American Journal of Cardiovascular Drugs

, Volume 18, Issue 3, pp 205–211 | Cite as

A Database Cohort Study to Assess the Risk of Angioedema Among Patients with Heart Failure Initiating Angiotensin-Converting Enzyme Inhibitors in the USA

  • Thy P. Do
  • Arpamas Seetasith
  • Rossella Belleli
  • Raymond G. Schlienger
  • Stefano Corda
  • Chakkarin Burudpakdee
  • Hendrik J. Streefkerk
  • Sigrid Behr
Original Research Article



Real-world evidence on the risk of angioedema associated with angiotensin-converting enzyme inhibitors (ACEIs) in patients with heart failure (HF) is scarce.


This non-interventional study aimed to estimate the incidence of and risk factors for angioedema in patients with HF initiating an ACEI in real-world practice.


This was a retrospective cohort study using claims data from the PharMetrics Plus database, supplemented with consumer health data, from 1 January 2007 to 31 March 2015. Patients with HF initiating an ACEI were followed up for a maximum of 1 year, until the first occurrence of angioedema or until cohort exit. Angioedema incidence rates were estimated and stratified by potential risk factors such as race, age, sex, and time from initiation of ACEI therapy. For each risk factor, the unadjusted and adjusted hazard ratio (HR) was calculated; exploratory analyses were carried out to account for all potential confounders.


We identified 21,639 patients with HF initiating an ACEI (mean age 58 years; 35.6% women; mean follow-up 205 days). The 1-year incidence of angioedema per 1000 patient-years was 3.3 [95% confidence interval (CI) 2.4–4.5]. The incidence was higher in Black [6.2 (95% CI 3.1–12.5)] than in non-black [2.9 (95% CI 2.1–4.1)] patients, higher in women [5.2 (95% CI 3.4–7.9)] than in men [2.3 (95% CI 1.5–3.6)], and greatest in the first 30 days of ACEI therapy.


The risk of angioedema in patients with HF initiating an ACEI observed in this study is in line with published estimates for the general patient population treated with ACEIs.



Medical writing support was provided by Noëlle L. O’Regan and Carly Sellick of PharmaGenesis London, London, UK, and was funded by Novartis Pharma AG.

Compliance with Ethical Standards

Conflict of interest

T. Do was an employee of Novartis at the time this study was conducted and is now an employee of Takeda Pharmaceutical International AG. R. Belleli was an employee of Novartis at the time this study was conducted and is now an employee of Numerus Analytics AG. H. Streefkerk was an employee of Novartis at the time this study was conducted and is now an employee of Piqur Therapeutics AG. A. Seetasith and C. Burudpakdee were contracted by Novartis Pharma AG to conduct this study. R. Schlienger, S. Corda, and S. Behr are employees of and stakeholders in Novartis Pharma AG.


This study was funded by Novartis Pharma AG, Basel, Switzerland.

Supplementary material

40256_2017_256_MOESM1_ESM.docx (30 kb)
Supplementary material 1 (DOCX 30 kb)


