Drug Safety

, Volume 30, Issue 12, pp 1093–1110

Cardiac Repolarisation and Drug Regulation

Assessing Cardiac Safety 10 Years after the CPMP Guidance
Current Opinion

Abstract

December 2007 marks the 10-year anniversary of the first regulatory guidance for evaluation of drug-induced QT interval prolongation. A decade on, it seems surprising that this document, which was released by the Committee on Proprietary Medicinal Products, caused such acrimony in the industry. Sponsors now routinely evaluate their new drugs for an effect on cardiac electrophysiology in preclinical studies, in addition to obtaining ECGs in all phases of drug development and conducting a formal thorough QT study in humans.

However, concurrently, new concerns have also emerged on broader issues related to the cardiovascular safety of drugs because of their potential to shorten the QT interval as well as to induce proischaemic, profibrotic or prothrombotic effects. Drugs may also have an indirect effect by adversely affecting one or more of the cardiovascular risk factors (e.g. through fluid retention or induction of dyslipidaemia).

In addition to peroxisome proliferator-activated receptor agonists and cyclo-oxygenase 2 selective inhibitors, three other drugs, darbepoetin alfa, pergolide and tegaserod, provide a more contemporary regulatory stance on tolerance of cardiovascular risk of drugs and their benefit-risk assessment. This recent, more assertive,risk-averse stance has significant implications for future drug development. These include the routine evaluation of cardiovascular safety for certain classes of drugs. Drugs that are intended for long-term use will almost certainly require long-term clinical evaluation in studies that enrol populations that most closely resemble the ultimate target population. Novel mechanisms of action and biomarkers by themselves are no guarantee of improved safety or benefits. Even some traditional biomarkers have come to be viewed with scepticism. Requirements for more extensive and earlier postmarketing assessment of clinical benefits and rare, but serious risks associated with new medicinal products should create a new standard of evidence for industry and regulators and almost certainly result in better assessment of benefit/risk, more effective and balanced regulatory actions and better care for patients.

References

  1. 1.
    Committee for Proprietary Medicinal Products. Points to consider: the assessment of the potential for QT interval prolongation by non-cardiovascular medicinal products. London: EMEA, 1997 Dec 17. Document no.: CPMP/986/96Google Scholar
  2. 2.
    Committee for Medicinal Products for Human Use. ICH note for guidance on the clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs (ICH E14). London: EMEA, 2005 May 25. Document no.: CHMP/ICH/2/04 [online]. Available from URL: http://www.emea.eu.int/pdfs/human/ich/000204en.pdf [Accessed 2007 Mar 22]Google Scholar
  3. 3.
    von Frey W. Weitere erfahrungen mit chinidin bei absoluter herzunregelmassigkeit. Berliner Klin Wochenschr 1918; 55: 849–53Google Scholar
  4. 4.
    Lewis T, Drury AN. Revised views of refractory period in relation to drugs reputed to prolong it and in relation to circus movement. Heart 1926; 13: 95–100 1106Google Scholar
  5. 5.
    Levy RL. Clinical studies with quinidine: the clinical toxicology of quinine. JAMA 1922; 79: 1108–13CrossRefGoogle Scholar
  6. 6.
    Gordon B, Matton M, Levine SA. The mechanism of death from quinidine and a method of resuscitation; an experimental study. J Clin Invest 1925; 1: 497–517PubMedCrossRefGoogle Scholar
  7. 7.
    Sagall EL, Horn CO, Riseman JEF. Studies on the action of quinidine in man: I. Measurement of the speed and duration of the effect following oral and intramuscular administration. Arch Intern Med 1943; 71: 460–73CrossRefGoogle Scholar
  8. 8.
    Sturnick M, Riseman JEF, Sagall EL. Studies on the action of quinidine in man: II. Intramuscular administration of a soluble preparation of quinidine in the treatment of acute cardiac arrhythmias. JAMA 1943; 121: 917–20CrossRefGoogle Scholar
  9. 9.
    Bellet S, Finkelstein D. Significance of QT prolongation in the electrocardiogram: based on the study of 168 cases. Am J Med Sci 1951; 222: 263–78PubMedCrossRefGoogle Scholar
  10. 10.
    Kerr WJ, Bender WL. Paroxysmal ventricular fibrillation with cardiac recovery in a case of auricular fibrillation with complete heart block while under quinidine [letter]. Heart 1921; 9: 269Google Scholar
  11. 11.
    Thomson GW. Quinidine as a cause of sudden death. Circulation 1956; 14: 757–65PubMedCrossRefGoogle Scholar
  12. 12.
    Jervell A, Lange-Nielsen F. Congenital deaf-mutism, functional heart disease with prolongation of QT interval and sudden death. Am Heart J 1957; 54: 59–68PubMedCrossRefGoogle Scholar
  13. 13.
    Levine SA, Woodworth CR. Congenital deaf-mutism, prolonged QT interval, syncopal attacks and sudden death. N Engl J Med 1958; 259: 412–7PubMedCrossRefGoogle Scholar
  14. 14.
    Romano C, Gemme G, Pongiglione R. Aritmie cardiache rare dell’ eta pediatrica: II. Accessi sincopali per fibrillazione ventricolare parossistica. (Presentazione del primo caso della letteratura pediatrica Italiana.). Clin Pediat 1963; 45: 656–83Google Scholar
  15. 15.
    Ward OC. A new familial cardiac syndrome in children. J Irish Med Assoc 1964; 54: 103–6Google Scholar
  16. 16.
