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3/9/2010
DISCLAIMER

CARDIOTOXICITY, HYPERGLYCEMIA
AND ANTIPSYCHOTIC MEDICATIONS
AMIT VASHIST, MD
PGY III
INTERNAL MEDICINE/PSYCHIATRY
NEITHER THE PUBLISHER NOR THE
AUTHORS ASSUME ANY LIABILITY FOR
ANY INJURY AND OR DAMAGE TO
PERSONS OR PROPERTY ARISING FROM
THIS WEBSITE AND ITS CONTENT.
Case Presentation 1

Mr. A, a 61
61--yearyear-old man with CAD and COPD,
was admitted to the ICU for respiratory failure. He
was intubated on admission to the hospital;
fortunately, his pulmonary function improved, and
he was extubated on the third hospital day.
Following extubation, he became agitated, and
psychiatric consultation was requested. Delirium
was diagnosed and IV haloperidol was
recommended.
Case Presentation 1 (Contd.)

Despite knowing that Mr. A's EKG revealed a
normal rate and rhythm, that his QTc was 440 ms,
and that the rest of his cardiac intervals were
normal, the medical resident was uncomfortable
with the recommendation. The resident noted that
he had seen “lots of problems” with IV
haloperidol and that he would rather not use it to
treat Mr. A since he had CAD.
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Case Presentation 2

A 4646-yearyear-old man was brought to the ER by his wife
after she noticed some apparent seizure
seizure--like activity
lasting one to two minutes, and included tongue biting
and urinary incontinence. His PMH included bipolar
d/o, DM, HTN and dyslipidemia. His medications
included metformin, lantus insulin, simvastatin,
lisinopril, paroxetine, lamotrigine and had not changed
for many months except for the recent addition of
paliperidone four days before his arrival to the ER.
EKG revealed A. fib., QTc of 461 ms and no acute
ST--T wave changes.
ST
Risk factors for cardiovascular/metabolic disease:
Considerations for patients with schizophrenia
Modifiable risk factors
Non-modifiable risk factors
Case Presentation 2 (Contd.)
The pt. had no chest pain, and all other labs
and vital signs were normal. He was admitted
for evaluation and given IV diltiazem with
resultant conversion to NSR
NSR, after which his
heart rate and QTc interval normalized. He
was discharged after one day.

Cardiovascular health status and
mortality rates associated with schizophrenia


Obesity
Gender
Dyslipidemia
Family history

Diabetes
Hypertension
Cardiovascular
Disease

Personal history
Age

Smoking

ATP III. JAMA. 2001;285:2486-2497.


Nearly 60% of the patients are obese.
Risk of developing diabetes is more than two
times higher than the general population.
70--80% smoke versus 25% in the general
70
population.
population
Approx. two times higher incidence of
cardiovascular disease mortality than general
population.
Sedentary lifestyle, poor dietary habits and
inadequate access to healthcare worsen the
situation.
Theisen FM et al. J Psychiatr Res. 2001;35:3392001;35:339-345.
Herrán A et al. Schizophr Res. 2000;41:3732000;41:373-381.
Allebeck P. Schizophr Bull. 1989;15:811989;15:81-89.
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Risk of cardiovascular and metabolic events in patients
with schizophrenia and in the general population
Cardiac complications associated with antipsychotics

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Weight gain
Adverse lipid profile
Orthostatic hypotension
Myocarditis
Cardiomyopathy
Torsades de Pointes (TdP)
V. fib. other than TdP
Enger et al, J Nerv Ment Dis (2004)
Consequences of Dyslipidemias

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Elevated cholesterol and LDL increase risk for
cardiovascular disease (CVD)1
Increased triglycerides1


I d
Independent
d t risk
i k factor
f t for
f CVD
Lowering lipids by 10% decreases
cardiovascular risk by 20%20%-30%2
Consequences of Diabetes

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Increased risk of cardiovascular disease
Macrovascular complications due to high
levels of cholesterol and triglycerides
Microvascular
i
l effects
ff



