Can angioedema (angioedema) develop in patients on Angiotensin-Converting Enzyme inhibitors (ACEi) after many years of use?

Angioedema Can Develop After Many Years of ACE Inhibitor Use

Yes, angioedema can definitely develop in patients taking ACE inhibitors even after many years of continuous therapy without previous episodes. 1 This potentially life-threatening adverse effect is not limited to the initial period of treatment.

Timing and Incidence of ACE Inhibitor-Induced Angioedema

• While angioedema most frequently occurs within the first month of ACE inhibitor therapy, it can occur even after many years of continuous use 1, 2
• Documented cases include angioedema developing after:
  • Up to 11 years of continuous lisinopril therapy 3
  • 24-48 months of treatment in several patients 4
• Incidence of ACE inhibitor-induced angioedema:
  • Approximately 0.1% to 0.7% of patients taking these medications 1
  • Likely underestimated due to poor recognition of late-onset cases 5

Risk Factors for ACE Inhibitor-Induced Angioedema

Certain patient populations have significantly higher risk:

• African American/Black patients (up to 3-fold higher risk) 1, 2, 4
• History of smoking 1, 2
• Female sex 1, 2
• Increasing age 1, 2
• Non-diabetic status (diabetic patients have lower risk) 1

Mechanism of Late-Onset Angioedema

The delayed onset of angioedema with ACE inhibitors is related to their mechanism:

• ACE inhibitors block the degradation of bradykinin and substance P 1, 2
• Susceptibility may be determined by levels or activity of other bradykinin-degrading enzymes 1
• Patients experiencing ACE inhibitor-associated angioedema have increased plasma bradykinin levels 1
• The cumulative effect on the bradykinin pathway can manifest even after years of seemingly safe use 2

Management of ACE Inhibitor-Induced Angioedema

When angioedema occurs in a patient on an ACE inhibitor:

1. Immediate discontinuation of the ACE inhibitor is the cornerstone of therapy 1, 2
2. Observe in a controlled environment due to risk of airway compromise 1
3. Be aware that:
   • The tendency to develop angioedema can persist for at least 6 weeks after discontinuation 1, 2
   • Standard treatments (antihistamines, corticosteroids, epinephrine) have limited efficacy 1, 2
   • Icatibant (bradykinin B2 receptor antagonist) may be beneficial in severe cases 2

Alternative Antihypertensive Considerations

After ACE inhibitor-induced angioedema:

• Do not rechallenge with another ACE inhibitor - this is a class effect, not a hypersensitivity reaction 1
• ARBs carry a modest risk of recurrent angioedema:
  • 2-17% risk in patients with prior ACE inhibitor-induced angioedema 1, 2, 6
  • For confirmed cases, risk is 0-9.2% 6
• Calcium channel blockers are generally considered safer alternatives 2

Clinical Pitfalls to Avoid

1. Failure to recognize the association: Many clinicians miss the connection between angioedema and ACE inhibitors, especially with late-onset cases
2. Continued ACE inhibitor use: Studies show ACE inhibitors are continued in up to 50% of patients despite documented angioedema 4
3. Inappropriate substitution: Switching to an ARB without recognizing the potential cross-reactivity risk 7
4. Underestimating severity: ACE inhibitor-induced angioedema can be fatal due to laryngeal obstruction 4

The long-term risk of angioedema with ACE inhibitors highlights the importance of considering this medication class in the differential diagnosis of any patient presenting with angioedema, regardless of how long they have been taking the medication.