    Selzer A, Wray HW. Quinidine syncope: paroxysmal ventricular fibrillation occurring during treatment of chronic atrial arrhythmias. Circulation 1964; 30: 17–26PubMedCrossRefGoogle Scholar
  17. 17.
    Dessertenne F. La tachycardie ventriculaire a deux foyers oppocees variable. Arch Mal Coeur Vaiss 1966; 59: 263–72PubMedGoogle Scholar
  18. 18.
    Morganroth J, Goin JE. Quinidine related mortality in the short-to-medium term treatment of ventricular arrhythmias: a meta analysis. Circulation 1991; 84: 1977–83PubMedCrossRefGoogle Scholar
  19. 19.
    Kelly HG, Fay JE, Laverty SG. Thioridazine hydrochloride (Mellaril): its effect on the electrocardiogram and a report of two fatalities with electrocardiographic abnormalities. Can Med Assoc J 1963; 89: 546–54PubMedGoogle Scholar
  20. 20.
    Wendkos MH. Thioridazine and electrocardiographic abnormalities [letter]. Can Med Assoc J 1963; 89: 1297PubMedGoogle Scholar
  21. 21.
    Graupner KI, Murphree OD, Meduna LJ. Electrocardiographic changes associated with the use thioridazine. J Cardiovasc Nurs 1964; 21: 344–50Google Scholar
  22. 22.
    Wendkos MH. The significance of electrocardiographic changes produced by thioridazine. J New Drugs 1964; 40: 322–32PubMedGoogle Scholar
  23. 23.
    Desautels S, Filteau C, St-Jean A. Ventricular tachycardia associated with administration of thioridazine hydrochloride (Mellaril): report of a case with a favourable outcome. Can Med Assoc J 1964; 90: 1030–1PubMedGoogle Scholar
  24. 24.
    Schoonmaker FW, Osteen RT, Greenfield Jr JC. Thioridazine (mellaril)-induced ventricular tachycardia controlled with an artificial pacemaker. Ann Intern Med 1966; 65: 1076–8PubMedGoogle Scholar
  25. 25.
    Burda CD. Electrocardiographic abnormalities induced by thioridazine (Mellaril). Am Heart J 1968; 76: 153–6PubMedCrossRefGoogle Scholar
  26. 26.
    Giles TD, Modlin RK. Death associated with ventricular arrhythmia and thioridazine hydrochloride. JAMA 1968; 205: 108–10PubMedCrossRefGoogle Scholar
  27. 27.
    Wendkos MH, Thornton CG. An electrocardiographic survey of thioridazine treated patients. Behav Neuropsychiatry 1969; 1: 18–22PubMedGoogle Scholar
  28. 28.
    Hollander PB, Cain RM. Effects of thioridazine on transmembrane potential and contractile characteristics of guinea pig hearts. Eur J Pharmacol 1971; 16: 129–35PubMedCrossRefGoogle Scholar
  29. 29.
    Wendkos MH. Cardiac changes related to phenothiazine therapy, with special reference to thioridazine. J Am Geriatr Soc 1967; 15: 20–8PubMedGoogle Scholar
  30. 30.
    Huston JR. Electrocardiographic changes produced by thioridazine and chlorpromazine. Am Heart J 1969; 77: 713–4PubMedCrossRefGoogle Scholar
  31. 31.
    Ban TA, St-Jean A. The effect of phenothiazines on the electrocardiogram. Can Med Assoc J 1964; 91: 537–40PubMedGoogle Scholar
  32. 32.
    Hollister LE, Kosek JC. Sudden death during treatment with phenothiazine derivatives. JAMA 1965; 192: 1035–8PubMedCrossRefGoogle Scholar
  33. 33.
    Ban TA, St Jean A. Electrocardiographic changes produced by phenothiazines. Am Heart J 1965; 70: 575–6PubMedCrossRefGoogle Scholar
  34. 34.
    Richardson HL, Graupner KI, Richardson ME. Intramyocardial lesions in patients dying suddenly and unexpectedly. JAMA 1966; 195: 254–60PubMedCrossRefGoogle Scholar
  35. 35.
    Lingjaerde O. Electrocardiographic changes, disturbances of cardiac rhythm, and sudden deaths during treatment with phenothiazine drugs [in Norwegian]. Tidsskr Nor Laegeforen 1967; 87: 90–4PubMedGoogle Scholar
  36. 36.
    Backman H, Elosuo R. The effect of neuroleptics on electrocardiograms. Acta Med Scand 1968; 183: 543–7PubMedCrossRefGoogle Scholar
  37. 37.
    Crane GE. Cardiac toxicity and psychotropic drugs. Dis Nerv Syst 1970; 31: 534–9PubMedGoogle Scholar
  38. 38.
    Thornton CC, Wendkos MH. EKG T-wave distortions among thioridazine-treated psychiatric inpatients (some correlates of the incidence and severity). Dis Nerv Syst 1971; 32: 320–3PubMedGoogle Scholar
  39. 39.
    Mogelvang JC, Petersen EN, Folke PE, et al. Antiarrhythmic properties of a neuroleptic butyrophenone, melperone, in acute myocardial infarction: a double-blind trial. Acta Med Scand 1980; 208: 61–4PubMedCrossRefGoogle Scholar
  40. 40.
    Smiseth OA, Platou ES, Refsum H, et al. Haemodynamic and metabolic effects of the antiarrhythmic drug melperone during acute left ventricular failure in dogs. Cardiovasc Res 1981; 15: 724–30PubMedCrossRefGoogle Scholar
  41. 41.
