Background
Conventional antipsychotic drugs have been implicated as a cause of ventricular arrhythmias and cardiac arrest, but no definitive information is available regarding atypical antipsychotics. We compared the effect of conventional and atypical antipsychotics on the risk of hospitalization for ventricular arrhythmias and cardiac arrest.
Methods
We conducted a case-control study on residents of nursing homes in 6 US states by using data from the Minimum Data Set linked to Medicare inpatient claims. Cases were residents hospitalized for ventricular arrhythmias or cardiac arrest between July 4, 1998, and December 30, 1999. For each case, we identified up to 5 controls residing in the same facility during the same period. The sample consisted of 649 cases and 2962 controls.
Results
Use of conventional antipsychotics was associated with a nearly 2-fold increase in risk of hospitalization for ventricular arrhythmias or cardiac arrest (adjusted odds ratio, 1.86; 95% confidence interval, 1.27-2.74). There was no increased risk associated with the use of atypical antipsychotics (odds ratio, 0.87; 95% confidence interval, 0.58-1.32). The risk of hospitalization for ventricular arrhythmias or cardiac arrest was highest among conventional users with cardiac disease (odds ratio, 3.27; 95% confidence interval, 1.95-5.47). However, cardiac disease and conventional antipsychotics did not show a synergistic effect (synergy index, 1.19).
Conclusions
Conventional but not atypical antipsychotics are associated with an increased risk of hospitalization for ventricular arrhythmias and cardiac arrest. The prescription of conventional antipsychotics in patients with cardiac disease should be carefully weighed.
Some antipsychotic medications have been associated with an increased risk of ventricular arrhythmias, cardiac arrest, and sudden death.1,2 The literature includes several case series in schizophrenic patients treated with thioridazine hydrochloride,1,3 haloperidol,4 and other conventional antipsychotics.5 More recently, epidemiologic studies6,7 have confirmed a direct relationship between conventional antipsychotics and the risk of sudden death. In patients treated for schizophrenia this increased risk has been attributed to the QT-prolonging properties of conventional antipsychotics.8,9
The newer, so-called atypical antipsychotics (clozapine, risperidone, olanzapine, quetiapine fumarate, ziprasidone hydrochloride, and aripiprazole) are more effective for the treatment of negative symptoms in schizophrenia and confer a lower risk of extrapyramidal side effects and tardive dyskinesia compared with conventional agents.10 This better safety profile has expanded indications for treatment. Indeed, atypical antipsychotics are considered the mainstay of treatment for older persons with behavioral symptoms associated with dementia who reside in nursing homes.11 Increasing use of atypical antipsychotics in diverse settings has been consistently documented.12,13
Despite experimental evidence that some atypical antipsychotics can also prolong QT interval,5 only clozapine has been linked to serious cardiac problems.14 Risperidone has a minimal effect on QT interval,5 and the only reported case of sudden death was not due to ventricular arrhythmias.15 A single epidemiologic study on schizophrenic patients has suggested an increased risk of ventricular arrhythmias and cardiac arrest associated with risperidone, a finding not endorsed by the authors of that study.6
We conducted a case-control study to estimate the effect of conventional- and atypical-antipsychotic use on the risk of hospitalization for ventricular arrhythmias or cardiac arrest among elderly residents of Medicare-Medicaid–certified nursing homes in 6 US states.
We used the Systematic Assessment of Geriatric Drug Use via Epidemiology database, which contains data from the Minimum Data Set (MDS). The MDS is a standardized, clinically based instrument used to assess residents in nursing homes across the United States. The MDS collects information on each resident’s demographic, functional, medical, psychological, and cognitive status. The Centers for Medicare and Medicaid Services require that each certified facility conduct an MDS assessment of all residents on admission and quarterly thereafter. Since June 22, 1998, the Centers for Medicare and Medicaid Services maintain a centralized repository of all MDS data. The Systematic Assessment of Geriatric Drug Use via Epidemiology database has been described in detail elsewhere16,17 and has been proven a useful resource for epidemiologic research.18 Data collected in the nursing homes of 6 states (Illinois, Maine, Mississippi, New York, Ohio, and South Dakota) were used in this study.
