Carvedilol Prophylaxis in Carvedilol Prophylaxis in Anthracycline-Induced Anthracycline-Induced

Cardiomyopathy Cardiomyopathy Yim de GuzmanYim de Guzman

COH Medicine RotationCOH Medicine RotationWestern University of Health Sciences College of Western University of Health Sciences College of

PharmacyPharmacyMarch 24, 2010March 24, 2010

ObjectivesObjectives

Patient case discussionPatient case discussionPathophysiology of anthracycline-induced Pathophysiology of anthracycline-induced

cardiomyopathycardiomyopathyPotential prevention strategies Potential prevention strategies 2008 ASCO guideline2008 ASCO guidelineCarvedilol as potential prophylactic Carvedilol as potential prophylactic

treatmenttreatmentConclusionConclusion

Patient PresentationPatient Presentation CR is a 31 yo Caucasian male with hx of neuroblastoma CR is a 31 yo Caucasian male with hx of neuroblastoma

at age of 1½ yo, starting chemotherapy with cytarabine at age of 1½ yo, starting chemotherapy with cytarabine and idarubicin 7+3 for recently diagnosed acute and idarubicin 7+3 for recently diagnosed acute myelogeous leukemiamyelogeous leukemia

HPI HPI C/O abdominal discomfort 10 days priorC/O abdominal discomfort 10 days prior Recent elbow, wrist, knuckle, shin and ankle painRecent elbow, wrist, knuckle, shin and ankle pain Episode of sweating on 3/2/2010Episode of sweating on 3/2/2010 More tired than usual, increased sleep and headachesMore 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: + AMLBone marrow biopsy: + AML Admitted to COH on 3/3/2010Admitted to COH on 3/3/2010

Patient PresentationPatient Presentation PMHPMH

Neuroblastoma: had surgery followed with 6 months of Neuroblastoma: had surgery followed with 6 months of chemotherapy and radiation therapy to lower abdomenchemotherapy and radiation therapy to lower abdomen

Pyloric stenosis as an infantPyloric stenosis as an infant SHSH

Quit smoking 2 years ago, prior had 10 years smoking historyQuit smoking 2 years ago, prior had 10 years smoking history Drinks alcohol occasionallyDrinks alcohol occasionally No history of IV drug useNo history of IV drug use Works full time for UPS as driverWorks full time for UPS as driver

FHFH Maternal aunt dx with ovarian and uterus CAMaternal aunt dx with ovarian and uterus CA Maternal grandfather dx with some types of CAMaternal 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)

Patient PresentationPatient Presentation

Current medsCurrent medsCytarabine 100 mg/mCytarabine 100 mg/m22 daily on d1-7 daily on d1-7 Idarubicin 12 mg/mIdarubicin 12 mg/m22 daily on d1-3 daily on d1-3 Acyclovir 400mg BIDAcyclovir 400mg BIDAllopurinol 300mg dailyAllopurinol 300mg dailyProtonix 40mg dailyProtonix 40mg daily

AllergiesAllergiesNKANKA

Laboratory ValuesLaboratory Values

LabsLabsWBC 1.8, H/H: 9.5/26.8, platelet 35, WBC 1.8, H/H: 9.5/26.8, platelet 35,

peripheral blasts 12%, peripheral blasts 12%, TestsTests

Echocardiogram on 3/4/2010Echocardiogram on 3/4/2010EF=64%EF=64%

Clinical questionClinical question Cardiomyopathy risk in CRCardiomyopathy risk in CR

Unknown chemotherapy received as childUnknown chemotherapy received as childCommon chemo regimen for neuroblastoma: Common chemo regimen for neuroblastoma:

daunorubicin/doxorubicin, cyclophosphamide, daunorubicin/doxorubicin, cyclophosphamide, carboplatin/cisplatin, and epotosidecarboplatin/cisplatin, and epotoside

Current idarubicin regimenCurrent idarubicin regimenCumulative dose=36mg/mCumulative dose=36mg/m22

5% risk of cardiomyopathy at cumulative dose of 150mg/m5% risk of cardiomyopathy at cumulative dose of 150mg/m22 - -290mg/m290mg/m22 (1)(1)

Potential need for further AT therapy Potential need for further AT therapy Is carvedilol an effective prophylactic treatment for Is carvedilol an effective prophylactic treatment for

AML patient against anthracycline-induced AML patient against anthracycline-induced cardiomyopathy?cardiomyopathy?