    Jefferson JW. A review of the cardiovascular effects and toxicity of tricyclic antidepressants. Psychosom Med 1975; 37: 160–79PubMedGoogle Scholar
  42. 42.
    Vohra J, Hunt D, Burrows G, et al. Intracardiac conduction defects following overdose of tricyclic antidepressant drugs. Eur J Cardiol 1975; 2: 443–52PubMedGoogle Scholar
  43. 43.
    Thorstrand C. Clinical features in poisonings by tricyclic antidepressants with special reference to the ECG. Acta Med Scand 1976; 199: 337–44PubMedCrossRefGoogle Scholar
  44. 44.
    Dumovic P, Burrows GD, Vohra J, et al. The effect of tricyclic antidepressant drugs on the heart. Arch Toxicol 1976; 35: 255–62PubMedCrossRefGoogle Scholar
  45. 45.
    Roos JC. Cardiac effects of antidepressant drugs: a comparison of the tricyclic antidepressants and fluvoxamine. Br J Clin Pharmacol 1983; 15 Suppl. 3: 439S–45SPubMedCrossRefGoogle Scholar
  46. 46.
    Picard R, Auzepy P, Chauvin JP. Syncopes and electrocardiographic changes caused by prenylamine [in French]. Ann Cardiol Angeiol (Paris) 1971; 20: 627–30Google Scholar
  47. 47.
    Bracchetti D, Frabetti L, Mambelli M. Prenylamine and syncopal crisis with prolonged Q-T [in Italian]. G Clin Med 1973; 54: 239–44 1107PubMedGoogle Scholar
  48. 48.
    Guijarro Morales A, Raya Pugnaire A, Martin Navajas JA, et al. Long QT, syncope caused by atypical ventricular fibrillation and chronic ingestion of prenylamine (review of the literature and report of a case) [in Spanish]. Rev Clin Esp 1976; 142: 163–70PubMedGoogle Scholar
  49. 49.
    Puritz R, Henderson MA, Baker SN, et al. Ventricular arrhythmias caused by prenylamine. BMJ 1977; 2: 608–9PubMedCrossRefGoogle Scholar
  50. 50.
    Manouvrier J, Sagot M, Caron C, et al. Nine cases of torsade de pointes with bepridil administration. Am Heart J 1986; 111: 1005–7PubMedCrossRefGoogle Scholar
  51. 51.
    Pinaud D, Chabanier A, Vergnoux H, et al. Bepridil and torsades de pointes: apropos of 11 cases [in French]. Ann Cardiol Angeiol (Paris) 1987; 36: 421–5Google Scholar
  52. 52.
    Viallon A, Page Y, Lafond P, et al. Bepridil and torsades de pointes: are the precautions of use respected? [in French]. Therapie 1994; 49: 431–4PubMedGoogle Scholar
  53. 53.
    Kaden F, Kubler W. Recurrent atypical ventricular tachycardia “torsade de pointes” following lidoflazine administration [in German]. Verh Dtsch Ges Inn Med 1977; 83: 1596–7PubMedGoogle Scholar
  54. 54.
    Tamas F, Zoltan K. Paroxysmal ventricular tachycardia associated with Adams-Stokes syndrome during treatment with Clinium [in Hungarian]. Orv Hetil 1977; 118: 1051–3PubMedGoogle Scholar
  55. 55.
    Kennelly BM. Comparison of lidoflazine and quindine in prophylactic treatment of arrhythmias. Br Heart J 1977; 39: 540–6PubMedCrossRefGoogle Scholar
  56. 56.
    Hanley SP, Hampton JR. Ventricular arrhythmias associated with lidoflazine: side-effects observed in a randomized trial. Eur Heart J 1983; 4: 889–93PubMedGoogle Scholar
  57. 57.
    Cannon III RO, Brush Jr JE, Schenke WH, et al. Beneficial and detrimental effects of lidoflazine in microvascular angina. Am J Cardiol 1990; 66: 37–41PubMedCrossRefGoogle Scholar
  58. 58.
    Perelman MS, McKenna WJ, Rowland E, et al. A comparison of bepridil with amiodarone in the treatment of established atrial fibrillation. Br Heart J 1987; 58: 339–44PubMedCrossRefGoogle Scholar
  59. 59.
    Fazekas T, Kiss Z. Torsade de pointes ventricular tachycardia associated with lidoflazine therapy [letter]. Eur Heart J 1984; 5: 343PubMedGoogle Scholar
  60. 60.
    Ridley JM, Dooley PC, Milnes JT, et al. Lidoflazine is a high affinity blocker of the HERG K+ channel. J Mol Cell Cardiol 2004; 36: 701–5PubMedCrossRefGoogle Scholar
  61. 61.
    Cocco G, Strozzi C, Chu D, et al. Torsades de pointes as a manifestation of mexiletine toxicity. Am Heart J 1980; 100 (6 Pt 1): 878–80PubMedCrossRefGoogle Scholar
  62. 62.
    Chia BL. Disopyramide-induced atypical ventricular tachyarrhythmia. Aust NZ Med J 1980; 10: 665–8CrossRefGoogle Scholar
  63. 63.
    Tzivoni D, Keren A, Stern S, et al. Disopyramide-induced torsade de pointes. Arch Intern Med 1981; 141: 946–7PubMedCrossRefGoogle Scholar
  64. 64.