The Systematic Assessment of Geriatric Drug Use via Epidemiology database links MDS data to the Medicare inpatient claim files (part A). These files provide the admission diagnosis and up to 10 discharge diagnoses for any hospitalization, recorded by the International Classification of Diseases, Ninth Revision (ICD-9) codes.19 We identified cases by inpatient hospitalizations in which either the admission or the primary diagnosis was for cardiac arrest (ICD-9 427.5) or ventricular arrhythmias including paroxysmal ventricular tachycardia (ICD-9 427.1), ventricular flutter and fibrillation (ICD-9 427.4), ventricular flutter (ICD-9 427.42), and ventricular fibrillation (ICD-9 427.41). We used the first hospitalization to define case status among persons with multiple hospitalizations. Between July 4, 1998, and December 30, 1999, we identified 934 hospitalizations that met our case definition.
We identified potential controls by inpatient hospitalizations in which the primary diagnosis at discharge was septicemia (ICD-9 038-038.9), gastrointestinal hemorrhage (ICD-9 578, 578.0, 578.1, 578.9), rectal bleeding (ICD-9 569.3), gastritis with bleeding (ICD-9 535.1), duodenitis with bleeding (ICD-9 535.6), or influenza (ICD-9 487, 487.0, 487.1, 487.9). We identified 18 856 potential controls. To minimize the potential confounding effect of specific characteristics of the facilities,20 each case was matched to a maximum of 5 controls residing within the same facility during the same period. We excluded cases for whom we could not identify at least 1 eligible control (n = 285). The final sample consisted of 649 cases and 2962 controls. Cases included residents hospitalized for cardiac arrest (40.6%), paroxysmal ventricular tachycardia (34.5%), and ventricular flutter or fibrillation (24.9%).
Nursing home staff recorded the name, dose, frequency, route of administration, whether the order was scheduled (standing order) or as needed, and the National Drug Code for up to 18 drugs taken by the resident in the 7 days before the assessment.
We identified, for any study participant, the most proximal assessment reporting drug information before the hospitalization and defined it as the index assessment. We defined as exposed those residents for whom any antipsychotic use was reported at the index assessment. Exposed residents were (1) users of atypical antipsychotics including risperidone, olanzapine, quetiapine, and clozapine; (2) users of conventional agents including chlorpromazine, chlorprothixene, fluphenazine hydrochloride, haloperidol, loxapine, molindone hydrochloride, perphenazine, promazine hydrochloride, thioridazine hydrochloride, thiothixene, and trifluoperazine hydrochloride; and (3) users of both classes of antipsychotics. Unexposed residents were those for whom no antipsychotic use was reported at the index assessment.
Sociodemographic characteristics including age, sex, and race or ethnicity, along with body mass index; indicators of functional, cognitive, and behavioral status; comorbid conditions; and concurrent drug use, were considered potential confounders.
To evaluate functional status, we used the Activities of Daily Living scale, a 7-item, 5-level score embedded in the MDS and based on the resident’s performance in 7 areas: dressing, eating, toileting, bathing, locomotion, transferring, and incontinence.21 We classified the degree of dependence as mild (score of 0-1), moderate (score of 2-3), or severe (score of 4-5).
We used the Cognitive Performance Scale to measure residents’ cognitive status. The Cognitive Performance Scale is a valid instrument and has excellent comparability with the Mini-Mental State Examination.22 The Cognitive Performance Scale score ranges from 0 (intact cognition) to 6 (severe dementia). We categorized cognitive impairment as follows: minimal (score of 0-1), moderate (score of 2-3), and severe (score of 4-6).
The degree of severity of behavioral problems was evaluated by an MDS-based index previously used in research23 and considered appropriate in a recent consensus statement.24 Residents were considered to have severe symptoms if they were verbally or physically abusive and socially inappropriate every day. Residents with moderate symptoms were those who were wandering, verbally or physically abusive, and socially inappropriate on occasions, but less than daily. If residents exhibited at least 1 of the previously mentioned symptoms but not all of them, or none of them, their condition was classified as mild or normal.
