Drug Safety

, Volume 35, Issue 1, pp 33–43 | Cite as

Cardiovascular Events in Patients taking Varenicline

A Case Series from Intensive Postmarketing Surveillance in New Zealand
  • Mira Harrison-Woolrych
  • Simran Maggo
  • Ming Tan
  • Ruth Savage
  • Janelle Ashton
Original Research Article

Abstract

Background: The smoking cessation medicine varenicline has been associated with an increased risk of cardiovascular adverse events compared with placebo in clinical trials. Cases of cardiovascular events, including myocardial infarction (MI) and cardiac dysrhythmias, have been noted from spontaneous reporting systems.

Objective: The aim of this study was to summarize and describe cardiovascular adverse reactions identified in a general population during intensive postmarketing surveillance of varenicline in New Zealand.

Methods: Observational prospective cohort study using prescription event monitoring methods. The patient cohort was established from pharmacy dispensing data sent directly to the Intensive Medicines Monitoring Programme (IMMP) for all New Zealand patients prescribed varenicline. Adverse cardiovascular events were identified from follow-up questionnaires completed by doctors, spontaneous reports and by record linkage to national datasets. Cardiovascular events were organized into clinical groupings for further clinical assessment, and key cases were identified.

Results: All New Zealand patients dispensed a prescription for varenicline from 1 April 2007 to 30 November 2010 were included in this study. At 31 January 2011, the IMMP varenicline events dataset included a total of 172 adverse events in the IMMP circulatory System Organ Class. There were 48 reports of myocardial ischaemia, including 12 reports of MI and 8 reports of angina. Two key cases of myocardial ischaemia suggested that this may have been induced by coronary artery spasm secondary to varenicline treatment. There were 50 reports of hypotensive events, with two key cases having documented hypotension associated with chest pain/tightness, and a further 27 reports of dysrhythmia events, including two unexplained sudden deaths.

Conclusions: This paper presents a series of cases of cardiovascular events in patients taking varenicline. Whilst there were multiple confounding factors in some patients, key cases were identified that suggested a possible mechanism of dysregulation of blood pressure leading to vasospasm or hypotension.