    Chow MJ, Piergies AA, Bowsher DJ, et al. Torsade de pointes induced by N-acetyl-procainamide. J Am Coll Cardiol 1984; 4: 621–4PubMedCrossRefGoogle Scholar
  65. 65.
    Goldstein RE, Tibbits PA, Oetgen WJ. Proarrhythmic effects of antiarrhythmic drugs. Ann NY Acad Sci 1984; 427: 94–100PubMedCrossRefGoogle Scholar
  66. 66.
    Torres V, Flowers D, Somberg JC. The arrhythmogenicity of antiarrhythmic agents. Am Heart J 1985; 109: 1090–7PubMedCrossRefGoogle Scholar
  67. 67.
    Horowitz LN, Zipes DP, Bigger JT, et al. Proarrhythmia, arrhythmogenesis of aggravation of arrhythmia: a status report, 1987. Am J Cardiol 1987; 59: 54E-6ECrossRefGoogle Scholar
  68. 68.
    Morganroth J. Comparative efficacy and safety of oral mexiletine and quinidine in benign or potentially lethal ventricular arrhythmias. Am J Cardiol 1987; 60: 1276–81PubMedCrossRefGoogle Scholar
  69. 69.
    Carmeliet E, Janssen PA, Marsboom R, et al. Antiarrhythmic, electrophysiologic and hemodynamic effects of lorcainide. Arch Int Pharmacodyn Ther 1978; 231: 104–30PubMedGoogle Scholar
  70. 70.
    Touboul P, Atallah G, Kirkorian G. Electrophysiologic effects of lorcainide (R 15889) in man [in French]. Arch Mal Coeur Vaiss 1981; 74: 1333–40PubMedGoogle Scholar
  71. 71.
    Senges J, Rizos I, Brachmann J, et al. Arrhythmogenic effects of toxic concentrations of the antiarrhythmic drug lorcainide on the isolated canine ventricle. J Pharmacol Exp Ther 1982; 223: 547–51PubMedGoogle Scholar
  72. 72.
    Keefe DL, Kates RE, Winkle RA. Comparative electrophysiology of lorcainide and norlorcainide in the dog. J Cardiovasc Pharmacol 1984; 6: 808–15PubMedCrossRefGoogle Scholar
  73. 73.
    Kates RE. Metabolites of cardiac antiarrhythmic drugs: their clinical role. Ann NY Acad Sci 1984; 432: 75–89PubMedCrossRefGoogle Scholar
  74. 74.
    Kesteloot H, Stroobandt R. Clinical experience of encainide (MJ 9067): a new anti-arrhythmic drug. Eur J Clin Pharmacol 1979; 16: 323–6PubMedCrossRefGoogle Scholar
  75. 75.
    Winkle RA, Mason JW, Griffin JC, et al. Malignant ventricular tachyarrhythmias associated with the use of encainide. Am Heart J 1981; 102:857–64PubMedCrossRefGoogle Scholar
  76. 76.
    Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. N Engl J Med 1989; 321: 406–12CrossRefGoogle Scholar
  77. 77.
    Hartigan-Go K, Bateman ND, Daly AK, et al. Stereoselective cardiotoxic effects of terodiline. Clin Pharmacol Ther 1996; 60: 89–98PubMedCrossRefGoogle Scholar
  78. 78.
    Committee on Safety of Medicines. Cardiac arrhythmias with halofantrine (Halfan). Curr Probl 1994; 20: 3Google Scholar
  79. 79.
    Bran S, Murray WA, Hirsh IB, et al. Long QT syndrome during high-dose cisapride. Arch Intern Med 1995; 155: 765–8PubMedCrossRefGoogle Scholar
  80. 80.
    Ahmed SR, Wolfe SM. Cisapride and torsades de pointes [letter]. Lancet 1995; 345: 508CrossRefGoogle Scholar
  81. 81.
    Peck CC, Temple R, Collins JM. Understanding consequences of concurrent therapies. JAMA 1993; 269: 1550–2PubMedCrossRefGoogle Scholar
  82. 82.
    Morganroth J, editor. QTc interval prolongation: Is it beneficial or harmful? Symposium proceedings. Philadelphia, Pennsylvania, October 29, 1992. Am J Cardiol 1993; 72: 1–59BGoogle Scholar
  83. 83.
    Lipicky RJ. A viewpoint on drugs that prolong the QTc interval. Am J Cardiol 1993; 72: 53–54BCrossRefGoogle Scholar
  84. 84.
    Roden DM. Current status of class III antiarrhythmic drug therapy. Am J Cardiol 1993; 72: 44–49BCrossRefGoogle Scholar
  85. 85.
    Botstein P. Is QT interval prolongation harmful? A regulatory perspective. Am J Cardiol 1993; 72: 50B-2BCrossRefGoogle Scholar
  86. 86.
    Waldo AL, Camm AJ, deRuyter H, et al. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators: Survival With Oral d-Sotalol. Lancet 1996; 348: 7–12PubMedCrossRefGoogle Scholar
  87. 87.
    Shah RR. The significance of QT interval during drug development. Br J Clin Pharmacol 2002; 54: 188–202PubMedCrossRefGoogle Scholar
  88. 88.
    Committee for Proprietary Medicinal Products opinion following an article 36 referral: sertindole. London: EMEA, 2002 Sep 13. Document no.: EMEA/CPMP/2852/02 [online]. Available from URL: http://www.emea.europa.eu/pdfs/human/referral/Sertindole/285202en.pdf [Accessed 2007 Oct 6]
  89. 89.
