 |
 |
|
|
|
 The QT interval, as measured in an ECG, includes the QRS complex, ST segment, and T wave, reflecting an overall duration of ventricular repolarization in the myocardium. Since QT duration changes with heart rate, a QTc is usually computed. There are many methods for correcting the QT duration for heart rate (1–5); however, Bazett’s formula, in which QTc = QT/(RR1/2), is most commonly used. (1). Various old and new antipsychotics have been temporally associated with the adverse alteration of cardiac electrophysiologic function (6–10). More specifically, recent attention has focused on the association between some antipsychotics and the prolongation of the QTc interval; an event that appears to be dose-related (11). When the QTc interval is prolonged it signifies a prolongation of ventricular repolarization, which may increase the risk of potentially lethal paroxysmal ventricular tachyarrythmias known as torsades de pointes. Although prominent in recent literature, the cardiovascular effects of antipsychotics are certainly not a new phenomenon. In fact, the quinidine-like properties of thioridazine have been known for more than 40 years (12). Of the conventional antipsychotics, the risk of prolonged QTc, torsades de pointes, and sudden death is higher in patients treated with thioridazine, mesoridazine, pimozide, and droperidol (11,13–15). However, these cardiovascular effects are not unique to the older agents and have also been observed with some atypical antipsychotics. Thus the use of sertindole was suspended in Europe in 1998 because of its association with sudden death and serious arrhythmia (16). The suspension of sertindole occurred when much attention was being paid to the arrhythmogenic effects of some nonsedating antihistamines (17–21). These coinciding events likely contributed to the medical community’s hyperawareness of the risks of QTc prolongation, torsades de pointes, and sudden death. This hyperawareness, combined with the observation of a modest QTc prolongation in the initial trials of ziprasidone, likely resulted in the 1998 FDA delay of its approval. For approval, the FDA requested that the makers of ziprasidone compare its QTc prolongation with that of thioridazine, haloperidol, risperidone, olanzapine, and quetiapine in drug naVve patients. The results showed that thioridazine lengthened patients’ QTc interval the most and haloperidol the least (22). Among the atypical agents, ziprasidone prolonged QTc to a greater extent than did the others; however, no sudden deaths were reported. Bolded warnings were added to the package label in 2001 when the FDA approved ziprasidone to treat psychosis. Various nonpsychotropic medications have also been implicated in prolonging the QTc interval, including some antiarrhythmics, antihypertensives, antibiotics, antifungal agents, and antihistamines (23). Sex, age, electrolyte disturbances, cardiac disease, endocrine or metabolic illnesses, and central nervous system insults are among the identified nonmedicinal risk factors (24,25). Electrolyte disturbances, particularly hypokalemia, may have special implications in a psychiatric setting because plasma potassium concentrations in patients with severe agitation have been significantly lower than in patients with mild agitation (26). According to the multiple hit hypothesis, it is rare that only one of the above factors is sufficient to cause drug-induced QTc prolongation. Usually, a combination of risk factors must exist to precipitate drug-induced torsades de pointes (25). To date, no studies regarding QTc risks in elderly psychiatric patients have been published. Age is the obvious concern in this patient population; however, other relevant risk factors predisposing these individuals to prolonged QTc intervals include the use of multiple medications, age-related changes in the pharmacokinetic processing of medications, and chronic and acute disease states. With the combination of these factors, it is reasonable to surmise that geriatric psychiatric patients are at higher risk for prolonged QTc interval. The primary objective of this study is therefore to determine the incidence of prolonged QTc intervals in a population of geriatric psychiatry inpatients. Our secondary objective is to examine the associations between prolonged QTc intervals and risk factors identified as determinants in prolonging the QTc interval. MethodsThis cross-sectional study was conducted at Riverview Hospital in Coquitlam, British Columbia. Riverview Hospital is a tertiary care psychiatric facility with about 160 geriatric beds. The geriatric program admits patients aged 60 years and older. Some patients are admitted for acute short-term treatment, whereas others may require longer