The MDS section on clinical diagnoses provided information about residents’ comorbid conditions.17 These were recorded by physicians on the basis of medical history, hospital charts or record review, or physical examination when appropriate. We also considered concomitant medications with a known effect to prolong the QT interval and those with antiarrhythmic effect.
We used conditional logistic regression models to quantify the effect of antipsychotic use on the likelihood of hospitalization for ventricular arrhythmias or cardiac arrest, simultaneously controlling for all potential confounders. Exposure categories in the first model included standing-order conventional-drug use, as-needed conventional-drug use, standing-order atypical-drug use, as-needed atypical-drug use, and use of both antipsychotic classes, with no antipsychotic use as the reference category. To estimate the effect of conventional relative to atypical antipsychotics, we used a second model including the same exposure categories with standing-order atypical-drug use as the reference category. We derived crude and adjusted odds ratios along with 95% confidence intervals from these models.
Since we hypothesized that preexisting cardiac disease could modify the effect of conventional antipsychotics on the risk of ventricular arrhythmias and cardiac arrest, we tested the interaction between any cardiac condition and conventional-antipsychotic use. We defined a resident as having a cardiac disease if at least 1 of the following diagnoses had been previously documented: cardiac arrhythmias, heart failure, coronary artery disease, or other heart disease. According to Rothman and Greenland,25 we combined cardiac disease and antipsychotic exposure into 1 variable with 12 levels. We included this variable in a conditional logistic regression model with “no antipsychotic use/no cardiac disease” as the reference category. We estimated the synergy index (SI), which measures interaction as a departure from additivity of the effects,25 as follows:
where A and B denote the presence of and Ā and 0macron; the absence of the 2 risk factors. In the absence of interaction between the two risk factors, the synergy index equals 1.
Statistical analysis was performed with SAS software, version 8 (SAS Institute Inc, Cary, NC).
Cases were younger and more likely to be male than were controls (Table 1). Residents in the control group were more likely to present a severe degree of functional impairment (48.6% vs 29.4%) and cognitive deficit (30.1% vs 14.5%). Cardiac diseases were more prevalent among cases, with a notable difference for heart failure (39.4% vs 26.6%). Instead, controls were more likely to be diagnosed as having Alzheimer disease (10.5% vs 7.8%) and other dementias (30.4% vs 24.1%). There was no difference in the prevalence of antipsychotic use between the 2 groups, but cases were more likely to use conventional agents (10.5% vs 7.2% among controls).
Table 2 shows that cases were more likely to be users of bronchodilators, antiarrhythmic drugs, angiotensin-converting enzyme inhibitors, vasodilators, loop diuretics, calcium channel blockers, β-blockers, and coagulation modifiers.
Among atypical agents, risperidone was the most commonly used medication and accounted for more than 70% of prescriptions (Table 3). Use of other agents, quetiapine and clozapine in particular, was infrequent. For atypical antipsychotics, nearly 100% of prescriptions were standing orders. Haloperidol was the leading conventional antipsychotic (nearly 50% of prescriptions), followed by thioridazine. In this category, as-needed use varied from 25% for chlorpromazine and chlorprothixene to 0% in the case of thioridazine and several other agents.
After control for potential confounders, users of conventional antipsychotics showed an 86% increase in the risk of hospitalization for ventricular arrhythmias or cardiac arrest (odds ratio, 1.86; 95% confidence interval, 1.27-2.74) relative to nonusers (Table 4). There was no increased risk associated with the use of atypical antipsychotics (odds ratio, 0.87; 95% confidence interval, 0.58-1.32). We repeated the analysis including risperidone users as a separate exposure category, and we observed no effect on the risk of being hospitalized for ventricular arrhythmias or cardiac arrest by either risperidone alone or the other atypical antipsychotics.
Table 5 shows the combined effect of antipsychotic use and the presence of cardiac disease on the likelihood of experiencing the outcome. Among residents receiving conventional antipsychotics, those with cardiac disease were 3.27 times (95% confidence interval, 1.95-5.47) and those with no cardiac disease were 2.05 times (95% confidence interval, 1.14-3.68) more likely to be hospitalized for ventricular arrhythmias and cardiac arrest, compared with nonusers without cardiac disease. The synergy index was 1.19, indicating no interaction between conventional-antipsychotic use and preexisting cardiac disease.
