Carvedilol Prophylaxis in Anthracycline-Induced Cardiomyopathy

1
Carvedilol Prophylaxis in Anthracycline-Induced
Cardiomyopathy

• Yim de Guzman
• COH Medicine Rotation
• Western University of Health Sciences College of
  Pharmacy
• March 24, 2010

2
Objectives

• Patient case discussion
• Pathophysiology of anthracycline-induced
  cardiomyopathy
• Potential prevention strategies
• 2008 ASCO guideline
• Carvedilol as potential prophylactic treatment
• Conclusion

3
Patient Presentation

• CR is a 31 yo Caucasian male with hx of
  neuroblastoma at age of 1½ yo, starting
  chemotherapy with cytarabine and idarubicin 73
  for recently diagnosed acute myelogeous leukemia
• HPI
• 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

4
Patient Presentation

• 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
• FH
• 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)

5
Patient Presentation

• 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
• Allergies
• NKA

6
Laboratory Values

• Labs
• WBC 1.8, H/H 9.5/26.8, platelet 35, peripheral
  blasts 12,
• Tests
• Echocardiogram on 3/4/2010
• EF64

7
Clinical question

• Cardiomyopathy risk in CR
• Unknown chemotherapy received as child
• Common chemo regimen for neuroblastoma
  daunorubicin/doxorubicin, cyclophosphamide,
  carboplatin/cisplatin, and epotoside
• Current idarubicin regimen
• Cumulative dose36mg/m2
• 5 risk of cardiomyopathy at cumulative dose of
  150mg/m2 -290mg/m2 (1)
• Potential need for further AT therapy
• Is carvedilol an effective prophylactic treatment
  for AML patient against anthracycline-induced
  cardiomyopathy?

8
Pathophysiology of Anthracycline-Induced
Cardiomyopathy

• Anthracyclines are potent antineoplastic agents
• Associated with irreversible cardiomyopathy
• 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
• Acute
• During administration of AT therapy
• Early
• Several days to months following AT therapy
• Delayed
• Years to decades following AT therapy

• Cardinal D. J Am Coll Cardiol. 2010 Jan
  1955(3)213-20.

9
Pathophysiology of Anthracycline-Induced
Cardiomyopathy

• 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/HM35
basicartic.asp
10
Risk Factors of AT-induced cardiomyopathy

• Cumulative dose
• Patient age
• Older and younger pts have increased risk at
  lower AT doses
• Preexisting cardiac dysfunction, hypertension
• Radiation therapy
• Prior mediastinal radiation
• Endothelial cell damage
• Compromise coronary artery blood flow
• Concurrent chemotherapy
• Taxanes
• Trastuzumab
• HSCT
• Cyclophosphamide
• TBI

11
Prognosis

• Anthracycline-induced cardiomyopathy has poorer
  prognosis compared to other forms of
  cardiomyopathy
• 2 year mortality rate of up to 60 (Cardinale)

12
Potential Strategies for AT-CMP Prevention

• Administration modifications
• Structural modifications
• Coenzyme Q10
• Vit A, Vit C and Vit E
• Dexrazoxane
• Carvedilol

13
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
Structural changes 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
Structural changes 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
Structural changes 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 Dec131(5)561-78

14
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.
Coenzyme Q10 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
Vitamin E Legha et al, 1982 Non-RCTs had negative results
Wouters KA. Br J Haematol. 2005 Dec131(5)561-78
15
Dexrazoxane

• EDTA-like chelator
• 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
• 9 RCTs
• 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
• Occurrence of HF
• (RR) 0.28, 95 CI (0.18 to 0.42) Plt0.00001
• Response rate
• 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
16
ASCO Guideline 2008
Hensley ML. J Clin Oncol. 2009 Jan 127(1)127-45.
17
Carvedilol

• Adrenergic blockade
• Non-selective Beta-blocker
• FDA approved for
• Heart failure
• Hypertension
• Impaired left ventricular function Myocardial
  infarction
• Non-FDA labeled indications
• Chronic angina
• Atrial arrhythmia
• Cardiac dysrhythmia
• Congestive cardiomyopathy
• CHF, nitrate tolerance
• Disease of liver
• Prophylaxis for gastroesophageal varices
• Surgical procedure

