Transcript Relative toxicity of SSRIs

RELATIVE TOXICITY OF
CITALOPRAM AND OTHER SSRIs
IN OVERDOSE
GK Isbister 1,2, IM Whyte 1,2, AH Dawson 1,2
1Department
of Clinical Toxicology, Newcastle Mater Hospital,
2Discipline of Clinical Pharmacology, University of Newcastle
Background
• Concern regarding citalopram overdose:
– reports of fatal cases
– cardiotoxicity and seizures with massive OD
• Case series (Sweden) suggested:
– prolonged QTc if > 600 mg
– seizures
– no deaths
CLASS OR INDIVIDUAL DRUG EFFECT ?
Aim
To define :
• spectrum of toxicity of SSRI overdose
• relative toxicity of individual SSRIs
– to investigate the cardiac toxicity of the
SSRIs in overdose
– to investigate the serotonergic effects of
SSRIs in overdose
Methods
• Cohort of inpatient overdose admissions
– Prospective data collection
• Inclusions :
– All SSRI overdoses presenting to Hunter Area
Toxicology Service (HATS)
• Exclusions :
– more than one SSRI ingested
– coingestion of TCA, venlafaxine, nefazodone
Methods
• Cases included were:
– SSRI dose > maximum daily dose
– SSRI alone
OR
– coingestant with no known effect on QT
• Only one ECG/admission per patient included:
– ECG with longest QT used to select cases
Methods
• Control group
• Overdoses of medications with no known
cardiotoxicity, or affect the QT or QRS interval
–
–
–
–
paracetamol
paracetamol/codeine
diazepam
temazepam
Methods
• Electrocardiograph:
– QT
– QTc
– QRS
• Clinical Features:
–
–
–
–
Incidence of arrhythmia
Bradycardia (HR < 60 bpm)
Tachycardia (HR > 100 bpm)
Hypotension (systolic BP < 90 mmHg)
Electrocardiographic Analysis
• RR, QT and QRS measured manually on ECGs
• QTc from Bazett’s formula
• QTc > 440 msec was defined as ABNORMAL
Analysis
• Statistical analysis :
– Comparison of proportion QTc > 440 msec
– Comparison of mean/median QTc (ANOVA)
• Logistic regression
– Dependent variable QTc>440 msec
– Independent variable : age, sex, DDD, time to
ingestion, SSRI type
– Forward stepwise logistic regression modelling
Results
• Poisoning admissions to HATS: 8909 cases
• 413 single SSRI admissions:
– 118 coingested cardiotoxic drugs
– 30 had no ECG done (10%)
• 265 admissions with 312 ECGs
• 236 ECG/patients were included
• 318 Control patients
Results
236 ECG/patients were included:
Citalopram
Sertraline
Paroxetine
Fluoxetine
Fluvoxamine
32
82
70
39
13
Median ECG parameters
Citalopram
Control Group
Fluox
Fluvox
Parox
P value *
Sert
QTc
423
432
433
423
450
436
0.003
QT
360
380
360
360
400
380
0.037
QRS
85
84
85
80
80
80
0.776
* ANOVA of medians (5 SSRIs and controls);
QTc > 440 msec
• 66% of citalopram overdoses with QTc > 440
msec
• Calculated the odds ratio of QTc > 440 msec
compared to control overdoses
• THEN did logistic regression
Drug
Odds
C.I. (95%)
Ratio
P
value
Fluoxetine
0.97
0.48 - 1.97
0.94
Fluvoxamine
0.35
0.08 – 1.62
0.18
Paroxetine
1.15
0.67 - 1.97
0.61
Citalopram
3.71
1.73 - 7.98 0.001
Sertraline
1.18
0.71 - 1.95 0.52
Drug Ingested
Controls
Fluoxetine
Fluvoxamine
Paroxetine
Citalopram
Sertraline
Age
DDD
Gender
1.00
1.00
0.38
1.10
3.79
1.17
1.02
1.01
Males
1.00
Females
2.48
0.482 - 2.090
0.080 - 1.787
0.625 - 1.945
1.672 - 8.591
0.657 – 2.072
1.004 – 1.028
0.996 - 1.022
0.993
0.220
0.736
0.001
0.599
0.011
0.168
1.643 – 3.730
<0.001
Clinical Effects
Control
Fluox
Fluvox
Parox
Cital
Sert
P value
Cardiovascular Effects
Arrhythmia
-
3%
0%
0%
3%
0%
0.504
*
Bradycardia
7%
10%
8%
9%
13%
6%
0.821
Tachycardia
17%
15%
0%
10%
13%
22%
0.224
Hypotension
-
0%
0%
0%
1%
0%
0.191
*
Citalopram overdose : Admission 6 hours
after overdose
Discharge 38 hours after overdose
Summary of Cardiac Toxicity
• Citalopram has significant cardiotoxicity:
–
–
–
–
Median QTc significantly longer
Median QT significantly longer
Proportion of QTc>440 msec significantly greater
Almost 4 times the risk of QTc prolongation
compared to control
– Potential for arrhythmias/bundle branch block
• Other SSRIs
– Appears to be much less risk
Limitations
• One ECG for each patient, but:
– Compared to controls (overdose controls)
– Adjusted for baseline; female significant
• QTc is marker of cardiotoxicity only, but:
– Poison Severity Score : moderate
– FDA : uses median QTc and proportion of
abnormal QTc in evaluation
Recommendations
• All patients with citalopram overdoses > 60
mg should have serial 12 lead ECGs and be
monitored until the QTc < 440 msec.
• Citalopram should be used with care in
patients with a history of cardiac disease or
arrhythmias, in particular bradycardia or
known long QT syndrome
Acknowledgements
• Steve Bowe : statistical analysis
• Toni Nash and Debbie Whyte for data entry
• Stuart Allen for data extraction