Published: 3 September 2020


Kounis syndrome – ‘Allergic angina’ associated with some medicines

Published: 3 September 2020
Prescriber Update 41(3): 58–59
September 2020

Key Messages

  • Kounis syndrome is a hypersensitivity reaction affecting the coronary arteries.
  • In Kounis syndrome. the release of inflammatory mediators in response to an allergic stimulus may result in coronary artery spasm, atheromatous plaque rupture and/or coronary stent thrombosis.
  • Consider Kounis syndrome in a patient who develops angina symptoms shortly after starting a medicine.

CARM case report

The Centre for Adverse Reactions Monitoring (CARM) recently received a report of coronary artery spasm associated with the use of amoxicillin/clavulanic acid injection in a 36-year-old male (CARM ID: 135996).

What is Kounis syndrome?

‘Allergic angina’ may occur in the context of an acute hypersensitivity reaction, a phenomenon known as Kounis syndrome.1 Kounis syndrome was first described in 19912 and although seemingly rare, it is increasingly recognised as an allergic reaction to medicines, foods and environmental allergens.3

The underlying mechanism for Kounis syndrome is mast cell activation and release of inflammatory mediators.4 Three variants of Kounis syndrome have been identified.1,4–6

  • Type I occurs in patients with structurally normal coronary arteries and no cardiovascular risk factors. The acute release of inflammatory mediators induces coronary vasospasm, which may or may not result in acute myocardial infarction.
  • Type II Kounis syndrome occurs in patients with pre-existing coronary artery disease, in whom the acute release of inflammatory mediators induces coronary vasospasm that may lead to plaque rupture and myocardial infarction.
  • Type III Kounis syndrome occurs in patients with a coronary artery stent, in whom the release of inflammatory mediators may result in stent thrombosis.

The acute coronary syndrome typically begins within one hour of exposure to the offending allergen, although longer onset times have been reported.5

Which medicines are associated with Kounis syndrome?

To date, Kounis syndrome has been associated with a variety of medicines including beta-lactam antibiotics,7 non-steroidal anti-inflammatory drugs,8 intravenous iron preparations9 and rocuronium.10 Currently in New Zealand, Kounis syndrome is listed in the data sheets for diclofenac,11,12 carboplatin,13,14 clopidogrel15 and Mersyndol (paracetamol + codeine + doxylamine).16

How is Kounis syndrome treated?

Management of Kounis syndrome involves removing the offending allergen, managing the acute coronary vasospasm, and treating the allergic response.6 Careful selection and use of medicines are needed when managing the acute condition to avoid further histamine release or exacerbation of coronary vasospasm.17


  1. Kounis NG. 2016. Kounis syndrome: an update on epidemiology, pathogenesis, diagnosis and therapeutic management. Clinical Chemistry and Laboratory Medicine 54(10): 1545–59. DOI: 10.1515/cclm-2016-0010 (accessed 16 July 2020).
  2. Kounis NG and Zavras GM. 1991. Histamine-induced coronary artery spasm: the concept of allergic angina. British Journal of Clinical Practice 45(2): 121–8.
  3. Kounis NG, Giannopoulos S, Soufras GD, et al. 2015. Foods, drugs and environmental factors: novel Kounis syndrome offenders. Internal Medicine 54(13): 1577–82. DOI: 10.2169/internalmedicine.54.3684 (accessed 15 July 2020).
  4. Hermans M, van Lennep JR, van Daele P, et al. 2019. Mast cells in cardiovascular disease: from bench to bedside. International Journal of Molecular Sciences 20(14): 3395. DOI: 10.3390/ijms20143395 (accessed 15 July 2020).
  5. Abdelghany M, Subedi R, Shah S, et al. 2017. Kounis syndrome: a review article on epidemiology, diagnostic findings, management and complications of allergic acute coronary syndrome. International Journal of Cardiology 232: 1–4. DOI: 10.1016/j.ijcard.2017.01.124 (accessed 15 July 2020).
  6. Fassio F, Losappio L, Antolin-Amerigo D, et al. 2016. Kounis syndrome: a concise review with focus on management. European Journal of Internal Medicine 30: 7–10. DOI: 10.1016/j.ejim.2015.12.004 (accessed 20 July 2020).
  7. Ridella M, Bagdure S, Nugent K, et al. 2009. Kounis syndrome following beta-lactam antibiotic use: review of literature. Inflammation & Allergy Drug Targets 8(1): 11–16. DOI 10.2174/187152809787582462 (accessed 20 July 2020).
  8. Renda F, Landoni G, Trotta F, et al. 2016. Kounis syndrome: an analysis of spontaneous reports from international pharmacovigilance database. International Journal of Cardiology 203: 217–20. DOI: 10.1016/j.ijcard.2015.10.003 (accessed 20 July 2020).
  9. European Medicines Agency. 2019. PRAC recommendations on signals - adopted at the 28–31 October 2019 PRAC meeting: 1.1 Iron sucrose, iron carboxymaltose, iron isomaltoside, iron dextran, sodium ferric gluconate – Arteriospasm coronary 25 November 2019. URL: (accessed 17 July 2020).
  10. European Medicines Agency. 2020. Scientific conclusions and grounds for the variation to the terms of the Marketing Authorisation(s) – Rocuronium.. URL: (accessed 17 July 2020).
  11. Novartis New Zealand Ltd. 2019. Voltaren Solution for Injection New Zealand Data Sheet 17 June 2019. URL: (accessed 17 July 2020).
  12. Novartis New Zealand Ltd. 2019. Diclofenac Sandoz New Zealand Data Sheet 9 September 2019. URL: (accessed 17 July 2020).
  13. Novartis New Zealand Ltd. 2019. Carboplatin EbeweNew Zealand Data Sheet 18 December 2019. URL: (accessed 17 July 2020).
  14. Pfizer New Zealand Ltd. 2020. DBL Carboplatin InjectionNew Zealand Data Sheet 21 January 2020. URL: (accessed 17 July 2020).
  15. Multichem NZ Ltd. 2020. Clopidogrel MultichemNew Zealand Data Sheet 4 February 2020. URL: (accessed 17 July 2020).
  16. Sanofi-Aventis New Zealand Ltd. 2020. Mersyndol New Zealand Data Sheet 15 June 2020. URL: (accessed 17 July 2020).
  17. Memon S, Chhabra L, Masrur S, et al. 2015. Allergic acute coronary syndrome (Kounis syndrome). Proceedings (Baylor University. Medical Center) 28(3): 358–62. DOI: 10.1080/08998280.2015.11929274 (accessed 20 July 2020).
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