stays for behavioural stabilization and (or) extensive treatment. Upon admission to the geriatric division, all patients receive an ECG. Each ECG is interpreted by a cardiologist. For this study, we identified all geriatric patients (that is, patients aged 60 years and older) who were admitted to our facility between May 1, 2003, and December 31, 2003. Those patients with a heart rate QTc interval calculated on their ECGs were eligible for the study. Bazett’s formula was used to calculate the QTc interval (1). For this study, we defined a priori that a prolonged QTc interval would be 450 ms and 460 ms for men and women, respectively (27,28). In addition to the ECG information, we collected data on demographic variables such as weight, sex, age, and Axis I and III diagnoses, as well as on recognized risk factors for prolonged QTc interval. Axis I and III diagnoses were obtained from the admission notes. We also identified medications documented in the scientific literature or identified by FDA-approved drug labelling to prolong the QTc interval (29,30). We conducted parametric analysis on continuous variables, using Student’s t test, assuming equal variances. To test categorical variables for independence, we performed the chi-square or Fisher’s exact test. The institution’s Research Advisory Committee as well as the University of British Columbia’s Ethic Committee approved the study protocol. ResultsDuring the study period, a total of 88 patients were admitted to the geriatric division of Riverview Hospital. Of these patients, 34 men and 42 women had calculated QTc intervals on their ECGs and therefore made up the study population. Overall, 71.1% of the study population had an Axis I diagnosis of dementia (various types). Other diagnoses (not mutually exclusive) in decreasing order included major depression (21.1%), psychosis NOS (13.2%), schizophrenia (7.9%), bipolar affective disorder (6.6%), and schizoaffective disorder (5.3%). Because age and sex are independent risk factors that influence the QTc interval, we initially compared the QTc intervals of men and women before and after stratifying the data according to age (individuals aged 60 to 69 years, aged 70 to 79 years, and aged 80 years and older). In each instance, no statistically significant difference was observed between men and women (data on file). Diagnostic risk factors that may contribute to QTc prolongation were also collected and are reported in Table 1. In this case, the data were stratified only according to QTc interval. As previously mentioned, the age- and sex-adjusted standard for a prolonged QTc interval was determined a priori as 450 ms and 460 ms for men and women, respectively (27,28). Using these values, we found that 29.4% of men (10 of 34) and 21.4% of women (9 of 42) had prolonged QTc intervals. This difference between men and women was not statistically significant. Hypertension (44.7%) and myocardial ischemia and (or) infarction (22.4%) were the most common identified nonmedicinal risk factors. For the latter, there was a trend toward significance for its association with the group of individuals with prolonged QTc intervals (P = 0.08, Table 1). When examining the effect of cumulative diagnostic risk factors on QTc interval (Table 1), we noted that the greatest proportion of individuals (52.6%) with prolonged QTc intervals had only one diagnostic risk factor. However, this was not significantly higher than the respective comparator with normal QTc intervals (35.1%). Further, an increase in the number of diagnostic risk factors did not correspond to an increase in the incidence of observed prolonged QTc interval.
We also reported on medications in which QTc prolongation is mentioned in FDA-approved labelling as a known action of the drug (29,30). According to this list, we identified a total of 43 QTc interval–prolonging medications in our study. Antipsychotics were the most commonly identified class of medication and included haloperidol (n = 1), risperidone (n = 10), and quetiapine (n = 14). The use of these antipsychotics was not statistically associated with prolonged QTc intervals (Table 2). Other medications identified as potentially prolonging the QTc interval included the antidepressants venlafaxine (n = 9), sertraline (n = 4), and fluoxetine (n = 1); the antibiotic levofloxacin (n = 2); and the bronchodilator salmeterol (n = 2). As was the case with the antipsychotics, none of these agents were found to be significantly associated with a prolonged QTc interval. The cumulative number of medicinal risk factors was also not associated with a prolonged QTc interval. In fact, 57.9% of patients with prolonged QTc intervals were not receiving any identified QTc-prolonging medications (Table 2).