    Opinion of the Committee for Proprietary Medicinal Products pursuant to Article 10 of Council Directive 75/319/EEC as amended: mizolastine. London: EMEA, 1996 Dec 18. Document no.: CPMP/1034/96-EN [online]. Available from URL: http://www.emea.europa.eu/pdfs/human/referral/103496en.pdf [Accessed 2007 Oct 6]
  90. 90.
    Chaufour S, Caplain H, Lilienthal N, et al. Study of cardiac repolarization in healthy volunteers performed with mizolastine, a new H1-receptor antagonist. Br J Clin Pharmacol 1999; 47: 515–20 1108PubMedCrossRefGoogle Scholar
  91. 91.
    Committee for Proprietary Medicinal Products. Note for guidance on the investigation of drug interactions. London: EMEA, 1997 Dec 17. Document no.: CPMP/EWP/560l95 [online]. Available from URL: http://www.emea.eu.int/pdfs/human/ewp/056095en.pdf [Accessed 2007 Mar 22]Google Scholar
  92. 92.
    Morganroth J, Brozovich FV, McDonald JT, et al. Variability of the QT measurement in healthy men: with implications for selection of an abnormal QT value to predict drug toxicity and proarrhythmia. Am J Cardiol 1991; 67: 774–6PubMedCrossRefGoogle Scholar
  93. 93.
    Morganroth J, Brown AM, Critz S, et al. Variability of the QTc interval: impact on defining drug effect and low-frequency cardiac event. Am J Cardiol 1993; 72: 26B-32BCrossRefGoogle Scholar
  94. 94.
    Pratt CM, Ruberg S, Morganroth J, et al. Dose-response relation between terfenadine (Seldane) and the QTc interval on the scalar electrocardiogram: distinguishing a drug effect from spontaneous variability. Am Heart J 1996; 131: 472–80PubMedCrossRefGoogle Scholar
  95. 95.
    Priori SG. Exploring the hidden danger of noncardiac drugs. J Cardiovasc Electrophysiol 1998; 9: 1114–6PubMedCrossRefGoogle Scholar
  96. 96.
    Haverkamp W, Breithardt G, Camm AJ, et al. The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. Report on a Policy Conference of the European Society of Cardiology. Eur Heart J 2000; 21: 1216–31PubMedCrossRefGoogle Scholar
  97. 97.
    Anderson MD, Al-Khatib SM, Roden DM, et al. Cardiac repolarization: Current knowledge, critical gaps, and new approaches to drug development and patient management. Am Heart J 2002; 144: 769–81PubMedGoogle Scholar
  98. 98.
    Hammond TG, Carlsson L, Davis AS, et al. Methods of collecting and evaluating non-clinical cardiac electrophysiology data in the pharmaceutical industry: results of an international survey. Cardiovasc Res 2001; 49: 741–50PubMedCrossRefGoogle Scholar
  99. 99.
    Assessment of the QT prolongation potential of non-antiarrhythmic drugs [draft guidance document]. Ottawa (ON): Ministry of Health, Health Products and Food Branch, 2001 Mar 15. Document no.: 01-103957-184Google Scholar
  100. 100.
    Development of drugs that alter ventricular repolarisation [draft document]. Bethesda (MD): Food and Drug Administration, 1999 Sep 2. (Data on file)Google Scholar
  101. 101.
    Concept paper on investigating drugs for their effect on cardiac repolarization. Bethesda (MD): Food and Drug Administration, Health Canada, 2003. (Data on file)Google Scholar
  102. 102.
    Committee for Medicinal Products for Human Use. ICH note for guidance on the nonclinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmacueticals (ICH S7B). London: EMEA, 2005 May 25. Document no.: CHMP/ICH/423/02 [online]. Available from URL: http://www.emea.eu.int/pdfs/human/ich/042302en.pdf [Accessed 2007 Mar 22]Google Scholar
  103. 103.
    Guide for the analysis and review of QT/QTc interval data. Ottawa (ON): Ministry of Health, Health Products and Food Branch, Health Canada, 2006 Nov 30. Document no.: 06-124690-618 [online]. Available from URL: http://www.hcsc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/qt_review_examen_e.pdf [Accessed 2007 Mar 22]
  104. 104.
    QT/QTc interval prolongation: guidance for product monograph content. Ottawa (ON): Ministry of Health, Health Products and Food Branch, Health Canada, 2006 Nov 30. Document no.: 06-124456-677 [online]. Available from URL: http://www.hcsc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/qt_pm_mp_e.pdf [Accessed 2007 Mar 22]
  105. 105.
    Health Canada question and answer document regarding the ICH S7B and E14 guidances. Ottawa (ON): Ministry of Health, Health Products and Food Branch, Health Canada, 2006 Nov 30. Document no.: 06-124711-745 [online]. Available from URL: http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/qt_qa_qr_e.pdf [Accessed 2007 Mar 22]
  106. 106.
    Giustetto C, Di Monte F, Wolpert C, et al. Short QT syndrome: clinical findings and diagnostic-therapeutic implications. Eur Heart J 2006; 27: 2440–7PubMedCrossRefGoogle Scholar
  107. 107.
    Cerrone M, Noujaim S, Jalife J. The short QT syndrome as a paradigm to understand the role of potassium channels in ventricular fibrillation. J Intern Med 2006; 259: 24–38PubMedCrossRefGoogle Scholar
  108. 108.
    Antzelevitch C, Oliva A. Amplification of spatial dispersion of repolarization underlies sudden cardiac death associated with catecholaminergic polymorphic VT, long QT, short QT and Brugada syndromes. J Intern Med 2006; 259: 48–58PubMedCrossRefGoogle Scholar
  109. 109.
