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Carvedilol Prophylaxis in Anthracycline-Induced Cardiomyopathy Yim de Guzman COH Medicine Rotation Western University of Health Sciences College of Pharmacy.

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Presentation on theme: "Carvedilol Prophylaxis in Anthracycline-Induced Cardiomyopathy Yim de Guzman COH Medicine Rotation Western University of Health Sciences College of Pharmacy."— 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 Patient case discussion Pathophysiology of anthracycline-induced cardiomyopathy Pathophysiology of anthracycline-induced cardiomyopathy Potential prevention strategies Potential prevention strategies 2008 ASCO guideline 2008 ASCO guideline Carvedilol as potential prophylactic treatment Carvedilol as potential prophylactic treatment Conclusion 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 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 HPI C/O abdominal discomfort 10 days prior C/O abdominal discomfort 10 days prior Recent elbow, wrist, knuckle, shin and ankle pain Recent elbow, wrist, knuckle, shin and ankle pain Episode of sweating on 3/2/2010 Episode of sweating on 3/2/2010 More tired than usual, increased sleep and headaches More tired than usual, increased sleep and headaches Pancytopenia: WBC 1.7, Hgb 9.7, platelet 34,000 Pancytopenia: WBC 1.7, Hgb 9.7, platelet 34,000 Bone marrow biopsy: + AML Bone marrow biopsy: + AML Admitted to COH on 3/3/2010 Admitted to COH on 3/3/2010

4 Patient Presentation PMH PMH Neuroblastoma: had surgery followed with 6 months of chemotherapy and radiation therapy to lower abdomen Neuroblastoma: had surgery followed with 6 months of chemotherapy and radiation therapy to lower abdomen Pyloric stenosis as an infant Pyloric stenosis as an infant SH SH Quit smoking 2 years ago, prior had 10 years smoking history Quit smoking 2 years ago, prior had 10 years smoking history Drinks alcohol occasionally Drinks alcohol occasionally No history of IV drug use No history of IV drug use Works full time for UPS as driver Works full time for UPS as driver FH FH Maternal aunt dx with ovarian and uterus CA Maternal aunt dx with ovarian and uterus CA Maternal grandfather dx with some types of CA Maternal grandfather dx with some types of CA Has one half sister and one full sister (match donor) Has one half sister and one full sister (match donor)

5 Patient Presentation Current meds Current meds Cytarabine 100 mg/m 2 daily on d1-7 Cytarabine 100 mg/m 2 daily on d1-7 Idarubicin 12 mg/m 2 daily on d1-3 Idarubicin 12 mg/m 2 daily on d1-3 Acyclovir 400mg BID Acyclovir 400mg BID Allopurinol 300mg daily Allopurinol 300mg daily Protonix 40mg daily Protonix 40mg daily Allergies Allergies NKA NKA

6 Laboratory Values Labs Labs WBC 1.8, H/H: 9.5/26.8, platelet 35, peripheral blasts 12%, WBC 1.8, H/H: 9.5/26.8, platelet 35, peripheral blasts 12%, Tests Tests Echocardiogram on 3/4/2010 Echocardiogram on 3/4/2010 EF=64% EF=64%

7 Clinical question Cardiomyopathy risk in CR Cardiomyopathy risk in CR Unknown chemotherapy received as child Unknown chemotherapy received as child Common chemo regimen for neuroblastoma: daunorubicin/doxorubicin, cyclophosphamide, carboplatin/cisplatin, and epotoside Common chemo regimen for neuroblastoma: daunorubicin/doxorubicin, cyclophosphamide, carboplatin/cisplatin, and epotoside Current idarubicin regimen Current idarubicin regimen Cumulative dose=36mg/m 2 Cumulative dose=36mg/m 2 5% risk of cardiomyopathy at cumulative dose of 150mg/m 2 -290mg/m 2 (1) 5% risk of cardiomyopathy at cumulative dose of 150mg/m 2 -290mg/m 2 (1) Potential need for further AT therapy Potential need for further AT therapy Is carvedilol an effective prophylactic treatment for AML patient against anthracycline-induced cardiomyopathy? Is carvedilol an effective prophylactic treatment for AML patient against anthracycline-induced cardiomyopathy?