  1. 1.
    Roger VL. Epidemiology of heart failure. Circ Res. 2013;113(6):646–59.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, et al. Heart disease and stroke statistics—2017 update: a report from the American Heart Association. Circulation. 2017;135(10):e146–603.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37(27):2129–200.CrossRefPubMedGoogle Scholar
  4. 4.
    Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM, et al. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the heart failure society of America. Circulation. 2016;134(13):e282–93.CrossRefPubMedGoogle Scholar
  5. 5.
    Sica DA, Black HR. Angioedema in heart failure: occurrence with ACE inhibitors and safety of angiotensin receptor blocker therapy. Congest Heart Fail. 2002;8(6):334–41, 45.Google Scholar
  6. 6.
    Rasmussen ER, von Buchwald C, Wadelius M, Prasad SC, Kamaleswaran S, Ajgeiy KK, et al. Assessment of 105 patients with angiotensin converting enzyme-inhibitor induced angioedema. Int J Otolaryngol. 2017;2017:1476402.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Miller DR, Oliveria SA, Berlowitz DR, Fincke BG, Stang P, Lillienfeld DE. Angioedema incidence in US veterans initiating angiotensin-converting enzyme inhibitors. Hypertension. 2008;51(6):1624–30.CrossRefPubMedGoogle Scholar
  8. 8.
    Brown NJ, Ray WA, Snowden M, Griffin MR. Black Americans have an increased rate of angiotensin converting enzyme inhibitor-associated angioedema. Clin Pharmacol Ther. 1996;60:8–13.CrossRefPubMedGoogle Scholar
  9. 9.
    Toh S, Reichman ME, Houstoun M, Ross Southworth M, Ding X, Hernandez AF, et al. Comparative risk for angioedema associated with the use of drugs that target the renin-angiotensin-aldosterone system. Arch Intern Med. 2012;172(20):1582–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Reichman ME, Wernecke M, Graham DJ, Liao J, Yap J, Chillarige Y, et al. Antihypertensive drug associated angioedema: effect modification by race/ethnicity. Pharmacoepidemiol Drug Saf. 2017;26(10):1190–6.CrossRefPubMedGoogle Scholar
  11. 11.
    Burkhart DG, Brown NJ, Griffin MR, Ray WA, Hammerstrom T, Weiss S. Angiotensin converting enzyme inhibitor-associated angioedema: higher risk in blacks than whites. Pharmacoepidemiol Drug Saf. 1996;5:149–54.CrossRefPubMedGoogle Scholar
  12. 12.
    Kostis JB, Kim HJ, Rusnak J, Casale T, Kaplan A, Corren J, et al. Incidence and characteristics of angioedema associated with enalapril. Arch Intern Med. 2005;165(14):1637–42.CrossRefPubMedGoogle Scholar
  13. 13.
    Loftus PA, Tan M, Patel G, Lin J, Helman S, Badhey A, et al. Risk factors associated with severe and recurrent angioedema: an epidemic linked to ACE-inhibitors. Laryngoscope. 2014;124(11):2502–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Makani H, Messerli FH, Romero J, Wever-Pinzon O, Korniyenko A, Berrios RS, et al. Meta-analysis of randomized trials of angioedema as an adverse event of renin-angiotensin system inhibitors. Am J Cardiol. 2012;110(3):383–91.CrossRefPubMedGoogle Scholar
  15. 15.
    Hill A, Bigby JA. Databases to track use of preventive services after implementation of the affordable care act. Mathematica Policy Research. 2014. Accessed 9 Jun 2017.
  16. 16.
    Go AS, Lee WY, Yang J, Lo JC, Gurwitz JH. Statin therapy and risks for death and hospitalization in chronic heart failure. JAMA. 2006;296(17):2105–11.CrossRefPubMedGoogle Scholar
  17. 17.
    McCullough PA, Philbin EF, Spertus JA, Kaatz S, Sandberg KR, Weaver WD, et al. Confirmation of a heart failure epidemic: findings from the Resource Utilization Among Congestive Heart Failure (REACH) study. J Am Coll Cardiol. 2002;39(1):60–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Saczynski JS, Andrade SE, Harrold LR, Tjia J, Cutrona SL, Dodd KS, et al. Mini-sentinel systematic evaluation of health outcome of interest definitions for studies using administrative and claims data: heart failure. Pharmacoepidemiol Drug Saf. 2012;21:10.CrossRefPubMedCentralGoogle Scholar
  19. 19.
    Inomata N. Recent advances in drug-induced angioedema. Allergol Int. 2012;61:545–57.CrossRefPubMedGoogle Scholar
  20. 20.
    Schneeweiss S, Gagne JJ, Glynn RJ, Ruhl M, Rassen JA. Assessing the comparative effectiveness of newly marketed medications: methodological challenges and implications for drug development. Clin Pharmacol Ther. 2011;90(6):777–90.CrossRefPubMedGoogle Scholar
  21. 21.
    The Henry J. Kaiser Family Foundation. Distribution of the nonelderly with Medicaid by race/ethnicity. 2016. Accessed 9 Jun 2017.
  22. 22.
    Centers for Medicare and Medicaid Services, Office of Enterprise Data and Analytics, CMS Chronic Conditions Data Warehouse. Total medicare enrollment. Accessed 16 Aug 2016.

Copyright information

© Springer International Publishing AG, part of Springer Nature 2017

Authors and Affiliations

  • Thy P. Do
    • 1
  • Arpamas Seetasith
    • 2
  • Rossella Belleli
    • 1
  • Raymond G. Schlienger
    • 1
  • Stefano Corda
    • 1
  • Chakkarin Burudpakdee
    • 2
  • Hendrik J. Streefkerk
    • 1
  • Sigrid Behr
    • 1
  1. 1.Novartis Pharma AGBaselSwitzerland
  2. 2.QuintilesIMSFairfaxUSA

Personalised recommendations