Transcript Carvedilol Prophylaxis in Anthracycline-Induced Cardiomyopathy

Carvedilol Prophylaxis in
Anthracycline-Induced
Cardiomyopathy
Yim de Guzman
COH Medicine Rotation
Western University of Health Sciences College of
Pharmacy
March 24, 2010
Objectives
Patient case discussion
 Pathophysiology of anthracycline-induced
cardiomyopathy
 Potential prevention strategies
 2008 ASCO guideline
 Carvedilol as potential prophylactic
treatment
 Conclusion
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Patient Presentation
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CR is a 31 yo Caucasian male with hx of neuroblastoma
at age of 1½ yo, starting chemotherapy with cytarabine
and idarubicin 7+3 for recently diagnosed acute
myelogeous leukemia
HPI
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C/O abdominal discomfort 10 days prior
Recent elbow, wrist, knuckle, shin and ankle pain
Episode of sweating on 3/2/2010
More tired than usual, increased sleep and headaches
Pancytopenia: WBC 1.7, Hgb 9.7, platelet 34,000
Bone marrow biopsy: + AML
Admitted to COH on 3/3/2010
Patient Presentation
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PMH
 Neuroblastoma: had surgery followed with 6 months of
chemotherapy and radiation therapy to lower abdomen
 Pyloric stenosis as an infant
SH
 Quit smoking 2 years ago, prior had 10 years smoking history
 Drinks alcohol occasionally
 No history of IV drug use
 Works full time for UPS as driver
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FH
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Maternal aunt dx with ovarian and uterus CA
Maternal grandfather dx with some types of CA
Has one half sister and one full sister (match donor)
Patient Presentation
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Current meds
Cytarabine 100 mg/m2 daily on d1-7
 Idarubicin 12 mg/m2 daily on d1-3
 Acyclovir 400mg BID
 Allopurinol 300mg daily
 Protonix 40mg daily
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Allergies
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NKA
Laboratory Values
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Labs
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WBC 1.8, H/H: 9.5/26.8, platelet 35,
peripheral blasts 12%,
Tests
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Echocardiogram on 3/4/2010
 EF=64%
Clinical question
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Cardiomyopathy risk in CR
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Unknown chemotherapy received as child
 Common
chemo regimen for neuroblastoma:
daunorubicin/doxorubicin, cyclophosphamide,
carboplatin/cisplatin, and epotoside
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Current idarubicin regimen
dose=36mg/m2
 5% risk of cardiomyopathy at cumulative dose of
150mg/m2 -290mg/m2 (1)
 Cumulative
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Potential need for further AT therapy
Is carvedilol an effective prophylactic
treatment for AML patient against
anthracycline-induced cardiomyopathy?
Pathophysiology of AnthracyclineInduced Cardiomyopathy
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Anthracyclines are potent antineoplastic agents
Associated with irreversible cardiomyopathy
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Chronic Heart failure (5%)2
Over 50% of pt treated with AT will have varying degree of
cardiomyopathy over 10-20 years post therapy2
Toxicity can occur at any stage of treatment
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Acute
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Early
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During administration of AT therapy
Several days to months following AT therapy
Delayed
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Years to decades following AT therapy
Cardinal D. J Am Coll Cardiol. 2010 Jan 19;55(3):213-20.
Pathophysiology of AnthracyclineInduced Cardiomyopathy
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Myocytes damage
 Free oxygen radicals
 Lipid peroxidation of
membrane
 Apoptosis
 Redox activation to a
semi-quinone
intermediate
 Generate
superoxide and
hydrogen
peroxide
 Mitochondrial dysfunction
 Decrease
mitochondrial Ca++
loading capacity
http://www.heartandmetabolism.org/issues/HM35/HM35basicartic.asp
Risk Factors of AT-induced
cardiomyopathy
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Cumulative dose
Patient age
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Preexisting cardiac dysfunction, hypertension
Radiation therapy
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Prior mediastinal radiation
Endothelial cell damage
Compromise coronary artery blood flow
Concurrent chemotherapy
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Older and younger pts have increased risk at lower AT doses
Taxanes
Trastuzumab
HSCT
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Cyclophosphamide
TBI
Prognosis
Anthracycline-induced cardiomyopathy
has poorer prognosis compared to other
forms of cardiomyopathy
 2 year mortality rate of up to 60%
(Cardinale)
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Potential Strategies for AT-CMP
Prevention
Administration modifications
 Structural modifications
 Coenzyme Q10
 Vit A, Vit C and Vit E
 Dexrazoxane
 Carvedilol
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Potential Strategies for AT-CMP Prevention
Potential preventive
strategies
Study
Results
Administration
modification
Legha et al, 1982
RCT
Decreased cardiotoxicity with continuous infusion
over 48 or 96 hr vs bolus
Structural changes
Epirubicin
Perez et al, 1991
RCT
Higher dose of epirubicin produced equivalent
toxicity to doxorubicin, 90mg/m2 vs 60mg/m2,
without increasing response rate and survival rate
in advanced breast cancer
Idarubicin
Anderlini et al, 1995
Platel et al, 1999
Creutzig et al, 2001
Preclinical studies showed that cardiac toxicity was
lower than doxorubicin
However, clinical data have not consistently
showed same effect
Mitoxantrone
Dorr et al, 1991
Alderton et al, 1992
Herman et al, 1997
In vitro and in vivo studies showed at clinically
equivalent doses, cardiotoxic effect was less
severe than doxorubicin
Liposomal doxorubicin
Batis et al, 2001
Harris et al, 2001
Safra 2003
RCTs in adults found activity is similar to
conventional formulation but cardiotoxicity is
significantly lower
Wouters KA. Br J Haematol. 2005 Dec;131(5):561-78
Potential Strategies for AT-CMP Prevention
Potential preventive
strategies
Study
Results
Coenzyme Q10
Non-RCTs: Cortes et al,
1978, Okuma et al, 1984,
Folkers et al, 1993
Reported treatment with coenzyme Q10 and
doxorubicin decreased incidence of cardiac
dysfunction.