The results of this study document that the use of conventional antipsychotics is associated with an increased risk of hospitalization for ventricular arrhythmias and cardiac arrest. Our findings are consistent with those of Ray and colleagues,7 who reported a 2-fold increase in the rate of sudden death among patients aged 15 to 84 years receiving conventional antipsychotics compared with nonusers. In particular, these authors found that the sudden death rate ratio for current users of 100 mg or less of thioridazine hydrochloride or its equivalent, compared with nonusers, was 1.30, significantly less than that for moderate-dose users (rate ratio, 2.39). In the current analysis, we found an 86% increase in the risk of hospitalization for ventricular arrhythmias and cardiac arrest among conventional-antipsychotic users. The daily doses in our study were generally low (eg, thioridazine hydrochloride daily dose mode was 50 mg) and within the recommended range for this population.24 Thus, our findings may indicate a particular sensitivity of the elderly population to the cardiotoxic effect of conventional antipsychotics.
In contrast, atypical antipsychotics did not appear to be associated with an increased risk of hospitalization for ventricular arrhythmias and cardiac arrest. Previous studies indicated that atypical antipsychotics do not affect QT interval when used at therapeutic doses.26-29 However, new evidence suggests that there could be important dose-related differences in the effect on QT interval.30,31 High doses of risperidone (mean dose, 7.2 mg) have been associated with a mean QT increase of 4.4 milliseconds in a double-blind comparison with olanzapine.30 Sporadic cases of risperidone overdose associated with severe QT prolongation have been described,32,33 but a review of the overdose profiles indicated that atypical antipsychotics are generally safe.34
Cardiac disease may be a predisposing factor for ventricular arrhythmias and cardiac arrest. We found consistently that the presence of a cardiac disease was a strong confounder in the relationship under study. However, the use of conventional antipsychotics and the presence of a cardiac disease did not show a synergistic effect on the risk of hospitalization for ventricular arrhythmias and cardiac arrest, pointing to the absence of a biological interaction.
Our study has several strengths. In times when atypical antipsychotics are rapidly replacing conventional antipsychotics12,13 and indications for the use of these drugs are expanding,11 this study provides new information on a still unresolved clinical question. A possible cardiovascular risk associated with atypical antipsychotics is a critical issue especially in view of the suspiciously high rates of venous thromboembolism35 and ischemic stroke reported among patients receiving these medications.36 Finally, given the nature of the outcome, no clinical trials investigating this issue would be deemed ethical and observational studies are invaluable.
This study also has some limitations. Since we used claims for outcome identification, we missed all cases of ventricular arrhythmias and cardiac arrest resulting in death before hospital referral. The use of claims data to assess the outcome may raise concerns of lack of accuracy and potential for misclassification. Nonetheless, cardiac events such as ventricular arrhythmias and cardiac arrest require electrocardiographic confirmation, and this may lower the potential for inaccuracy. In our database there is no available information on QT-interval measurements. However, QT interval is more a marker of risk than a mechanism of arrhythmia, prolongation does not necessarily result in ventricular arrhythmias, and there is no established safety threshold.37,38 Atypical-antipsychotic use has been associated with body weight increase and dyslipidemia.39 Because of the limited duration of the study, we could not assess the possible impact of these risk factors on the outcome. Finally, no information was available on other potential confounders such as electrolyte disturbances, heart rate variability,40 and other predisposing conditions.41
In conclusion, this study has documented that conventional but not atypical antipsychotics are associated with an increased risk of hospitalization for ventricular arrhythmias and cardiac arrest. An increased risk is present even for doses within the recommended range. Thus, physicians should use these drugs cautiously among elderly patients, especially those with cardiac disease. We have documented an increased relative risk of an event that is exceedingly rare. Therefore, the clinical relevance of the estimated effect size at the population level should be judged by taking into account the low background rate of the event. Moreover, atypical antipsychotics are not more efficacious than conventional agents,42 nor is there sufficient evidence to claim an overall superior cardiac side effect profile of atypical antipsychotics compared with conventional agents. In fact, the use of these agents may be challenged by newer adverse effects: substantial weight gain and elevated cholesterol and insulin levels, which might in turn affect cardiac health.43 Thus, therapeutic choice should be based on a careful evaluation of the patient’s individual needs and risk profile, along with the beneficial and harmful effects of both classes of antipsychotics.