    Shah RR. Interpretation of clinical ECG data: understanding the risk from non-antiarrhythmic drugs. In: Morganroth J, Gussak I, editors. Cardiac safety of noncardiac drugs: practical guidelines for clinical research and drug development. Totowa (NJ): Humana Press Inc., 2004: 259–98Google Scholar
  110. 110.
    Gussak I, Brugada P, Brugada J, et al. Idiopathic short QT interval: a new clinical syndrome. Cardiology 2000; 94: 99–102PubMedCrossRefGoogle Scholar
  111. 111.
    Brugada R, Hong K, Dumaine R, et al. Sudden death associated with short-QT syndrome linked to mutations in hERG. Circulation 2004; 109: 30–5PubMedCrossRefGoogle Scholar
  112. 112.
    Bellocq C, van Ginneken AC, Bezzina CR, et al. Mutation in the KCNQ1 gene leading to the short QT interval syndrome. Circulation 2004; 109: 2394–7PubMedCrossRefGoogle Scholar
  113. 113.
    Priori SG, Pandit SV, Rivolta I, et al. A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene. Circ Res 2005; 96: 800–7PubMedCrossRefGoogle Scholar
  114. 114.
    Antzelevitch C, Pollevick GD, Cordeiro JM, et al. Loss of function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation 2007; 115: 442–9PubMedCrossRefGoogle Scholar
  115. 115.
    Algra A, Tijssen JGP, Roelandt JRTC, et al. QT interval variables from 24-hour electrocardiography and the 2-year risk of sudden death. Br Heart J 1993; 70: 43–8PubMedCrossRefGoogle Scholar
  116. 116.
    Viskin S, Tester D, Ish-Shalom M, et al. Is idiopathic ventricular fibrillation a short QT syndrome? Comparison of QT intervals of patients with idiopathic ventricular fibrillation and healthy controls. Heart Rhythm 2004; 1: 587–91PubMedCrossRefGoogle Scholar
  117. 117.
    Reinig MG, Engel TR. The shortage of short QTs. Chest 2007; 132(1): 246–9PubMedCrossRefGoogle Scholar
  118. 118.
    Gallagher MM, Magliano G, Yap YG, et al. Distribution and prognostic significance of QT intervals in the lowest half centile in 12,012 apparently healthy persons. Am J Cardiol 2006; 98: 933–5PubMedCrossRefGoogle Scholar
  119. 119.
    Anttonen O, Junttila MJ, Rissanen H, et al. Prevalence and prognostic significance of short QT interval in a middle-aged Finnish population. Circulation 2007; 116: 714–20PubMedCrossRefGoogle Scholar
  120. 120.
    Bezzina CR, Verkerk AO, Busjahn A, et al. A common polymorphism in KCNH2 (HERG) hastens cardiac repolarization. Cardiovasc Res 2003; 59: 27–36PubMedCrossRefGoogle Scholar
  121. 121.
    Escande D, Thuringer D, Le Guern S, et al. Potassium channel openers act through an activation of ATP-sensitive K+ channels in guinea-pig cardiac myocytes. Pflugers Arch 1989; 414: 669–75PubMedCrossRefGoogle Scholar
  122. 122.
    Robert E, Delye B, Aya G, et al. Comparison of proarrhythmogenic effects of two potassium channel openers, levcromakalim (BRL 38227) and nicorandil (RP 46417): a high-resolution mapping study on rabbit heart. J Cardiovasc Pharmacol 1997; 29: 109–18 1109PubMedCrossRefGoogle Scholar
  123. 123.
    Robert E, Aya AG, de la Coussaye JE, et al. Dispersion-based reentry: mechanism of initiation of ventricular tachycardia in isolated rabbit hearts. Am J Physiol 1999; 276 (2 Pt 2): H413–23PubMedGoogle Scholar
  124. 124.
    de La Coussaye JE, Eledjam JJ, Bruelle P, et al. Electrophysiologic and arrhythmogenic effects of the potassium channel agonist BRL 38227 in anesthetized dogs. J Cardiovasc Pharmacol 1993; 22: 722–30CrossRefGoogle Scholar
  125. 125.
    Tosaki A, Szerdahelyi P, Engelman RM, et al. Potassium channel openers and blockers: do they possess proarrhythmic or antiarrhythmic activity in ischemic and reperfused rat hearts? J Pharmacol Exp Ther 1993; 267: 1355–62PubMedGoogle Scholar
  126. 126.
    Extramiana F, Antzelevitch C. Amplified transmural dispersion of repolarization as the basis for arrhythmogenesis in a canine ventricular wedge model of short QT syndrome. Circulation 2004; 110: 3661–6PubMedCrossRefGoogle Scholar
  127. 127.
    DeSilvey DL, Moss AJ. Primidone in the treatment of the long QT syndrome: QT shortening and ventricular arrhythmia suppression. Ann Intern Med 1980; 93: 53–4PubMedGoogle Scholar
  128. 128.
    Chinushi M, Aizawa Y, Furushima H, et al. Nicorandil suppresses a hump on the monophasic action potential and torsade de pointes in a patient with idiopathic long QT syndrome. Jpn Heart J 1995; 36: 477–81PubMedCrossRefGoogle Scholar
  129. 129.
