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Clinical Autonomic Research

, Volume 22, Issue 6, pp 275–280 | Cite as

Rationale for the prevention of syncope trial IV: assessment of midodrine

  • Satish R. RajEmail author
  • Peter D. Faris
  • Maureen McRae
  • Robert S. Sheldon
Research Article

Abstract

Background

Vasovagal syncope is a common problem associated with a poor quality of life, which improves when the frequency of syncope is reduced. Effective pharmacological therapies for vasovagal syncope have been elusive. Midodrine is a pro-drug whose primary metabolite is an alpha-1 adrenoreceptor agonist. A few studies have suggested that it may be beneficial in syncope, but all have had significant methodological limitations. A placebo-controlled clinical trial of midodrine for the prevention of vasovagal syncope is needed.

Structure of study

The prevention of syncope trial IV (POST 4) is a multicenter, international, randomized, placebo-controlled study of midodrine in the prevention of vasovagal syncope. The primary end point is the time to first recurrence of syncope. Patients will be randomized 1:1 to receive midodrine 10–30 mg/day or matching placebo, and followed for 1 year. Secondary end points include syncope frequency, presyncope, and quality of life. Primary analysis will be performed with an intention-to-treat approach, with a secondary on-treatment analysis.

Power calculations

A total sample size of 112, split equally between the two groups, achieves 85 % power to detect a 50 % relative risk reduction when the event rates are 55 and 27.5 % in the placebo and midodrine arms. Allowing for 20 % dropout, we propose to enroll 140 patients.

Registration

POST 4 is registered with http://www.clinicaltrials.gov (NCT01456481).

Implications

This study will be the first adequately powered trial to determine whether midodrine is effective in preventing vasovagal syncope. If it is effective, then midodrine may become the first-line pharmacological therapy for this condition.

Keywords

Vasovagal syncope Randomized clinical trial Quality of life 

Notes

Acknowledgments

This study was supported by a grant MOP-115124 from the Canadian Institutes of Health Research, Ottawa, Canada to RSS. AA Pharma (Vaughn, Ontario, Canada) provided the midodrine and placebo capsules.