DiscussionIt is recognized that, in women, taking drugs that can prolong the QTc interval is associated with an increased risk of torsades de pointes (31). This sex difference has also been noted in a cohort of individuals with mental disorders (32). Conversely, our data do not find any statistically significant difference between men and women for QTc interval. Unlike the previous studies, however, our study population consisted of individuals aged 60 years and older. This suggests that age may be an important covariate in explaining this discrepancy. This is supported by various lines of chronological data starting with the fact that no sex differences in QTc are present in newborns (33). Indeed, it is only around puberty that a difference in QT interval is observed between the sexes (34). At this time, the QT interval shortens in men but remains steady in women. This sex difference in QT interval has been explained as an increase in circulating androgens (35). During the fifth and the sixth decade of life, the shortened QT interval in men slowly returns to initial values (34) Thus the fact that we show no difference in QTc interval between sexes is not in opposition to other studies but, rather, is reflective of our geriatric population. We also assessed diagnostic risk factors for their contribution to the QTc interval. Although no diagnostic risk factors were found to contribute to a prolonged QTc interval, we noted a trend toward significance for individuals with a history of myocardial ischemia and (or) infarction to have a prolonged QTc interval. This is likely the result of damage to the myocardium that then affects cardiac conduction. An increase in the number of diagnostic risk factors was not found to significantly increase the QTc intervals (Table 1). According to this finding, one may speculate that, in a geriatric population, diagnostic risk factors do not have a cumulative effect on the QTc interval. Alternatively, some of the diagnostic risk factors associated with prolonged QTc interval may be of minor importance in the geriatric population. Finally, we examined whether prescribed medications (that have been documented to influence QTc interval) had any impact on the QTc interval in our study population. Our data failed to show any increase in the proportion of patients having a prolonged QTc interval as a result of antipsychotics, antidepressants, or antibiotics (Table 2). As above, an increase in the number of medicinal risk factors was not found to significantly increase the QTc intervals. Our study has limitations that must be considered. First, our design is cross-sectional and not experimental. This type of observational study design provides weaker empirical evidence than experimental studies because of the potential presence of large confounding biases when there is an unknown association between a factor and an outcome. In other words, the symmetry of unknown confounders cannot be maintained. Nonetheless, this type of study design is valuable because it provides preliminary evidence that can be used as the basis for hypotheses in stronger experimental studies, such as randomized controlled trials. Our relatively small study sample size is a second limitation. As such, any conclusion regarding the influence of sex or risk factors on QTc interval may be limited, and a type II error cannot be excluded. A third limitation is that our a priori definition of prolonged QTc interval may be considered conservative. However, definitions of prolonged QTc have ranged anywhere from 370 ms to 460 ms for men and 400 ms to 490 ms for women (28,36). In any event, the QTc interval is only a surrogate marker for the prediction of a serious adverse drug reaction such as syncope or death owing to torsades de pointes. As with other surrogate markers, its relation to the event of interest is limited. In other words, the risk of serious adverse drug reactions is not a linear function of the QTc interval. That said, however, a QTc interval