8 Pathophysiology of Anthracycline- Induced Cardiomyopathy Anthracyclines are potent antineoplastic agents Anthracyclines are potent antineoplastic agents Associated with irreversible cardiomyopathy Associated with irreversible cardiomyopathy Chronic Heart failure (5%) 2 Chronic Heart failure (5%) 2 Over 50% of pt treated with AT will have varying degree of cardiomyopathy over 10-20 years post therapy 2 Over 50% of pt treated with AT will have varying degree of cardiomyopathy over 10-20 years post therapy 2 Toxicity can occur at any stage of treatment Toxicity can occur at any stage of treatment Acute Acute During administration of AT therapy During administration of AT therapy Early Early Several days to months following AT therapy Several days to months following AT therapy Delayed Delayed Years to decades following AT therapy Years to decades following AT therapy Cardinal D. J Am Coll Cardiol. 2010 Jan 19;55(3):213-20. Cardinal D. J Am Coll Cardiol. 2010 Jan 19;55(3):213-20.

9 Pathophysiology of Anthracycline- Induced Cardiomyopathy Myocytes damage Myocytes damage Free oxygen radicals Free oxygen radicals Lipid peroxidation of membrane Lipid peroxidation of membrane Apoptosis Apoptosis Redox activation to a semi-quinone intermediate Redox activation to a semi-quinone intermediate Generate superoxide and hydrogen peroxide Generate superoxide and hydrogen peroxide Mitochondrial dysfunction Mitochondrial dysfunction Decrease mitochondrial Ca++ loading capacity Decrease mitochondrial Ca++ loading capacity http://www.heartandmetabolism.org/issues/HM35/HM35basicartic.asp

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

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

12 Potential Strategies for AT-CMP Prevention Administration modifications Administration modifications Structural modifications Structural modifications Coenzyme Q10 Coenzyme Q10 Vit A, Vit C and Vit E Vit A, Vit C and Vit E Dexrazoxane Dexrazoxane Carvedilol Carvedilol

13 Potential Strategies for AT-CMP Prevention Potential preventive strategies StudyResults Administration modification Legha et al, 1982 RCT Decreased cardiotoxicity with continuous infusion over 48 or 96 hr vs bolus Structural changesEpirubicin 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

14 Potential Strategies for AT-CMP Prevention Potential preventive strategies StudyResults Coenzyme Q10Non-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, 1994Found no difference in outcome Vitamin ACiaccio 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 CShimpo et al, 1991Delays general toxicity of docorubicin and prevents cardiac toxicity in mice and guinea-pigs. However, in vivo data shows variable results Vitamin EMyers et al, 1977 Wang et al, 1980 Animal studies showed reduced cardiac toxicity in acute high doxorubicin doses Legha et al, 1982Non-RCTs had negative results Wouters KA. Br J Haematol. 2005 Dec;131(5):561-78

15 Dexrazoxane EDTA-like chelator EDTA-like chelator Bind iron that is release from intracellular storage secondary to lipid peroxidation, acting as cofactor for free radicals 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 Data from meta-analysis: Cardioprotective interventions for cancer patients receiving anthracyclines 9 RCTs 9 RCTs 692 adult patient received dexrazoxane 692 adult patient received dexrazoxane 711 adult patient in control group (either placebo or nothing) 711 adult patient in control group (either placebo or nothing) 8 studies: solid tumors with majority being breast cancer 8 studies: solid tumors with majority being breast cancer 1 study: leukemia 1 study: leukemia Occurrence of HF Occurrence of HF (RR) = 0.28, 95% CI (0.18 to 0.42) P<0.00001 (RR) = 0.28, 95% CI (0.18 to 0.42) P<0.00001 Response rate Response rate RR = 0.88, 95% CI (0.77 to 1.01) P = 0.06 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 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 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. 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 1;27(1):127-45. 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

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

18 Carvedilol Proposed mechanism for prevention of AT-induced cardiomyopathy Proposed mechanism for prevention of AT-induced cardiomyopathy Potent anti-oxidant Potent anti-oxidant 10x more potent than alpha-tocopherol 10x more potent than alpha-tocopherol Metabolites 1,000 more potent Metabolites 1,000 more potent Accumulates in myocardium plasma membrane Accumulates in myocardium plasma membrane 10,000x more in cell membrane than in extracelluar medium 10,000x more in cell membrane than in extracelluar medium Inhibit formation of reactive oxygen radicals Inhibit formation of reactive oxygen radicals Prevent lipid peroxidation Prevent lipid peroxidation Prevent formation of vacuoles Prevent formation of vacuoles Scavenger for oxygen free radicals Scavenger for oxygen free radicals Prevent depletion of endogenous anti-oxidants Prevent depletion of endogenous anti-oxidants Vit E Vit E Glutathione Glutathione Matsui H. Life Sciences Life Sci. 1999;65(12):1265-74. Spallarossa P. Journal of Molecular and Cellular Cardiology 37 (2004) 837–846