References

  1. 1.
    Connolly SJ, Sheldon R, Roberts RS, Gent M (1999) The North American vasovagal pacemaker study (VPS). A randomized trial of permanent cardiac pacing for the prevention of vasovagal syncope. J Am Coll Cardiol 33:16–20PubMedCrossRefGoogle Scholar
  2. 2.
    Connolly SJ, Sheldon R, Thorpe KE, Roberts RS, Ellenbogen KA, Wilkoff BL, Morillo C, Gent M (2003) Pacemaker therapy for prevention of syncope in patients with recurrent severe vasovagal syncope: second vasovagal pacemaker study (VPS II): a randomized trial. JAMA 289:2224–2229PubMedCrossRefGoogle Scholar
  3. 3.
    Ganzeboom KS, Mairuhu G, Reitsma JB, Linzer M, Wieling W, van DN (2006) Lifetime cumulative incidence of syncope in the general population: a study of 549 Dutch subjects aged 35–60 years. J Cardiovasc Electrophysiol 17:1172–1176PubMedCrossRefGoogle Scholar
  4. 4.
    Kaufmann H, Saadia D, Voustianiouk A (2002) Midodrine in neurally mediated syncope: a double-blind, randomized, crossover study. Ann Neurol 52:342–345PubMedCrossRefGoogle Scholar
  5. 5.
    Lamarre-Cliche M, Souich P, Champlain J, Larochelle P (2008) Pharmacokinetic and pharmacodynamic effects of midodrine on blood pressure, the autonomic nervous system, and plasma natriuretic peptides: a prospective, randomized, single-blind, two-period, crossover, placebo-controlled study. Clin Ther 30:1629–1638PubMedCrossRefGoogle Scholar
  6. 6.
    Malik P, Koshman ML, Sheldon R (1997) Timing of first recurrence of syncope predicts syncopal frequency after a positive tilt table test result. J Am Coll Cardiol 29:1284–1289PubMedCrossRefGoogle Scholar
  7. 7.
    Manyari DE, Rose S, Tyberg JV, Sheldon RS (1996) Abnormal reflex venous function in patients with neuromediated syncope. J Am Coll Cardiol 27:1730–1735PubMedCrossRefGoogle Scholar
  8. 8.
    Morillo CA, Eckberg DL, Ellenbogen KA, Beightol LA, Hoag JB, Tahvanainen KU, Kuusela TA, Diedrich AM (1997) Vagal and sympathetic mechanisms in patients with orthostatic vasovagal syncope. Circulation 96:2509–2513PubMedCrossRefGoogle Scholar
  9. 9.
    Mosqueda-Garcia R, Furlan R, Fernandez-Violante R, Desai T, Snell M, Jarai Z, Ananthram V, Robertson RM, Robertson D (1997) Sympathetic and baroreceptor reflex function in neurally mediated syncope evoked by tilt. J Clin Invest 99:2736–2744PubMedCrossRefGoogle Scholar
  10. 10.
    Mosqueda-Garcia R, Furlan R, Tank J, Fernandez-Violante R (2000) The elusive pathophysiology of neurally mediated syncope. Circulation 102:2898–2906PubMedCrossRefGoogle Scholar
  11. 11.
    Olde Nordkamp LR, van DN, Ganzeboom KS, Reitsma JB, Luitse JS, Dekker LR, Shen WK, Wieling W (2009) Syncope prevalence in the ED compared to general practice and population: a strong selection process. Am J Emerg Med 27:271–279PubMedCrossRefGoogle Scholar
  12. 12.
    Olshansky B (2007) Placebo and nocebo in cardiovascular health: implications for healthcare, research, and the doctor–patient relationship. J Am Coll Cardiol 49:415–421PubMedCrossRefGoogle Scholar
  13. 13.
    Perez-Lugones A, Schweikert R, Pavia S, Sra J, Akhtar M, Jaeger F, Tomassoni GF, Saliba W, Leonelli FM, Bash D, Beheiry S, Shewchik J, Tchou PJ, Natale A (2001) Usefulness of midodrine in patients with severely symptomatic neurocardiogenic syncope: a randomized control study. J Cardiovasc Electrophysiol 12:935–938PubMedCrossRefGoogle Scholar
  14. 14.
    Posch W, Lindner W (1989) Quantification of midodrine and its active metabolite in plasma using a high performance liquid chromatography column switching technique. Biomed Chromatogr 3:153–156PubMedCrossRefGoogle Scholar
  15. 15.
    Qingyou Z, Junbao D, Chaoshu T (2006) The efficacy of midodrine hydrochloride in the treatment of children with vasovagal syncope. J Pediatr 149:777–780PubMedCrossRefGoogle Scholar
  16. 16.
    Raj SR, Rose S, Ritchie D, Sheldon RS (2006) The Second Prevention of Syncope Trial (POST II)—a randomized clinical trial of fludrocortisone for the prevention of neurally mediated syncope: rationale and study design. Am Heart J 151:1186–1187PubMedCrossRefGoogle Scholar
  17. 17.
    Raviele A, Brignole M, Sutton R, Alboni P, Giani P, Menozzi C, Moya A (1999) Effect of etilefrine in preventing syncopal recurrence in patients with vasovagal syncope: a double-blind, randomized, placebo-controlled trial. The Vasovagal Syncope International Study. Circulation 99:1452–1457PubMedCrossRefGoogle Scholar