exceeding 500 ms is generally recognized as a substantial risk to the patient and should prompt the physician to reevaluate the risks and benefits of the current therapy and assess all potential underlying predisposing factors. In our study population, 2 individuals had QTc intervals greater than 500 ms. The first individual was a 77-year-old man with an Axis I diagnosis of dementia and 2 diagnostic risk factors (that is, myocardial ischemia and obesity). The other was an 88-year-old woman with an Axis I diagnosis of depression and no known risk factors for prolonged QTc interval. Neither of these individuals received any medications known to prolong the QTc interval. ConclusionTo the best of our knowledge, this is the first study that has examined QTc intervals in a group of geriatric psychiatry patients. The overall significance of this study is perhaps the finding that neither diagnostic nor medicinal risk factors (either individually or cumulatively) affected the QTc interval. These results are surprising because one might expect this group of patients (some with multiple risk factors) to be most at risk for QTc prolongation. The preliminary findings imply that, in this patient population, the QTc interval may not be influenced by recognized risk factors to the same extent as observed in the adult population. Despite our data, we believe that it is still prudent to monitor for significant changes in QTc intervals in this patient population. The results of this study need to be verified with a prospectively designed study. FundingThis study received no funding or support. References1. Bazett HC. An analysis of time relations of electrocardiograms. Heart 1920;7:353–67. 2. Fridericia LS. Duration of systole in electrocardiogram. Acta Medica Scand 1920;53:469. 3. Sagie A, Larson MG, Goldberg RJ, Bengtson JR, Levy D. An improved method for adjusting the QT interval for heart rate (the Framingham heart study). Am J Cardiol 1992;70:797–801. 4. Hodges M, Salerno D, Erlien D. Bazett’s QT correction reviewed: evidence that a linear QT correction for heart rate is better. J Am Coll Cardiol 1983;1:694. 5. Rautaharju PM, Zhou SH, Wong S, Calhoun HP, Berenson GS, Prineas R, and others. Sex differences in the evolution of electrocardiographic QT interval with age. Can J Cardiol 1992;8:690–5. 6. Donatine B, Le Blaye I, Krupp P. Transient cardiac pacing is insufficiently used to treat arrhythmia associated with thioridazine. Cardiology 1992;81:340–1. 7. Fulop G, Phillips RA, Shapiro AK, Gomes JA, Shapiro E, Nordlie JW. ECG changes during haloperidol and pimozide treatment for Tourette’s disorder. Am J Psychiatry 1987;144:673–5. 8. Metzger E, Friedman R. Prolongation of the corrected QT and torsades de pointes cardiac arrhythmia associated with intravenous haloperidol in the medically ill. J Clin Psychopharmacol 1993;13:128–32. 9. Flugelman MY, Tal A, Pollack S, Hefez A, Weisstub EB, Gotsman MS, and others. Psychotropic drugs and long QT syndromes: case reports. J Clin Psychiatry 1985;46:290–1. 10. Barnett AA. Safety concerns over antipsychotic drug: sertindole. Lancet 1996;348:256. 11. Reilly JG, Ayis SA, Ferrier IN, Jones SJ, Thomas SH. QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients. Lancet 2000;355:1048–52. 12. Kelly HG, Fay JE, Laverty SG. Thioridazine hydrochloride (mellaril): its effect on the electrocardiogram and a report of two fatalities with electrocardiographic abnormalities. CMAJ 1963:89;546–54. 13. Mehtonen O-P, Aranko K, Malkonen L, Vapaatalo H. A survey of sudden death associated with the use of antipsychotic or antidepressant drugs; 49 cases in Finland. Acta Psychiatr Scand 1991;84:58–64. 14. Glassman AH, Bigger JT. Antipsychotic drugs: prolonged QTc interval, torsades de pointes, and sudden death. Am J Psychiatry 2001;158:1774–82. 15. Glassman AH. Clinical management of cardiovascular risks during treatment with psychotropic drugs. J Clin Psychiatry 2002;63(Suppl 9):12–7. 