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Carvedilol Prophylaxis in Anthracycline-Induced Cardiomyopathy

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Presentation on theme: "Carvedilol Prophylaxis in Anthracycline-Induced Cardiomyopathy"— Presentation transcript:

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 7+3 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 Allergies
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 Tests
WBC 1.8, H/H: 9.5/26.8, platelet 35, peripheral blasts 12%, Tests Echocardiogram on 3/4/2010 EF=64%

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 dose=36mg/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 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 Jan 19;55(3):

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

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 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 Dec;131(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. 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 Dec;131(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) P< 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 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 Jan 1;27(1):

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. 1999;65(12): Spallarossa P. Journal of Molecular and Cellular Cardiology 37 (2004) 837–846

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,

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 Dec 5;48(11):

23 RCT: Protective effects of carvedilol against anthracycline-induced cardiomyopathy
Carvedilol group mean EF: 70.5 vs. 69.7, respectively; p=0.3 Control group mean EF: 68.9 vs. 52.3; p=0.001 Kalay N. J Am Coll Cardiol Dec 5;48(11):

24 RCT: Protective effects of carvedilol against anthracycline-induced cardiomyopathy
Kalay N. J Am Coll Cardiol Dec 5;48(11):

25 RCT: Protective effects of carvedilol against anthracycline-induced cardiomyopathy
Results Primary outcome: Heart failure (EF < 50%) 1 (4%) pt from carvedilol group developed HF 5 (20%) pt from control group developed HF ARR=16%, RRR=80%, NNT=6 Systolic diameters Carvedilol group: 31.4 ± 5.4 mm vs ± 6.6 mm; p 0.7 Control group: 30.3 ± 5.2 mm vs ± 5.3 mm; p Diastolic diameters Carvedilol group: 47.6 ± 5.6 mm vs ± 3.7mm; p 0.8 Control group: 45.6 ± 5.0 mm vs ± 5.6 mm; p

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 >70% 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 Nov;13(11): Cardinale D, Colombo A, Lamantia G, et al. Anthracycline-induced cardiomyopathy: clinical relevance and response to pharmacologic therapy. J Am Coll Cardiol Jan 19;55(3): 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 Jan 1;27(1): Kalay N; Basar E; Ozdogru I; et al. Protective effects of carvedilol against anthracycline-induced cardiomyopathy. J Am Coll Cardiol Dec 5;48(11): Matsui H, Morishima I, Numaguchi Y, et al. Protective effects of carvedilol against doxorubicin-induced cardiomyopathy in rats. Life Sci. 1999;65(12): Santos DL, Moreno AJ, Leino RL, et al. Carvedilol protects against doxorubicin-induced mitochondrial cardiomyopathy. Toxicol Appl Pharmacol Dec 15;185(3): Wouters KA, Kremer LC, Miller TL, et al. Protecting against anthracycline-induced myocardial damage: a review of the most promising strategies. Br J Haematol Dec;131(5): Review.

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