1. Wirshing et al. J Clin Psychiatry. 2002;63:856.
2. Sacks et al. N Engl J Med. 1996;335:1001.
Retinopathies
blindness
Nephropathies
kidney failure
Peripheral neuropathies
physical pain
Lindenmayer et al. J Clin Psychiatry. 2001;62(suppl 23):30.
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Survival of Diabetics Without a History
of MI Is Similar to That of Nondiabetics
Who Are PostPost-MI
CV mortaliity (%)
50
No prior MI
Obesity and mortality risk
Mortality 2.5
ratio
2.0
42
Prior MI
40
15.9
20
10
1.0
15.4
n=
69
1304
Nondiabetic
169
890
0.0
Diabetic


Olanzapine, clozapine and quetiapine have been
associated with increases in serum triglycerides, modest
increases in total cholesterol but limited impact on LDL.
Recent switch data also suggest that there may be direct,
adipocyte--independent effects of metabolically offending
adipocyte
antipsychotic meds on serum lipids.
0
20
25
Low
Moderate
30
35
High
Very high
40
45
Adapted from Gray 1989
Diabetes and glucose tolerance

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Minimal effects of aripiprazole and ziprasidone on serum
p
lipids
Mechanisms contributing to hyperlipidemia have
focussed on weight gain, dietary changes and
development of insulin resistance
Moderate Very low
BMI
Effects on lipid profile

Men
Women
0.5
2.1
MI = myocardial infarction.
Haffner et al. N Engl J Med. 1998;339:229.

Cardiovascular and gall
bladder disease
diabetes mellitus
15
1.5
30
0
Digestive and
pulmonary disease

Mechanisms
Patients taking olanzapine have a 44-fold greater
risk of developing T2DM than do those taking
typical antipsychotics. Similar risk with
clozapine.
l
i
The incidence of clinically significant weight gain
with aripiprazole and ziprasidone is considerably
less than that with olanzapine, hence the risk of
developing metabolic syndrome with these 2
agents is comparable to placebo.
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Mean change in weight gain in patients receiving
antipsychotic meds
Mean change in weight with antipsychotics
Metabolic disturbances associated with antipsychotic
agents
Dyslipidemia
Clozapine
Weight gain Diabetes
Risk
+++
+
Olanzapine
+++
+
+
D
D
Risperidone ++
Quetiapine
*
13.2
11.0
8.8
6.6
4.4
2.2
0
-2.2
-4.4
-6.6
Allison et al. Am J Psychiatry. 1999;156:1686.
J Clin Psychiatry and Schizophr Res
Drug
6
5
4
3
2
1
0
-1
-2
-3
Weight change (lb)
Weight chan
nge (kg)
Estimated Weight Change at 10 Weeks on “Standard” Dose
Tachycardia

+
++
D
D
Aripiprazole +/-
_
_
Ziprasidone +/-
_
_
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Mostly secondary to anticholinergic effects of
antipsychotics.
Exacerbated by α1α1- adrenergic receptor
antagonism seen commonly among lower
potency antipsychotics and clozapine.
Prolonged tachycardia can increase myocardial
oxygen demand and could contribute to
cardiac ischemia and subsequently
cardiomyopathy.
American Diabetes Association. Consensus Development Conference on antipsychotic drugs and obesity and diabetes. Diabetes Care, 2004.
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Myocarditis and Cardiomyopathy
Orthostatic hypotension
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Most common CV side effect
Can occur with any antipsychotic
Mediated by α1α1-adrenergic antagonism
Could be of particular concern in the elderly wherein
orthostasis could result in neurologic symptoms like
lightheadedness in a mild form and presyncope or
syncope in the severe form.
Clozapine has the strongest association, whereas
olanzapine and ziprasidone have the lowest incidence.
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An uncommon, but potentially fatal effect
from clozapine use.
15 cases of myocarditis and 8 cases of
cardiomyopathy reported between 1993 and
1999 in
i Australia
li from
f
approximately
i
l 8000
patients starting clozapine during that period.
All 15 cases of myocarditis occurred within 3
weeks of starting treatment and included 5
patient deaths.
Review of electrocardiogram (ECG)
and intervals
0.2 s
QRS
1 mv