References

  1. 1.
    Hays JT, Ebbert JO. Varenicline for tobacco dependence. N Engl J Med 2008; 359(19): 2018–24PubMedCrossRefGoogle Scholar
  2. 2.
    Mihalak KB, Carroll FI, Luetje CW. Varenicline is a partial agonist at α4β2 and a full agonist at α7 neuronal nicotinic receptors. Mol Pharmacol 2006; 70(3): 801–5PubMedCrossRefGoogle Scholar
  3. 3.
    Roddy E. Bupropion and other non-nicotine pharmaco-therapies. BMJ 2004; 328(7438): 509–11PubMedCrossRefGoogle Scholar
  4. 4.
    Tonstad S. Smoking cessation efficacy and safety of varenicline, an [alpha]4[beta]2 nicotinic receptor partial agonist. J Cardiovasc Nurs 2006; 21(6): 433–6PubMedGoogle Scholar
  5. 5.
    Tonstad S, Rollema H. Varenicline in smoking cessation. Expert Rev Respir Med 2010; 4(3): 291–9PubMedCrossRefGoogle Scholar
  6. 6.
    Oncken C, Gonzales D, Nides M, et al. Efficacy and safety of the novel selective nicotinic acetylcholine receptor partial agonist, varenicline, for smoking cessation. Arch Intern Med 2006; 166(15): 1571–7PubMedCrossRefGoogle Scholar
  7. 7.
    Tsai S-T, Cho H-J, Cheng H-S, et al. A randomized, placebo-controlled trial of varenicline, a selective [alpha]4[beta]2 nicotinic acetylcholine receptor partial agonist, as a new therapy for smoking cessation in Asian smokers. Clin Ther 2007; 29(6): 1027–39PubMedCrossRefGoogle Scholar
  8. 8.
    Williams KE, Reeves KR, Billing CB, et al. A double-blind study evaluating the long-term safety of varenicline for smoking cessation. Curr Med Res Opin 2007; 23(4): 793–801PubMedCrossRefGoogle Scholar
  9. 9.
    Nides M, Oncken C, Gonzales D, et al. Smoking cessation with varenicline, a selective alpha4beta2 nicotinic receptor partial agonist: results from a 7-week, randomized, placebo-and bupropion-controlled trial with 1-year follow-up. Arch Intern Med 2006; 166(15): 1561–8PubMedCrossRefGoogle Scholar
  10. 10.
    Aubin HJ, Bobak A, Britton JR, et al. Varenicline versus transdermal nicotine patch for smoking cessation: results from a randomised open-label trial. Thorax 2008; 63(8): 717–24PubMedCrossRefGoogle Scholar
  11. 11.
    Hays JT, Ebbert JO, Sood A. Efficacy and safety of varenicline for smoking cessation. Am J Med 2008; 121 (4Suppl. 1): S32–42PubMedCrossRefGoogle Scholar
  12. 12.
    Harrison-Woolrych M. Psychiatric reactions with varenicline: interim results from intensive monitoring in New Zealand. Prescriber Update 2009 March 2011 [online]. Available from URL: URL: http://www.medsafe.govt.nz/profs/PUArticles/Varenicline%20Interim%20Results-May09.htm [Accessed 2011 Jul 15]
  13. 13.
    Harrison-Woolrych M, Ashton J. Psychiatric adverse events associated with varenicline: an intensive postmarketing prospective cohort study in New Zealand. Drug Saf 2011; 34(9): 763–72PubMedCrossRefGoogle Scholar
  14. 14.
    Pfizer. New Zealand data sheet for Champix. March 2011 [online]. Available from URL: http://www.medsafe.govt.nz/profs/datasheet/c/Champixtab.pdf [Accessed 2011 Jun 15]
  15. 15.
    Pfizer. Summary of product characteristics for Champix [online]. Available from URL: http://www.medicines.org.uk/emc/document.aspx?documentId=19045 [Accessed 2011 Jun 15]
  16. 16.
    Rigotti NA, Pipe AL, Benowitz NL, et al. Efficacy and safety of varenicline for smoking cessation in patients with cardiovascular disease: a randomized trial. Circulation 2010; 121(2): 221–9PubMedCrossRefGoogle Scholar
  17. 17.
    FDA. Chantix (varenicline): label change — risk of certain cardiovascular adverse events [online]. Available from URL: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm259469.htm [Accessed 2011 Jun 15]
  18. 18.
    Singh S, Loke YK, Spangler JG, et al. Risk of serious adverse cardiovascular events associated with varenicline: a systematic review and meta-analysis. CMAJ 2011; 183(12): 1359–66PubMedCrossRefGoogle Scholar
  19. 19.
    Coulter DM. The New Zealand intensive medicines monitoring programme. Pharmacoepidemiol Drug Saf 1998; 7(2): 79–90PubMedCrossRefGoogle Scholar
  20. 20.
    Harrison-Woolrych M, Coulter DM. PEM in New Zealand. In: Mann R, Andrews EB, editors. Pharmacovigilance. 2nd ed. Chichester: John Wiley and Sons Ltd, 2007: 313–28Google Scholar
  21. 21.
    Kunac DL, Harrison-Woolrych M, Tatley MV. Pharmacovigilance in New Zealand: the role of the New Zealand Pharmacovigilance Centre in facilitating safer medicines use. N Z Med J 2008; 121(1283): 76–89PubMedGoogle Scholar
  22. 22.
    Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet 2000; 356(9237): 1255–9PubMedCrossRefGoogle Scholar
  23. 23.
    Karch FE, Lasagna L. Adverse drug reactions: a critical review. JAMA 1975; 234(12): 1236–41PubMedCrossRefGoogle Scholar
  24. 24.
    Erhardt L. Cigarette smoking: an undertreated risk factor for cardiovascular disease. Atherosclerosis 2009; 205(1): 23–32PubMedCrossRefGoogle Scholar
  25. 25.
    New Zealand Guidelines Group. The assessment and management of cardiovascular risk. Wellington: New Zealand Guidelines Group, 2006: 26Google Scholar