Correspondence: Rosa Liperoti, MD, MPH, Centro di Medicina dell’Invecchiamento, Dipartimento di Scienze Gerontologiche, Geriatriche e Fisiatriche, Università Cattolica del Sacro Cuore Largo A. Gemelli, 8 00168 Rome, Italy (rossella_liperoti@rm.unicatt.it).
Accepted for Publication: July 31, 2004.
Financial Disclosure: None.
Funding/Support: This study was supported by grant R37 AG11624-06s1 from the National Institute on Aging, National Institutes of Health, Bethesda, Md.
1.Straus
SMBleumink
GSDieleman
JP
et al. Antipsychotics and the risk of sudden cardiac death.
Arch Intern Med 2004;1641293- 1297
PubMedGoogle ScholarCrossref 2.Shader
RIGreenblatt
DJ Potassium, antipsychotic agents, arrhythmias, and sudden death.
J Clin Psychopharmacol 1998;18427- 428
PubMedGoogle ScholarCrossref 6.Hennessy
SBilker
WBKnauss
JS
et al. Cardiac arrest and ventricular arrhythmia in patients taking antipsychotic drugs: cohort study using administrative data.
BMJ 2002;3251070- 1074
PubMedGoogle ScholarCrossref 7.Ray
WAMeredith
SThapa
PBMeador
KGHall
KMurray
KT Antipsychotics and the risk of sudden cardiac death.
Arch Gen Psychiatry 2001;581161- 1167
PubMedGoogle ScholarCrossref 8.Studenik
CLemmens-Gruber
RHeistracher
P Proarrhythmic effects of antidepressants and neuroleptic drugs on isolated, spontaneously beating guinea-pig Purkinje fibers.
Eur J Pharm Sci 1999;7113- 118
PubMedGoogle ScholarCrossref 9.Reilly
JGAyis
SAFerrier
INJones
SJThomas
SH QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients.
Lancet 2000;3551048- 1052
PubMedGoogle ScholarCrossref 11.American Geriatrics Society and American Association for Geriatric Psychiatry, Consensus statement on improving the quality of mental health care in US nursing homes: management of depression and behavioral symptoms associated with dementia.
J Am Geriatr Soc 2003;511287- 1298
PubMedGoogle ScholarCrossref 12.Hermann
RCYang
DEttner
SLMarcus
SCYoon
CAbraham
M Prescription of antipsychotic drugs by office-based physicians in the United States, 1989-1997.
Psychiatr Serv 2002;53425- 430
PubMedGoogle Scholar 13.Liperoti
RMor
VLapane
KLPedone
CGambassi
GBernabei
R The use of atypical antipsychotics in nursing homes.
J Clin Psychiatry 2003;641106- 1112
PubMedGoogle ScholarCrossref 14.Modai
IHirschmann
SRava
A
et al. Sudden death in patients receiving clozapine treatment: a preliminary investigation.
J Clin Psychopharmacol 2000;20325- 327
PubMedGoogle ScholarCrossref 15.Ravin
DSLevenson
JW Fatal cardiac event following initiation of risperidone therapy.
Ann Pharmacother 1997;31867- 870
PubMedGoogle Scholar 16.Bernabei
RGambassi
GLapane
KL
et al. Characteristics of the SAGE database: a new resource for research on outcomes in long-term care: SAGE (Systematic Assessment of Geriatric drug use via Epidemiology) Study Group.
J Gerontol A Biol Sci Med Sci 1999;54M25- M33
PubMedGoogle ScholarCrossref 17.Gambassi
GLandi
FPeng
L
et al. Validity of diagnostic and drug data in standardized nursing home assessments: potential for geriatric pharmacoepidemiology.
Med Care 1998;36167- 179
PubMedGoogle ScholarCrossref 18.Gambassi
GLapane
KLSgadari
A
et al. Effects of angiotensin-converting enzyme inhibitors and digoxin on health outcomes of very old patients with heart failure.