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QT
interval
PR
interval
P
Normal QT interval

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T
U
PR
ST
segment segment
Guyton and Hall 2000
Corrected QT interval (QTc) values adjust
QT interval measurements for heart rate.
A normal Q
QTc interval is defined as <450
ms for women and <430 ms for men.
The duration of the QT interval varies
inversely with heart rate.
Moss 1993
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QT prolongation
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Can predispose patients to syncope,
ventricular arrhythmias, and sudden
death.
May increase
i
the
h risk
i k off torsade
d de
d
pointes, a potentially fatal ventricular
arrhythmia.
Potential Consequences of QTc
Interval Prolongation
QTc prolongation
Rarely
Torsade de pointes arrhythmia
(syncope)
Rarely
Ventricular fibrillation
Clinically significant prolonged QTc
values are defined as >500 ms.
Welch and Chue 2000; Moss 1986; Glassman and Bigger 2001; Litherland 1997
Effects of Orally
Orally--Administered Antipsychotics
on the QT Interval
Sudden death
Glassman and Bigger. Am J Psychiatry. 2001;158:1774.
Ray et al. Arch Gen Psychiatry. 2001;58:1161.
Effect of antipsychotic drugs on QTc
prolongation
Mean QTc
change
from
baseline*
(ms)
40
35
30
25
20
15
10
5
0
-5
OlanzapineRisperidoneQuetiapineHaloperidol ZiprasidoneThioridazine
20 mg
160 mg 300 mg
16 mg
750 mg 15 mg
(n=24)
(n=31)
(n=27)
(n=25)
(n=27)
(n=30)
FDA Psychopharmacological Drug Advisory Committee, July 2000
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Atypicals and the risk of sudden cardiac
death
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Methods
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Cohort was restricted to persons 30 to 74 years
of age.
Typical antipsychotics analyzed were
haloperidol and thioridazine.
thioridazine
Atypicals included were quetiapine,
olanzapine, risperidone and clozapine.
Do atypical antipsychotic meds carry the same
or a reduced risk of serious ventricular
arrythmias and sudden cardiac death than
typical antipsychotics?
Ray et al conducted a retrospective cohort
study of Medicaid enrollees in Tennessee.
Study groups included users of single typical,
atypical and matched non users of
antipsychotics.
Results
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Current users of typical antipsychotics had an
incidence rate ratio of 1.99 compared to non users.
Atypical antipsychotics had an incidence ratio of
2 26
2.26.
Among users of atypicals, the incidence rate ratios
increased from 1.59 for those on low doses to 2.42
for those taking higher doses.
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The CATIE Schizophrenia Study
Limitations of this study
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Though several provisions were made to avoid
confounding factors, there exists a serious
potential for the same.
This study did not assess the mechanisms by
which antipsychotics increased the risk of
sudden cardiac death.
What about ziprasidone??
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What Should We Monitor?
CATIE Study (Contd.)
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Olanzapine and quetiapine were associated with
increased risk; whereas risk decreased in
patients treated with perphenazine, risperidone,
and ziprasidone
ziprasidone.
Overall differences in CAD risk appeared
secondary to lowering of total cholesterol in
patients treated with risperidone and
ziprasidone, and increase in HDL with
perphenazine and ziprasidone.
The study objective was to examine effects of
different antipsychotic treatments on estimates
of 10 year CAD risk calculated by the
Framingham Heart Study Formula.
Change
h
in
i 10 year risk
i k for
f CHD was comparedd
between treatment groups in 1125 patients
followed for 18 months.
Antipsychotic meds involved were olanzapine,
perphenazine, quetiapine, risperidone and
ziprasidone.
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Physical Exam
 Check weight - each visit
 Check blood pressure - each visit
Lab Tests
 Hemoglobin A1c - every 3
3––6 months
 Fasting blood glucose - every 3 months
 Triglycerides - every 3 months
 Cholesterol - every 3 months
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ADA Screening Guidelines for Patients
on Second
Second--Generation Antipsychotics1
Baseline
4 Weeks
8 Weeks
12 Weeks
X
X
X
Clinical insights for optimal cardiac
safety with antipsychotics
Annually
Personal family history
X
Weight (BMI)
Overweight (25.0-29.9)
Obese (30.0)
X
Waist circumference
(<40″ in males, <35″ in females)2
X
Blood pressure
X
X
X
Fasting plasma glucose
IFG (100-125 mg/dL)3
Diabetes (126 mg/dL)3
X
X
X
Fasting lipid profile
Total cholesterol (<200 mg/dL)2
HDL (>40)2
LDL (<100)2
TG (<150)2
X
X
X