RCT: Larussi et al, 1994
Found no difference in outcome
Vitamin A
Ciaccio et al, 1993,
Livrea et al, 1995
Study in rat heart and brain membrane treated
with anthracycline showed peroxidation inhibition
No clear results from in vivo study
Vitamin C
Shimpo et al, 1991
Delays general toxicity of docorubicin and
prevents cardiac toxicity in mice and guinea-pigs.
However, in vivo data shows variable results
Vitamin E
Myers et al, 1977
Wang et al, 1980
Animal studies showed reduced cardiac toxicity
in acute high doxorubicin doses
Legha et al, 1982
Non-RCTs had negative results
Wouters KA. Br J Haematol. 2005 Dec;131(5):561-78
Dexrazoxane
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EDTA-like chelator
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Bind iron that is release from intracellular storage secondary to lipid
peroxidation, acting as cofactor for free radicals
Data from meta-analysis: Cardioprotective interventions for cancer
patients receiving anthracyclines
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9 RCTs
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Occurrence of HF
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(RR) = 0.28, 95% CI (0.18 to 0.42) P<0.00001
Response rate
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692 adult patient received dexrazoxane
711 adult patient in control group (either placebo or nothing)
8 studies: solid tumors with majority being breast cancer
1 study: leukemia
RR = 0.88, 95% CI (0.77 to 1.01) P = 0.06
Patients treated with dexrazoxane might have a lower anti-tumor response
rate
Meta-analysis of survival showed no significant difference between the
dexrazoxane and control group
Conclude that if the risk of cardiac damage is expected to be high, it might
be justified to use dexrazoxane in patients with cancer treated with
anthracyclines.
Dalen E. Cochrane Database Syst Rev 2005;(1): CD003917
ASCO Guideline 2008
Use in adult patients with other malignancies:
Use of dexrazoxane can be considered in adult
patients who have received more than 300mg/m2 of
doxorubicin-based therapy
Caution should be exercised in the use of
dexrazoxane in settings in which doxorubicin-based
therapy has been shown to improve survival
Hensley ML. J Clin Oncol. 2009 Jan 1;27(1):127-45.
Carvedilol
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Adrenergic blockade
Non-selective Beta-blocker
FDA approved for
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Heart failure
Hypertension
Impaired left ventricular function – Myocardial infarction
Non-FDA labeled indications
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Chronic angina
Atrial arrhythmia
Cardiac dysrhythmia
Congestive cardiomyopathy
CHF, nitrate tolerance
Disease of liver
Prophylaxis for gastroesophageal varices
Surgical procedure
Carvedilol
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Proposed mechanism for prevention of AT-induced
cardiomyopathy
Potent anti-oxidant
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10x more potent than alpha-tocopherol
Metabolites 1,000 more potent
Accumulates in myocardium plasma membrane
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Inhibit formation of reactive oxygen radicals
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10,000x more in cell membrane than in extracelluar medium
Prevent lipid peroxidation
Prevent formation of vacuoles
Scavenger for oxygen free radicals
Prevent depletion of endogenous anti-oxidants
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Vit E
Glutathione
Matsui H. Life Sciences Life Sci. 1999;65(12):1265-74.