    Shimizu W, Antzelevitch C. Effects of a K+ channel opener to reduce transmural dispersion of repolarization and prevent torsade de pointes in LQT1, LQT2, and LQT3 models of the long QT syndrome. Circulation 2000; 102: 706–12PubMedCrossRefGoogle Scholar
  130. 130.
    Salata JJ, Jurkiewicz NK, Wang J, et al. A novel benzodiazepine that activates cardiac slow delayed rectifier K+ currents. Mol Pharmacol 1998; 53: 220–30Google Scholar
  131. 131.
    Kang J, Chen X-L, Wang H, et al. Discovery of a small molecule activator of the human ether-ago-go-related gene (hERG) cardiac K+ channel. Mol Pharmacol 2005; 67: 827–36PubMedCrossRefGoogle Scholar
  132. 132.
    Zhou J, Augelli-Szafran CE, Bradley JA, et al. Novel potent human ether-a-go-go-related gene (hERG) potassium channel enhancers and their in vitro antiarrhythmic activity. Mol Pharmacol 2005; 68: 876–84PubMedGoogle Scholar
  133. 133.
    Shah RR. Thalidomide, drug safety and early drug regulation in the UK. Adverse Drug React Toxicol Rev 2001; 20: 199–255PubMedGoogle Scholar
  134. 134.
    Committee for Proprietary Medicinal Products. Note for guidance on clinical investigation of medicinal products for the treatment of cardiac failure. London: EMEA, 1999 Dec 16. Document no.: CPMP/EWP/235/95 [online]. Available from URL: http://www.emea.eu.int/pdfs/human/ewp/023595en.pdf [Accessed 2007 Mar 22]Google Scholar
  135. 135.
    Fishman AP. Aminorex to Fen/Phen: an epidemic foretold. Circulation 1999; 99: 156–61PubMedCrossRefGoogle Scholar
  136. 136.
    Follath F, Burkart F, Schweizer W. Drug-induced pulmonary hypertension? BMJ 1971; 1: 265–6PubMedCrossRefGoogle Scholar
  137. 137.
    Douglas JG, Munro JF, Kitchin AH, et al. Pulmonary hypertension and fenfluramine. BMJ 1981; 283: 881–3PubMedCrossRefGoogle Scholar
  138. 138.
    Roche N, Labrune S, Braun JM, et al. Pulmonary hypertension and dexfenfluramine. Lancet 1992; 339: 436–7PubMedCrossRefGoogle Scholar
  139. 139.
    Hickey A, Buchbinder NA, Naqvi TZ. Dose and duration of fenfluramine-phentermine therapy impacts the risk of significant valvular heart disease. Am J Cardiol 2000; 86: 107–10PubMedCrossRefGoogle Scholar
  140. 140.
    Sachdev M, Miller WC, Ryan T, et al. Effect of fenfluramine-derivative diet pills on cardiac valves: a meta-analysis of observational studies. Am Heart J 2002; 144: 1065–73PubMedCrossRefGoogle Scholar
  141. 141.
    Jollis JG, Landolfo CK, Kisslo J, et al. Fenfluramine and phentermine and cardiovascular findings: effect of treatment duration on prevalence of valve abnormalities. Circulation 2000; 101: 2071–7PubMedCrossRefGoogle Scholar
  142. 142.
    Ioannides-Demos LL, Proietto J, Tonkin AM, et al. Safety of drug therapies used for weight loss and treatment of obesity. Drug Safety 2006; 29: 277–302PubMedCrossRefGoogle Scholar
  143. 143.
    Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005; 352: 1092–102PubMedCrossRefGoogle Scholar
  144. 144.
    Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA 2005; 294: 2581–6PubMedCrossRefGoogle Scholar
  145. 145.
    Ott E, Nussmeier NA, Duke PC, et al. Efficacy and safety of the cyclooxygenase 2 inhibitors parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery. J Thorac Cardiovasc Surg 2003; 125: 1481–92PubMedCrossRefGoogle Scholar
  146. 146.
    Nussmeier NA, Whelton AA, Brown MT, et al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 2005; 352: 1081–91PubMedCrossRefGoogle Scholar
  147. 147.
    Nussmeier NA, Whelton AA, Brown MT, et al. Safety and efficacy of the cyclooxygenase-2 inhibitors parecoxib and valdecoxib after noncardiac surgery. Anesthesiology 2006; 104; 518–26PubMedCrossRefGoogle Scholar
  148. 148.
    Opinion of the Committee for Medicinal Products for Human Use pursuant to Article 5(3) of Regulation (EC) no. 726/2004: non-selective non-steroidal anti-inflammatory drugs (NSAIDs). London: EMEA, 2006 Oct 18. Document no.: EMEA/CHMP/410051/2006Google Scholar
  149. 149.
    Pfizer commended for fast response on torcetrapib. Scrip 2006 Dec 8; (3216): 15Google Scholar
  150. 150.
    Bristol-Myers Squibb and Merck. Pargluva Advisory Committee briefing document (NDA 21-865). Endocrinologic and Metabolic Drugs Advisory Committee Meeting. Bethesda (MD): Food and Drug Administration, 2005 Sep 9Google Scholar
  151. 151.
    Chen L, Yang B, McNulty JA, et al. GI262570, a peroxisome proliferator-activated receptor agonist, changes electrolytes and water reabsorption from the distal nephron in rats. J Pharmacol Exp Ther 2005; 312: 718–25PubMedCrossRefGoogle Scholar
  152. 152.