18
Carvedilol

• Proposed mechanism for prevention of AT-induced
  cardiomyopathy
• Potent anti-oxidant
• 10x more potent than alpha-tocopherol
• Metabolites 1,000 more potent
• Accumulates in myocardium plasma membrane
• 10,000x more in cell membrane than in
  extracelluar medium
• Inhibit formation of reactive oxygen radicals
• Prevent lipid peroxidation
• Prevent formation of vacuoles
• Scavenger for oxygen free radicals
• Prevent depletion of endogenous anti-oxidants
• Vit E
• Glutathione

Matsui H. Life Sciences Life Sci.
199965(12)1265-74. Spallarossa P. Journal of
Molecular and Cellular Cardiology 37 (2004)
837846
19
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
Fig C Light micrograph of doxorubicin and
carvedilol treated rat cardiac myocytes
Santos DL. Toxicology and Applied Pharmacology
185, 218-227
20
RCT Protective effects of carvedilol against
anthracycline-induced cardiomyopathy

• Patient diagnosed with malignancy and planned AT
  therapy with doxorubicin or epirubicin
• Exclusion criteria
• 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

21
RCT Protective effects of carvedilol against
anthracycline-induced cardiomyopathy

• Design of study
• Randomized
• Single-blinded
• Placebo-controlled
• Arms of study
• 25 patients received 12.5mg once daily carvedilol
  before start of CT
• 25 patients received placebo
• Duration
• 6 months during CT
• Primary end point
• Systolic function

22
RCT Protective effects of carvedilol against
anthracycline-induced cardiomyopathy
Kalay N. J Am Coll Cardiol. 2006 Dec
548(11)2258-62.
23
RCT Protective effects of carvedilol against
anthracycline-induced cardiomyopathy

• Carvedilol group mean EF 70.5 vs. 69.7,
  respectively p0.3
• Control group mean EF 68.9 vs. 52.3 p0.001

Kalay N. J Am Coll Cardiol. 2006 Dec
548(11)2258-62.
24
RCT Protective effects of carvedilol against
anthracycline-induced cardiomyopathy
Kalay N. J Am Coll Cardiol. 2006 Dec
548(11)2258-62.
25
RCT Protective effects of carvedilol against
anthracycline-induced cardiomyopathy

• Results
• Primary outcome Heart failure (EF lt 50)
• 1 (4) pt from carvedilol group developed HF
• 5 (20) pt from control group developed HF
• ARR16, RRR80, NNT6
• Systolic diameters
• 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
• 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

26
Limitations

• Limited number of enrolled patients-low power
• Found less mortality in carvedilol group but was
  not significant
• Only evaluated early cardiotoxic effect of AT
• 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

27
Carvedilol ADR

• Cardiovascular bradyarrhythmia, hypotension
  peripheral edema, atrioventricular block
• Endocrine metabolic hyperglycemia, weight gain
• Gastrointestinal diarrhea
• Neurologic dizziness
• Reproductive erectile dysfunction
• Other fatigue

28
Conclusion

• Carvedilol ppx in AT therapy show promising
  protective effect against cardiomyopathy
• However, need larger randomized trial to further
  investigate the protective effect

29
Back to CR

• May be an option for CR
• Young without added risk factors
• Unclear on cumulative dose of AT
• Future need for further AT therapy
• Confirmed persistent AML with gt70 blast in
  marrow post induction regimen
• Avoid possible malignant protective effect from
  Dexrazoxane

30
References

• Anderlini P, Benjamin RS, Wong FC, et al.
  Idarubicin cardiotoxicity a retrospective study
  in acute myeloid leukemia and myelodysplasia. J
  Clin Oncol. 1995 Nov13(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 1955(3)213-20.
• 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 127(1)127-45.
• Kalay N Basar E Ozdogru I et al. Protective
  effects of carvedilol against anthracycline-induce
  d cardiomyopathy. J Am Coll Cardiol. 2006 Dec
  548(11)2258-62.
• Matsui H, Morishima I, Numaguchi Y, et al.
  Protective effects of carvedilol against
  doxorubicin-induced cardiomyopathy in rats. Life
  Sci. 199965(12)1265-74.
• Santos DL, Moreno AJ, Leino RL, et al. Carvedilol
  protects against doxorubicin-induced
  mitochondrial cardiomyopathy. Toxicol Appl
  Pharmacol. 2002 Dec 15185(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
  Dec131(5)561-78. Review.