X
Normal values (in parentheses) based on 2007 ADA Guidelines and National Cholesterol
Education Program (NCEP) Guidelines.
1. ADA. Diabetes Care. 2004;27(2):596-601.
2. Adult Treatment Panel. JAMA. 2001;285(19):2486-2497
3. ADA. Diabetes Care. 2007;30(suppl 1):S4-S41.
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Probe for patient and/or family history of dizziness,
syncope, palpitations, arrhythmias, or sudden death
Evaluate overdose risk
Consider patient’s use of coronary vasospastic
substances,
bt
suchh as nicotine
i ti or cocaine
i
Maintain normal electrolyte levels, especially
potassium and magnesium
Monitor for alcohol use, dehydration, and diuretics
which may cause abnormal electrolyte levels
Monitor for drug interactions with metabolic
inhibitors and drugs that prolong the QT interval.
Concerns regarding prolonged QTc

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Prolonged QTc is an unreliable and a crude
predictor of TdP.
There have been rare postpost-marketing reports of
TdP (in the presence of multiple confounding
factors) with quetiapine,
quetiapine risperidone and
ziprasidone in which no causal relationship was
established.
For pts. taking antipsychotics who experience
symptoms that could indicate the occurrence of
TdP (dizziness, palpitations, or syncope), further
evaluation like Holter monitoring may be useful.
EKG monitoring guidelines
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No need to routinely perform an EKG
before initiating antipsychotic therapy in
pts. without any risk factors for QTc
prolongation.
prolongation
Obtain a baseline EKG in pts with risk
factors for QTc prolongation or cardiac
problems, including a hx of cardiac disease,
HR < 50, hypokalemia, hypomagnesemia,
or chronic alcohol abuse.
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In a nutshell
EKG monitoring guidelines (contd.)
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No need to perform an EKG when the doses
of antipsychotic meds are increased, since
changes in QTc do not appear to be dose
dose-related in a clinically significant way at
clinically relevant doses.
Baseline EKG before initiating
antipsychotics if: personal hx of heart
disease or syncope; family hx of sudden
death, or congenital long QT syndrome.

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Patients with severe mental illness have higher
standardized mortality rates from cardiovascular
disease than the general population.
Certain cardiovascular adverse effects like
orthostasis, tachycardia and lethal tachyarrhythmias
from QTc prolongation are of less concern with
atypical antipsychotics.
Traditional risk factors for cardiovascular morbidity
and mortality are of significant concern during
atypical antipsychotic treatment particularly for
olanzapine and clozapine.
Weiden et al, 2002
Summary (contd.)
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Clozapine and olanzapine are associated with greatest risk of
insulin resistance, or T2DM, but there are cases linked to
exposure with other atypicals.
Adiposity--independent mechanisms have also been shown
Adiposity
increase the propensity of certain antipsychotics to cause
insulin resistance.
Myocarditis and QTc prolongation may result in fatal
dysrhythmias, yet these events are exceedingly rare and
contribute nominally to excessive CV mortality seen among
patients with schizophrenia
Current practice guidelines suggest trials of metabolically
more neutral agent like aripiprazole and ziprasidone when
appropriate, and routine monitoring of weight, lipids and
glucose for all patients receiving antipsychotic treatment.
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