Documented hemostasis: Hemoglobin stable for ≥24 hours with no transfusion requirement and no clinical or imaging evidence of ongoing bleeding. 1, 2
• Adequate renal function: Creatinine <220 μmol/L (2.5 mg/dL) and estimated glomerular filtration rate >30 mL/min/1.73 m². 1
• Normal potassium: Serum potassium <5.5 mmol/L before restarting spironolactone. 1, 3
• No planned invasive procedures in the next 48–72 hours that could disrupt hemostasis. 1, 2
• Bleeding source identified and controlled: The etiology must be known and definitively managed. 1, 2

Contraindications That Delay Restart

• Potassium ≥5.5 mmol/L: Halve the spironolactone dose or delay restart until potassium normalizes. 1
• Creatinine >220 μmol/L (2.5 mg/dL): Delay spironolactone and monitor renal function closely; if creatinine rises to >310 μmol/L (3.5 mg/dL), do not restart. 1
• High rebleeding risk: Unresolved vascular pathology, hepatic tumor, or coagulopathy that cannot be corrected. 1, 2
• Concurrent use of ACEI with sacubitril/valsartan: Never combine spironolactone with both an ARNI and an ACEI due to excessive hyperkalemia risk. 1

Timing of Restart

Standard Approach

• Restart spironolactone 48–72 hours after documented hemostasis for major bleeding events, prioritizing 72 hours for higher bleeding-risk scenarios such as intracranial or gastrointestinal hemorrhage. 1, 2, 4
• Earlier restart at 48 hours may be considered in patients with severe heart failure (NYHA class III–IV) who are at high risk of decompensation without mineralocorticoid receptor antagonist therapy. 1

Risk-Stratified Timing

• High heart failure risk (restart closer to 48 hours if stable):

  • LVEF ≤35% with NYHA class III–IV symptoms. 1
  • Recent hospitalization for acute decompensated heart failure within 30 days. 1
  • Elevated natriuretic peptides (NT-proBNP >1000 pg/mL or BNP >250 pg/mL). 1

• Moderate heart failure risk (restart at 72 hours if stable):

  • LVEF ≤40% with NYHA class II symptoms. 1
  • Stable outpatient on GDMT without recent decompensation. 1

Restart Protocol

Step 1: Confirm Stability (24–48 Hours Post-Bleed)

• Repeat hemoglobin at 24 hours and ensure decline is <2 g/dL to verify stable hemoglobin. 1, 2
• Recheck potassium and creatinine to ensure K+ <5.5 mmol/L and creatinine <220 μmol/L (2.5 mg/dL). 1
• Repeat imaging if indicated for any new symptoms suggesting rebleeding (abdominal pain, neurological change, hemodynamic instability). 1, 2

Step 2: Resume Spironolactone at Appropriate Dose

• Restart at 25 mg once daily (the standard starting dose), even if the patient was previously on 50 mg daily. 1
• Do not use alternate-day dosing initially unless potassium is borderline (5.0–5.4 mmol/L), in which case start 25 mg every other day. 1
• Recheck potassium and creatinine at 1 week and 4 weeks after restarting spironolactone. 1

Step 3: Titrate to Target Dose

• Consider uptitration to 50 mg daily after 4–8 weeks if potassium remains <5.5 mmol/L, creatinine is stable, and the patient has no adverse effects. 1
• Do not uptitrate if potassium rises to 5.5–6.0 mmol/L; instead, reduce dose to 25 mg every other day and monitor closely. 1
• Stop spironolactone immediately if potassium ≥6.0 mmol/L and treat hyperkalemia urgently. 1

Special Considerations with Sacubitril/Valsartan

Managing Hypotension Risk

• Reduce loop diuretic dose empirically by 50% before restarting spironolactone if the patient is euvolemic or volume-depleted post-bleeding, as this mitigates hypotensive effects of sacubitril/valsartan. 1
• Ensure systolic blood pressure ≥100 mmHg before restarting spironolactone; sacubitril/valsartan exerts more pronounced blood pressure effects than ACEIs/ARBs, and adding spironolactone may compound hypotension. 1
• Monitor blood pressure closely for 1 week after restarting spironolactone, as the combination of ARNI and mineralocorticoid receptor antagonist increases hypotension risk. 3

Managing Hyperkalemia Risk

• The combination of sacubitril/valsartan and spironolactone significantly increases hyperkalemia risk (10% incidence in hospitalized patients), particularly in those with baseline renal impairment. 3
• Check potassium at 1 week, 4 weeks, and then monthly for 3 months after restarting spironolactone in patients on sacubitril/valsartan. 1, 3
• Avoid potassium supplements and potassium-sparing diuretics (amiloride, triamterene) when using spironolactone with sacubitril/valsartan. 1
• Consider patiromer or sodium zirconium cyclosilicate if potassium rises to 5.5–5.9 mmol/L and spironolactone is essential for heart failure management. 1

Renal Function Monitoring

• The combination of sacubitril/valsartan and spironolactone increases risk of acute kidney injury, particularly in patients with baseline eGFR <60 mL/min/1.73 m². 5, 3
• A creatinine rise of up to 20% from baseline is acceptable and does not mandate discontinuation of spironolactone if potassium is normal and the patient is clinically stable. 1
• Stop spironolactone if creatinine rises >50% from baseline or exceeds 310 μmol/L (3.5 mg/dL), and reassess volume status and other nephrotoxic medications. 1

Common Pitfalls to Avoid

• Do not restart spironolactone before 48 hours, even if hemoglobin stabilizes at 24 hours, as rebleeding risk remains elevated in the first 48 hours. 1, 2, 4
• Do not combine spironolactone with an ACEI if the patient is on sacubitril/valsartan, as triple renin-angiotensin-aldosterone system blockade dramatically increases hyperkalemia and renal dysfunction risk. 1
• Do not restart spironolactone at the previous maintenance dose (e.g., 50 mg daily); always restart at 25 mg daily and retitrate based on potassium and renal function. 1
• Do not delay potassium monitoring; the first week after restarting spironolactone is the highest-risk period for hyperkalemia, particularly in patients on sacubitril/valsartan. 1, 3
• Do not withhold spironolactone indefinitely in patients with LVEF ≤35% and NYHA class III–IV symptoms, as mortality benefit is substantial (30% relative risk reduction in RALES trial). 1

When Spironolactone Cannot Be Restarted

• Consider eplerenone as an alternative if spironolactone causes gynecomastia or breast discomfort, though it has similar hyperkalemia risk. 1
• Reassess need for mineralocorticoid receptor antagonist if potassium remains >5.5 mmol/L despite dietary restriction and diuretic adjustment; the mortality benefit may not outweigh hyperkalemia risk in this scenario. 1
• Optimize other GDMT components (beta-blocker, sacubitril/valsartan, SGLT2 inhibitor) to maximum tolerated doses if spironolactone cannot be restarted. 1
• Re-evaluate risk-benefit every 1–3 months, as renal function and potassium handling may improve over time, allowing future spironolactone initiation. 1, 2