Spallarossa P. Journal of Molecular and Cellular Cardiology 37 (2004) 837–846
AT-induced cardiac myocyte in rat
model
Fig B: Light micrograph of doxorubicin-treated rat
cardiac myocytes
Fig A: Light micrograph of normal cardiac
myocyte
Santos DL. Toxicology and Applied Pharmacology 185, 218-227
Fig C: Light micrograph of doxorubicin and carvedilol
treated rat cardiac myocytes
RCT: Protective effects of carvedilol against
anthracycline-induced cardiomyopathy
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Patient diagnosed with malignancy and planned AT
therapy with doxorubicin or epirubicin
Exclusion criteria:
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Previous chemotherapy or radiotherapy
Presence of CHF symptoms or established CMP
Hx of CAD
Presence of moderate to severe mitral or aortic valve disease
Any CI to carvedilol
Bundle branch block
Thyroid function disorder
Other comorbid disease
Taking other drugs that affect cardiac function
RCT: Protective effects of carvedilol against
anthracycline-induced cardiomyopathy
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Design of study
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Arms of study
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25 patients received 12.5mg once daily carvedilol before start of
CT
25 patients received placebo
Duration
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Randomized
Single-blinded
Placebo-controlled
6 months during CT
Primary end point
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Systolic function
RCT: Protective effects of carvedilol against
anthracycline-induced cardiomyopathy
Kalay N. J Am Coll Cardiol. 2006 Dec 5;48(11):2258-62.
RCT: Protective effects of carvedilol against
anthracycline-induced cardiomyopathy
Kalay N. J Am Coll Cardiol. 2006 Dec 5;48(11):2258-62.
•
Carvedilol group mean
EF: 70.5 vs. 69.7,
respectively; p=0.3
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Control group mean EF:
68.9 vs. 52.3; p=0.001
RCT: Protective effects of carvedilol against
anthracycline-induced cardiomyopathy
Kalay N. J Am Coll Cardiol. 2006 Dec 5;48(11):2258-62.
RCT: Protective effects of carvedilol against
anthracycline-induced cardiomyopathy
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Results
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Primary outcome: Heart failure (EF < 50%)
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Systolic diameters
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1 (4%) pt from carvedilol group developed HF
5 (20%) pt from control group developed HF
ARR=16%, RRR=80%, NNT=6
Carvedilol group: 31.4 ± 5.4 mm vs. 32.2 ± 6.6 mm; p 0.7
Control group: 30.3 ± 5.2 mm vs. 38.0 ± 5.3 mm; p 0.0001
Diastolic diameters
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Carvedilol group: 47.6 ± 5.6 mm vs. 47.4 ± 3.7mm; p 0.8
Control group: 45.6 ± 5.0 mm vs. 50.9 ± 5.6 mm; p 0.008
Limitations
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Limited number of enrolled patients-low power
Found less mortality in carvedilol group but was
not significant
Only evaluated early cardiotoxic effect of AT
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Early CMP depend on cumulative dose of AT
Late CMP can occur to patient with any dose
Most patient were solid tumor with other types
not specified
Patient were blinded but clinicians were not
blinded
Carvedilol ADR
Cardiovascular: bradyarrhythmia,
hypotension peripheral edema,
atrioventricular block
 Endocrine metabolic: hyperglycemia,
weight gain
 Gastrointestinal: diarrhea
 Neurologic: dizziness
 Reproductive: erectile dysfunction
 Other: fatigue
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Conclusion
Carvedilol ppx in AT therapy show
promising protective effect against
cardiomyopathy
 However, need larger randomized trial to
further investigate the protective effect
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Back to CR
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May be an option for CR
Young without added risk factors
 Unclear on cumulative dose of AT
 Future need for further AT therapy
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 Confirmed
persistent AML with >70% blast in
marrow post induction regimen
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Avoid possible malignant protective effect
from Dexrazoxane
References
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Anderlini P, Benjamin RS, Wong FC, et al. Idarubicin cardiotoxicity: a retrospective study in
acute myeloid leukemia and myelodysplasia. J Clin Oncol. 1995 Nov;13(11):2827-34.
Cardinale D, Colombo A, Lamantia G, et al. Anthracycline-induced cardiomyopathy: clinical
relevance and response to pharmacologic therapy. J Am Coll Cardiol. 2010 Jan 19;55(3):21320.
Dalen E; Caron H; Dickinson H; Kremer L. Cardioprotective interventions for cancer patients
receiving anthracyclines. Cochrane Database Syst Rev 2005;(1): CD003917
Hensley ML; Hagerty KL; Kewalramani T; et al. American Society of Clinical Oncology 2008
clinical practice guideline update: use of chemotherapy and radiation therapy protectants. J
Clin Oncol. 2009 Jan 1;27(1):127-45.
Kalay N; Basar E; Ozdogru I; et al. Protective effects of carvedilol against anthracyclineinduced cardiomyopathy. J Am Coll Cardiol. 2006 Dec 5;48(11):2258-62.
Matsui H, Morishima I, Numaguchi Y, et al. Protective effects of carvedilol against doxorubicininduced cardiomyopathy in rats. Life Sci. 1999;65(12):1265-74.
Santos DL, Moreno AJ, Leino RL, et al. Carvedilol protects against doxorubicin-induced
mitochondrial cardiomyopathy. Toxicol Appl Pharmacol. 2002 Dec 15;185(3):218-27.
Wouters KA, Kremer LC, Miller TL, et al. Protecting against anthracycline-induced myocardial
damage: a review of the most promising strategies. Br J Haematol. 2005 Dec;131(5):561-78.
Review.