Is it safe to take losartan (Angiotensin II Receptor Antagonist) and Entresto (sacubitril/valsartan) together?

Taking Losartan and Entresto Together is Not Safe

It is not safe to take losartan and Entresto (sacubitril/valsartan) together as this combination creates a dual blockade of the renin-angiotensin system that increases risks of hypotension, hyperkalemia, and acute renal failure without additional clinical benefits. 1

Understanding the Medications and Their Interaction

What are these medications?

• Losartan: An angiotensin II receptor blocker (ARB) that blocks the effects of angiotensin II at receptor sites
• Entresto (sacubitril/valsartan): A combination medication containing:
  • Sacubitril: A neprilysin inhibitor
  • Valsartan: An ARB (same class as losartan)

Why they shouldn't be combined

1. Dual ARB effect: Entresto already contains valsartan (an ARB), making losartan redundant and potentially harmful 2, 1
2. FDA warning: The drug label for Entresto explicitly warns against combining it with other RAS inhibitors, including ARBs 1
3. Guidelines recommendation: Current guidelines advise against combining multiple RAS inhibitors 3

Evidence Against This Combination

The FDA label for Entresto clearly states:

• "Do not coadminister aliskiren with valsartan tablets in patients with diabetes" 1
• "Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure)" 1

The 2009 ACC/AHA guidelines state:

• "Until further information is available, the routine combined use of all 3 inhibitors of the renin-angiotensin system cannot be recommended" 3
• "There is little information available about the addition of ARBs to therapy with both ACEIs and aldosterone antagonists, but risks of renal dysfunction and hyperkalemia would be further increased" 3

The 2024 DCRM guidelines specifically note:

• "Sacubitril/valsartan should not be used with other RAS inhibitors, including ARBs, ACE inhibitors, or aliskiren" 3

Potential Risks of Combining These Medications

1. Increased risk of hypotension (dangerously low blood pressure)
2. Hyperkalemia (high potassium levels)
3. Acute renal failure or worsening kidney function
4. No additional clinical benefit over using either agent alone

Proper Use of These Medications

• For heart failure patients: Entresto (sacubitril/valsartan) is typically used as a replacement for an ACE inhibitor or ARB, not in addition to one 3
• Transition protocol: When switching from losartan to Entresto, a 36-hour washout period is recommended to minimize risk of angioedema

Clinical Recommendation

For patients currently taking losartan who might benefit from Entresto:

1. Discontinue losartan
2. Wait 36 hours (washout period)
3. Begin Entresto at appropriate starting dose based on prior ARB/ACE inhibitor dose

For patients currently taking Entresto:

• Do not add losartan under any circumstances

Common Pitfalls to Avoid

• Misunderstanding Entresto's composition: Some clinicians forget that Entresto already contains an ARB (valsartan)
• Incomplete medication reconciliation: Failing to recognize that a patient is already on multiple RAS inhibitors
• Ignoring drug interaction warnings: Electronic health record alerts about this dangerous combination should never be overridden

The evidence is clear that combining losartan with Entresto creates unnecessary risks without providing additional clinical benefits for mortality, morbidity, or quality of life outcomes.