    Manufacturers of some diabetes drugs to strengthen warning on heart failure risk. Bethesda (MD): Food and Drug Administration, 2007 Aug 14 [online]. Available from URL: http://www.fda.gov/bbs/topics/NEWS/2007/NEW01683.html [Accessed 2007 Oct 6]
  153. 153.
    Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macro Vascular Events): a randomised controlled trial. Lancet 2005; 366: 1279–89PubMedCrossRefGoogle Scholar
  154. 154.
    Holleman F, Gerdes VE, de Vries JH, et al. Trial of pioglitazone for the secondary prevention of cardiovascular events in patients with diabetes mellitus type 2: insufficient evidence [in Dutch]. Ned Tijdschr Geneeskd 2006; 150: 358–60PubMedGoogle Scholar
  155. 155.
    Avandia safety scare hits GlaxoSmithKline. Scrip 2007 May 25: (3262): 23Google Scholar
  156. 156.
    Slørdal L, Spigset O. Heart failure induced by non-cardiac drugs. Drug Safety 2006; 29: 567–86PubMedCrossRefGoogle Scholar
  157. 157.
    Dahlof CG, Mathew N. Cardiovascular safety of 5HT1B/1D agonists: is there a cause for concern? Cephalalgia 1998; 18: 539–45PubMedCrossRefGoogle Scholar
  158. 158.
    Kerkela R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 2006; 12: 908–16PubMedCrossRefGoogle Scholar
  159. 159.
    FDA directs ADHD drug manufacturers to notify patients about cardiovascular adverse events and psychiatric adverse events. Bethesda (MD): Food and Drug Administration, 2007 Feb 21 1110 [online]. Available from URL: http://www.fda.gov/bbs/topics/NEWS/2007/NEW01568.html [Accessed 2007 Apr 9]
  160. 160.
    FDA strengthens safety information for erythropoiesis-stimulating agents (ESAs). Bethesda (MD): Food and Drug Administration, 2007 Mar 9 [online]. Available from URL: http://www.fda.gov/bbs/topics/NEWS/2007/NEW01582.html [Accessed 2007 Oct 6].
  161. 161.
    Jiminez-Jiminez F, Lopez-Alvarez J, Sanchez-Chapado M, et al. Retroperitoneal fibrosis in a patient treated with pergolide. Clin Neuropharm 1995; 18: 277–9CrossRefGoogle Scholar
  162. 162.
    Shaunak S, Wilkins A, Pilling JB, et al. Pericardial, retroperitoneal, and pleural fibrosis induced by pergolide. J Neurol Neurosurg Psychiatry 1999, 81Google Scholar
  163. 163.
    Zanettini R, Antonini A, Gatto G, et al. Valvular heart disease and the use of dopamine agonists for Parkinson’s disease. N Engl J Med 2007; 356: 39–46PubMedCrossRefGoogle Scholar
  164. 164.
    Schade R, Andersohn F, Suissa S, et al. Dopamine agonists and the risk of cardiac-valve regurgitation. N Engl J Med 2007; 356: 29–38PubMedCrossRefGoogle Scholar
  165. 165.
    FDA announces voluntary withdrawal of pergolide products. Bethesda (MD): Food and Drug Administration, 2007 Mar 29 [online]. Available from URL: http://www.fda.gov/bbs/topics/NEWS/2007/NEW01596.html [Accessed 2007 Apr 9]
  166. 166.
    FDA announces discontinued marketing of GI drug, Zelnorm, for safety reasons. Bethesda (MD): Food and Drug Administration, 2007 Mar 30 [online]. Available from URL: http://www.fda.gov/bbs/topics/NEWS/2007/NEW01597.html [Accessed 2007 Apr 9]
  167. 167.
    Temple R. Premarketing risk assessment: special conditions. Risk assessment public meeting. Bethesda (MD): Food and Drug Administration, 2003 Apr 9 [online]. Available from URL: http://www.fda.gov/cder/meeting/RM/rtemple/rtemple.ppt [Accessed 2007 Apr 9]Google Scholar
  168. 168.
    Note for guidance for industry: premarketing risk assessment. Bethesda (MD): Food and Drug Administration, 2005 Mar 29 [online]. Available from URL: http://www.fda.gov/cder/guidance/6357fnl.pdf [Accessed 2007 Apr 9]
  169. 169.
    Committee for Medicinal Products for Human Use. Guidance on planning pharmacovigilance activities. London: EMEA, 2004 Dec 1. Document no.: (ICH E2E) CPMP/ICH/5716/03 [online]. Available from URL: http://www.emea.eu.int/pdfs/human/ich/571603en.pdf [Accessed 2007 Apr 9]Google Scholar
  170. 170.
    Committee for Medicinal Products for Human Use. Guideline on risk management systems for medicinal products for human use. London: EMEA, 2005 Nov 14. Document no.: EMEA/CHMP/96268/2005 [online]. Available from URL: http://www.emea.europa.eu/pdfs/human/euleg/9626805en.pdf [Accessed 2007 Apr 9]Google Scholar
  171. 171.
    Guidance for industry: development and use of risk minimization action plans. Bethesda (MD): Food and Drug Administration, 2005 Mar 29 [online]. Available from URL: http://www.fda.gov/cder/guidance/6358fnl.pdf [Accessed 2007 Apr 9]
  172. 172.
    _Andrews E, Dombeck M. The role of scientific evidence of risks and benefits in determining risk management policies for medications. Pharmacoepidemiol Drug Saf 2004; 13: 599–608PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2007

Authors and Affiliations

  1. 1.Rashmi Shah Consultancy LtdGerrards CrossUK

Personalised recommendations