16. Rawlins M. Committee on safety of medicines. Suspension of availability of serdolect (sertindole). Available: www.doh.gov.uk/cmo/cmo9816.htm. Accessed 2004 September 14. 17. Good AP, Rockwood R, Schad P. Loratadine and ventricular tachycardia. Am J Cardiol 1994;74:207. 18. Manahan BP, Ferguson CL, Killeavy ES, Lloyd BK, Troy J, Cantilena LR Jr. Torsades de pointes occurring in association with terfenadine. JAMA 1990;264:2788–90. 19. Pinto YM, van Gelder IC, Heeringa M, Crijns JH. QT lengthening and life-threatening arrhythmias associated with fexofenadine. Lancet 1999;353:980. 20. Josefson D. Hay fever drug to be banned by the FDA. Br Med J 1997;314:248. 21. [Anonymous]. FDA announces plan to halt marketing of terfenadine [news]. Am J Health Syst Pharm 1997;54:342. 22. Pfizer Inc. Briefing document for Zeldox capsules (ziprasidone HCL). FDA psychopharmacological drugs advisory committee meeting July 19, 2000. Available: www.fda.gov/ohrmus/dockets/ac/00/backgrd/3619b1a.pdf. Accessed 2004 September 14. 23. Tann HL, How CH, Lauer MR, Sung RJ. Electrophysiologic mechanisms of the long QT interval syndrome and torsades de pointes. Ann Intern Med 1995;122:701–14. 24. Vieweg, WVR. Mechanisms and risks of electrocardiographic QT interval prolongation when using antipsychotic drugs. J Clin Psychiatry 2002;63(suppl 9):18–24. 25. Zareba W, Lin DA. Antipsychotic drugs and QT interval prolongation. Psychiatr Q 2003;74:291–306. 26. Hatta K, Takahashi T, Nakamura H. Hypokalemia and agitation in acute psychosis patients. Psychiatry Res 1999;86:85–8. 27. Moss AJ, Robinson J. Clinical features of the idiopathic long QT syndrome. Circulation 1992;85(Suppl 1):1140–4. 28. Moss AJ. Measurement of the QT interval and the risk associated with QTc interval prolongation: a review. Am J Cardiol 1993;72;23B–25B. 29. Curtis LH, Ostbye T, Sendershy V, Hutchinson S, LaPointe NMA, Al-Khatib SM, and others. Prescription of QT-prolonging drugs in a cohort of about 5 million outpatients. Am J Med 2003;114:135–41. 30. Woosley RL. Drugs that prolong the QT interval and/or induce torsades de pointes. Available: www.torsades.org. Accessed 2004 September 14. 31. Makkar RR, Fromm BS, Steinman RT, Meissner MD, Lehmann MH. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA 1993;270:2590–7. 32. Ito H, Kono T, Ishida S, Maeda H. Gender difference in QTc prolongation of people with mental disorders. Ann Gen Hosp Psychiatry 2004;3:3–9. 33. Stramba-Badiale M, Spagnolo D, Bosi G, Schwartz PJ. Are gender differences in QTc present at birth? MISNES investigators. Multicenter Italian study on neonatal electrocardiography and sudden infant death syndrome. Am J Cardiol 1995;75:1277–8. 34. Rautaharju PM, Zhou SH, Wong S, Calhoun HP, Berenson GS, Prineas R, and others. Sex differences in the evolution of the electrocardiographic QT interval with age. Can J Cardiol 1992;8:690–5. 35. Lehmann MH, Timothy KW, Frankovich D, Fromm M, Keating M, Locati M, and others. Age-gender influence on the rate-corrected QT interval and the QT-heart rate relation in families with genotypically characterized long QT syndrome. J Am Coll Cardiol 1997;29:93–9. 36. Garson A. How to measure the QT interval—what is normal? Am J Cardiol 1993;72:14B–16B. Author(s)Manuscript received April 2005, revised, and accepted January 2006. 1. Pharmacy Professional Practice Leader , Department of Pharmacy, Riverview Hospital, Coquitlam, British Columbia. 2. Research Associate, Geriatric Psychiatry Program, Department of Geriatrics, Riverview Hospital, Coquitlam, British Columbia. 3. Fourth-year pharmaceutical student, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia. 4. Research Psychopharmacologist, Department of Research, Riverview Hospital, Coquitlam, British Columbia. 5. Clincial Associate Professor, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia. Address for correspondence: Dr J Dumontet, Department of Pharmacy, Riverview Hospital, 2601 Lougheed Highway, Coquitlam, BC, V3C 4J2 e-mail: jdumontet@bcmhs.bc.ca
1 | 2
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||