  18. 18.
    Romme JJ, van DN, Go-Schon IK, Reitsma JB, Wieling W (2011) Effectiveness of midodrine treatment in patients with recurrent vasovagal syncope not responding to non-pharmacological treatment (STAND-trial). Europace 13:1639–1647PubMedCrossRefGoogle Scholar
  19. 19.
    Rose MS, Koshman ML, Ritchie D, Sheldon R (2009) The development and preliminary validation of a scale measuring the impact of syncope on quality of life. Europace 11:1369–1374PubMedCrossRefGoogle Scholar
  20. 20.
    Rose MS, Koshman ML, Spreng S, Sheldon R (2000) The relationship between health-related quality of life and frequency of spells in patients with syncope. J Clin Epidemiol 53:1209–1216PubMedCrossRefGoogle Scholar
  21. 21.
    Serletis A, Rose S, Sheldon AG, Sheldon RS (2006) Vasovagal syncope in medical students and their first-degree relatives. Eur Heart J 27:1965–1970PubMedCrossRefGoogle Scholar
  22. 22.
    Sheldon R, Connolly S, Rose S, Klingenheben T, Krahn A, Morillo C, Talajic M, Ku T, Fouad-Tarazi F, Ritchie D, Koshman ML (2006) Prevention of Syncope Trial (POST): a randomized, placebo-controlled study of metoprolol in the prevention of vasovagal syncope. Circulation 113:1164–1170PubMedCrossRefGoogle Scholar
  23. 23.
    Sheldon R, Koshman ML, Wilson W, Kieser T, Rose S (1998) Effect of dual-chamber pacing with automatic rate-drop sensing on recurrent neurally mediated syncope. Am J Cardiol 81:158–162PubMedCrossRefGoogle Scholar
  24. 24.
    Sheldon R, Rose S, Connolly S (2003) Prevention of Syncope Trial (POST): a randomized clinical trial of beta blockers in the prevention of vasovagal syncope; rationale and study design. Europace 5:71–75PubMedCrossRefGoogle Scholar
  25. 25.
    Sheldon R, Rose S, Connolly S, Ritchie D, Koshman ML, Frenneaux M (2006) Diagnostic criteria for vasovagal syncope based on a quantitative history. Eur Heart J 27:344–350PubMedCrossRefGoogle Scholar
  26. 26.
    Sheldon R, Rose S, Flanagan P, Koshman ML, Killam S (1996) Risk factors for syncope recurrence after a positive tilt-table test in patients with syncope. Circulation 93:973–981PubMedCrossRefGoogle Scholar
  27. 27.
    Sheldon RS, Amuah JE, Connolly SJ, Rose S, Morillo CA, Talajic M, Kus T, Fouad-Tarazi F, Klingenheben T, Krahn AD, Sheldon A, Koshman ML, Ritchie D (2009) Design and use of a quantitative scale for measuring presyncope. J Cardiovasc Electrophysiol 20:888–893PubMedCrossRefGoogle Scholar
  28. 28.
    Stewart JM, McLeod KJ, Sanyal S, Herzberg G, Montgomery LD (2004) Relation of postural vasovagal syncope to splanchnic hypervolemia in adolescents. Circulation 110:2575–2581PubMedCrossRefGoogle Scholar
  29. 29.
    Sun BC, Emond JA, Camargo CA Jr (2005) Direct medical costs of syncope-related hospitalizations in the United States. Am J Cardiol 95:668–671PubMedCrossRefGoogle Scholar
  30. 30.
    Verheyden B, Liu J, van DN, Westerhof BE, Reybrouck T, Aubert AE, Wieling W (2008) Steep fall in cardiac output is main determinant of hypotension during drug-free and nitroglycerine-induced orthostatic vasovagal syncope. Heart Rhythm 5:1695–1701PubMedCrossRefGoogle Scholar
  31. 31.
    Ward CR, Gray JC, Gilroy JJ, Kenny RA (1998) Midodrine: a role in the management of neurocardiogenic syncope. Heart 79:45–49PubMedGoogle Scholar
  32. 32.
    Yamazaki R, Tsuchida K, Aihara H (1987) Effects of midodrine on experimentally induced postural hypotension and venous pooling in dogs. Res Commun Chem Pathol Pharmacol 58:323–337PubMedGoogle Scholar
  33. 33.
    Yamazaki R, Tsuchida K, Aihara H (1988) Effects of alpha-adrenoceptor agonists on cardiac output and blood pressure in spinally anesthetized ganglion-blocked dogs. Arch Int Pharmacodyn Ther 295:80–93PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Satish R. Raj
    • 1
    Email author
  • Peter D. Faris
    • 2
  • Maureen McRae
    • 3
  • Robert S. Sheldon
    • 3
  1. 1.Division of Clinical Pharmacology, Departments of Medicine and PharmacologyVanderbilt UniversityNashvilleUSA
  2. 2.Alberta Health ServicesCalgaryCanada
  3. 3.Libin Cardiovascular Institute of AlbertaUniversity of CalgaryCalgaryCanada

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