  26. 26.
    Shakir SA. PEM in the UK. In: Mann R, Andrews EB, editors. Pharmacovigilance. 2nd ed. Chichester: John Wiley and Sons, 2007: 307–16Google Scholar
  27. 27.
    Institute for Safe Medication Practices. Strong safety signal seen for new varenicline risks [online]. Available from URL: http://www.ismp.org/docs/vareniclinestudy.asp [Accessed 2011 Jun 15]
  28. 28.
    Nawrot TS, Perez L, Künzli N, et al. Public health importance of triggers of myocardial infarction: a comparative risk assessment. Lancet 2011; 377(9767): 732–40PubMedCrossRefGoogle Scholar
  29. 29.
    Prinzmetal M, Kennamer R, Merliss R, et al. Angina pectoris: I. A variant form of angina pectoris: preliminary report. Am J Med 1959; 27: 375–88PubMedCrossRefGoogle Scholar
  30. 30.
    Myerburg RJ, Kessler KM, Mallon SM, et al. Life-threatening ventricular arrhythmias in patients with silent myocardial ischemia due to coronary artery spasm. N Engl J Med 1992; 326(22): 1451–5PubMedCrossRefGoogle Scholar
  31. 31.
    Chevalier P, Dacosta A, Defaye P, et al. Arrhythmic cardiac arrest due to isolated coronary artery spasm: long-term outcome of seven resuscitated patients. J Am Coll Cardiol 1998; 31(1): 57–61PubMedCrossRefGoogle Scholar
  32. 32.
    Krahn AD, Healey JS, Chauhan V, et al. Systematic assessment of patients with unexplained cardiac arrest. Circulation 2009; 120(4): 278–85PubMedCrossRefGoogle Scholar
  33. 33.
    Kido S, Ishii Y, Hasebe N, et al. Significance of coronary risk factors and coronary arteriosclerosis for coronary vasospasm. J Cardiol 1998; 31(3): 135–43PubMedGoogle Scholar
  34. 34.
    Sugiishi M, Takatsu F. Cigarette smoking is a major risk factor for coronary spasm. Circulation 1993; 87(1): 76–9PubMedCrossRefGoogle Scholar
  35. 35.
    Conroy WG, Berg DK. Neurons can maintain multiple classes of nicotinic acetylcholine receptors distinguished by different subunit compositions. J Biol Chem 1995; 270(9): 4424–31PubMedCrossRefGoogle Scholar
  36. 36.
    Sueda S, Kohno H, Fukuda H, et al. Clinical impact of selective spasm provocation tests: comparisons between acetylcholine and ergonovine in 1508 examinations. Coron Artery Dis 2004; 15(8): 491–7PubMedCrossRefGoogle Scholar
  37. 37.
    Geevasinga NM, Mahunt N. Call-Fleming syndrome associated with varenicline [online]. Available from URL: http://www.anzan2011.com/abstract/62.asp [Accessed 2011 Sep 1]
  38. 38.
    Niedermaier O, Smith M, Beightol L, et al. Influence of cigarette smoking on human autonomic function. Circulation 1993; 88(2): 562–71PubMedCrossRefGoogle Scholar
  39. 39.
    Dunn FG. Hypertension and myocardial infarction. J Am Coll Cardiol 1983; 1 (2 Part 1): 528–32PubMedCrossRefGoogle Scholar
  40. 40.
    Madhavan S, Ooi W, Cohen H, et al. Relation of pulse pressure and blood pressure reduction to the incidence of myocardial infarction. Hypertension 1994; 23(3): 395–401PubMedCrossRefGoogle Scholar
  41. 41.
    Cosentino F, Volpe M. Hypertension, stroke, and endothelium. Curr Hypertens Rep 2005; 7(1): 68–71PubMedCrossRefGoogle Scholar
  42. 42.
    Moore C, Wang Y, Ramage AG. Cardiovascular effects of activation of central a7 and α4β2 nAChRs: a role for vasopressin in anaesthetized rats. Br J Pharmacol 2008; 153(8): 1728–38PubMedCrossRefGoogle Scholar
  43. 43.
    Belluardo N, Mudó G, Blum M, et al. Central nicotinic receptors, neurotrophic factors and neuroprotection. Behav Brain Res 2000; 113(1–2): 21–34PubMedCrossRefGoogle Scholar
  44. 44.
    Gourine AV, Wood JD, Burnstock G. Purinergic signalling in autonomic control. Trends Neurosci 2009; 32(5): 241–8PubMedCrossRefGoogle Scholar
  45. 45.
    Dampney RA. Functional organization of central pathways regulating the cardiovascular system. Physiol Rev 1994; 74(2): 323–64PubMedGoogle Scholar
  46. 46.
    Pilowsky PM, Goodchild AK. Baroreceptor reflex pathways and neurotransmitters: 10 years on. J Hypertens 2002; 20(9): 1675–88PubMedCrossRefGoogle Scholar
  47. 47.
    Guyenet PG. The sympathetic control of blood pressure. Nat Rev Neurosci 2006; 7(5): 335–46PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2012

Authors and Affiliations

  • Mira Harrison-Woolrych
    • 1
  • Simran Maggo
    • 2
  • Ming Tan
    • 1
  • Ruth Savage
    • 3
    • 4
  • Janelle Ashton
    • 1
    • 3
  1. 1.Intensive Medicines Monitoring Programme, New Zealand Pharmacovigilance Centre, Department of Preventive and Social MedicineUniversity of Otago Medical SchoolDunedinNew Zealand
  2. 2.Department of Pharmacology & ToxicologyUniversity of OtagoDunedinNew Zealand
  3. 3.Centre for Adverse Reactions Monitoring, New Zealand Pharmacovigilance Centre, Department of Preventive and Social MedicineUniversity of Otago Medical SchoolDunedinNew Zealand
  4. 4.Department of Public Health and General PracticeUniversity of Otago ChristchurchChristchurchNew Zealand

Personalised recommendations