19 AT-induced cardiac myocyte in rat model Santos DL. Toxicology and Applied Pharmacology 185, 218-227 Fig A: Light micrograph of normal cardiac myocyte Fig B: Light micrograph of doxorubicin-treated rat cardiac myocytes Fig C: Light micrograph of doxorubicin and carvedilol treated rat cardiac myocytes

20 RCT: Protective effects of carvedilol against anthracycline-induced cardiomyopathy Patient diagnosed with malignancy and planned AT therapy with doxorubicin or epirubicin Patient diagnosed with malignancy and planned AT therapy with doxorubicin or epirubicin Exclusion criteria: Exclusion criteria: Previous chemotherapy or radiotherapy Previous chemotherapy or radiotherapy Presence of CHF symptoms or established CMP Presence of CHF symptoms or established CMP Hx of CAD Hx of CAD Presence of moderate to severe mitral or aortic valve disease Presence of moderate to severe mitral or aortic valve disease Any CI to carvedilol Any CI to carvedilol Bundle branch block Bundle branch block Thyroid function disorder Thyroid function disorder Other comorbid disease Other comorbid disease Taking other drugs that affect cardiac function Taking other drugs that affect cardiac function

21 RCT: Protective effects of carvedilol against anthracycline-induced cardiomyopathy Design of study Design of study Randomized Randomized Single-blinded Single-blinded Placebo-controlled Placebo-controlled Arms of study Arms of study 25 patients received 12.5mg once daily carvedilol before start of CT 25 patients received 12.5mg once daily carvedilol before start of CT 25 patients received placebo 25 patients received placebo Duration Duration 6 months during CT 6 months during CT Primary end point Primary end point Systolic function Systolic function

22 RCT: Protective effects of carvedilol against anthracycline-induced cardiomyopathy Kalay N. J Am Coll Cardiol. 2006 Dec 5;48(11):2258-62.

23 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 Control group mean EF: 68.9 vs. 52.3; p=0.001

24 RCT: Protective effects of carvedilol against anthracycline-induced cardiomyopathy Kalay N. J Am Coll Cardiol. 2006 Dec 5;48(11):2258-62.

25 RCT: Protective effects of carvedilol against anthracycline-induced cardiomyopathy Results Results Primary outcome: Heart failure (EF < 50%) Primary outcome: Heart failure (EF < 50%) 1 (4%) pt from carvedilol group developed HF 1 (4%) pt from carvedilol group developed HF 5 (20%) pt from control group developed HF 5 (20%) pt from control group developed HF ARR=16%, RRR=80%, NNT=6 ARR=16%, RRR=80%, NNT=6 Systolic diameters 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 Limited number of enrolled patients-low power Found less mortality in carvedilol group but was not significant Found less mortality in carvedilol group but was not significant Only evaluated early cardiotoxic effect of AT Only evaluated early cardiotoxic effect of AT Early CMP depend on cumulative dose of AT Early CMP depend on cumulative dose of AT Late CMP can occur to patient with any dose Late CMP can occur to patient with any dose Most patient were solid tumor with other types not specified Most patient were solid tumor with other types not specified Patient were blinded but clinicians were not blinded Patient were blinded but clinicians were not blinded

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

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

29 Back to CR May be an option for CR May be an option for CR Young without added risk factors Young without added risk factors Unclear on cumulative dose of AT Unclear on cumulative dose of AT Future need for further AT therapy Future need for further AT therapy Confirmed persistent AML with >70% blast in marrow post induction regimen Confirmed persistent AML with >70% blast in marrow post induction regimen Avoid possible malignant protective effect from Dexrazoxane Avoid possible malignant protective effect from Dexrazoxane

30 References 1. 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. 2. 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):213- 20. 3. Dalen E; Caron H; Dickinson H; Kremer L. Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database Syst Rev 2005;(1): CD003917 4. 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. 5. Kalay N; Basar E; Ozdogru I; et al. Protective effects of carvedilol against anthracycline- induced cardiomyopathy. J Am Coll Cardiol. 2006 Dec 5;48(11):2258-62. 6. Matsui H, Morishima I, Numaguchi Y, et al. Protective effects of carvedilol against doxorubicin- induced cardiomyopathy in rats. Life Sci. 1999;65(12):1265-74. 7. 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. 8. 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.


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