Arch Intern Med 2000;16053- 60
PubMedGoogle ScholarCrossref 19.World Health Organization, International Classification of Diseases, Ninth Revision (ICD-9). Geneva, Switzerland World Health Organization1977;
20.Intrator
OCastle
NGMor
V Facility characteristics associated with hospitalization of nursing home residents: results of a national study.
Med Care 1999;37228- 237
PubMedGoogle ScholarCrossref 21.Katz
SMoskowitz
RWJackson
BAJafee
MW Studies of illness in the aged: the index of ADL: a standardized measure of biological and psychosocial function.
JAMA 1963;185914- 919
PubMedGoogle ScholarCrossref 23.Gambassi
GLapane
KLSgadari
ALandi
FMor
VBernabei
R Measuring health outcomes for older people using the SAGE database.
Can J Aging 2000;19
((suppl 2))
67- 86
Google ScholarCrossref 24.Snowden
MSato
KRoy-Byrne
P Assessment and treatment of nursing home residents with depression or behavioral symptoms associated with dementia: a review of the literature.
J Am Geriatr Soc 2003;511305- 1317
PubMedGoogle ScholarCrossref 25.Rothman
KJGreenland
S Concepts of interaction. Rothman
KJGreenland
S
Modern Epidemiology. 2nd ed. Philadelphia, Pa Lippincott-Raven Publishers1998;329- 342
Google Scholar 26.Glassman
AHBigger
JT
Jr Antipsychotic drugs: prolonged QTc interval, torsades de pointes, and sudden death.
Am J Psychiatry 2001;1581774- 1778
PubMedGoogle ScholarCrossref 27.Kang
UGKwon
JSAhn
YM
et al. Electrocardiographic abnormalities in patients treated with clozapine.
J Clin Psychiatry 2000;61441- 446
PubMedGoogle ScholarCrossref 29.Small
JGHirsch
SRArvanitis
LAMiller
BGLink
CGSeroquel Study Group, Quetiapine in patients with schizophrenia: a high- and low-dose double-blind comparison with placebo.
Arch Gen Psychiatry 1997;54549- 557
PubMedGoogle ScholarCrossref 30.Tran
PVHamilton
SHKuntz
AJ
et al. Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders.
J Clin Psychopharmacol 1997;17407- 418
PubMedGoogle ScholarCrossref 31.Conley
RRMahmoud
R A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder.
Am J Psychiatry 2001;158765- 774
PubMedGoogle ScholarCrossref 33.Kopala
LCDay
CDillman
BGardner
D A case of risperidone overdose in early schizophrenia: a review of potential complications.
J Psychiatry Neurosci 1998;23305- 308
PubMedGoogle Scholar 37.Crouch
MALimon
LCassano
AT Clinical relevance and management of drug-related QT interval prolongation.
Pharmacotherapy 2003;23881- 908
PubMedGoogle ScholarCrossref 39.Nasrallah
H A review of the effect of atypical antipsychotics on weight.
Psychoneuroendocrinology 2003;28
((suppl 1))
83- 96
PubMedGoogle ScholarCrossref 40.Agelink
MWMajewski
TWurthmann
C
et al. Effects of newer atypical antipsychotics on autonomic neurocardiac function: a comparison between amisulpride, olanzapine, sertindole, and clozapine.
J Clin Psychopharmacol 2001;218- 13
PubMedGoogle ScholarCrossref 41.Coulter
DMBate
AMeyboom
RHLindquist
MEdwards
IR Antipsychotic drugs and heart muscle disorder in international pharmacovigilance: data mining study.
BMJ 2001;3221207- 1209
PubMedGoogle ScholarCrossref 42.Lee
PEGill
SSFreedman
M
et al. Atypical antipsychotic drugs in the treatment of behavioural and psychological symptoms of dementia: systematic review.
BMJ 2004;32975
PubMedGoogle ScholarCrossref 43.Melkersson
KDahl
ML Adverse metabolic effects associated with atypical antipsychotics: literature review and clinical implications.
Drugs 2004;64701- 723
PubMedGoogle ScholarCrossref