Pathophysiology of Anthracycline-Pathophysiology of Anthracycline-Induced CardiomyopathyInduced Cardiomyopathy

Anthracyclines are potent antineoplastic agentsAnthracyclines are potent antineoplastic agents Associated with irreversible cardiomyopathyAssociated with irreversible cardiomyopathy

Chronic Heart failure (5%)Chronic Heart failure (5%)22

Over 50% of pt treated with AT will have varying degree of Over 50% of pt treated with AT will have varying degree of cardiomyopathy over 10-20 years post therapycardiomyopathy over 10-20 years post therapy22

Toxicity can occur at any stage of treatmentToxicity can occur at any stage of treatment AcuteAcute

During administration of AT therapyDuring administration of AT therapy EarlyEarly

Several days to months following AT therapySeveral days to months following AT therapy DelayedDelayed

Years to decades following AT therapyYears 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.

Pathophysiology of Anthracycline-Pathophysiology of Anthracycline-Induced CardiomyopathyInduced Cardiomyopathy

Myocytes damageMyocytes damage Free oxygen radicalsFree oxygen radicals

Lipid peroxidation of Lipid peroxidation of membranemembrane

ApoptosisApoptosis Redox activation to a Redox activation to a

semi-quinone semi-quinone intermediate intermediate

Generate Generate superoxide and superoxide and hydrogen hydrogen peroxideperoxide

Mitochondrial dysfunctionMitochondrial dysfunction Decrease Decrease

mitochondrial Ca++ mitochondrial Ca++ loading capacityloading capacity

http://www.heartandmetabolism.org/issues/HM35/HM35basicartic.asp

Risk Factors of AT-induced Risk Factors of AT-induced cardiomyopathycardiomyopathy

Cumulative doseCumulative dose Patient agePatient age

Older and younger pts have increased risk at lower AT dosesOlder and younger pts have increased risk at lower AT doses Preexisting cardiac dysfunction, hypertensionPreexisting cardiac dysfunction, hypertension Radiation therapyRadiation therapy

Prior mediastinal radiationPrior mediastinal radiation Endothelial cell damageEndothelial cell damage Compromise coronary artery blood flowCompromise coronary artery blood flow

Concurrent chemotherapyConcurrent chemotherapy TaxanesTaxanes TrastuzumabTrastuzumab

HSCTHSCT CyclophosphamideCyclophosphamide TBITBI

PrognosisPrognosis

Anthracycline-induced cardiomyopathy Anthracycline-induced cardiomyopathy has poorer prognosis compared to other has poorer prognosis compared to other forms of cardiomyopathyforms of cardiomyopathy

2 year mortality rate of up to 60% 2 year mortality rate of up to 60% (Cardinale)(Cardinale)

Potential Strategies for AT-CMP Potential Strategies for AT-CMP PreventionPrevention

Administration modificationsAdministration modificationsStructural modificationsStructural modificationsCoenzyme Q10Coenzyme Q10Vit A, Vit C and Vit EVit A, Vit C and Vit EDexrazoxaneDexrazoxaneCarvedilolCarvedilol

Potential Strategies for AT-CMP PreventionPotential Strategies for AT-CMP PreventionPotential preventive strategies

Study Results

Administration modification

Legha et al, 1982RCT

Decreased cardiotoxicity with continuous infusion over 48 or 96 hr vs bolus

Structural changes EpirubicinPerez et al, 1991RCT

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, 1999Creutzig et al, 2001

Preclinical studies showed that cardiac toxicity was lower than doxorubicin However, clinical data have not consistently showed same effect

MitoxantroneDorr et al, 1991Alderton et al, 1992Herman et al, 1997

In vitro and in vivo studies showed at clinically equivalent doses, cardiotoxic effect was less severe than doxorubicin

Liposomal doxorubicinBatis et al, 2001Harris et al, 2001Safra 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):561-78Wouters KA. Br J Haematol. 2005 Dec;131(5):561-78

Potential Strategies for AT-CMP PreventionPotential 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 inhibitionNo 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, 1977Wang 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):561-78Wouters KA. Br J Haematol. 2005 Dec;131(5):561-78

DexrazoxaneDexrazoxane EDTA-like chelatorEDTA-like chelator

Bind iron that is release from intracellular storage secondary to lipid Bind iron that is release from intracellular storage secondary to lipid peroxidation, acting as cofactor for free radicalsperoxidation, acting as cofactor for free radicals

Data from meta-analysis: Cardioprotective interventions for cancer Data from meta-analysis: Cardioprotective interventions for cancer patients receiving anthracyclines patients receiving anthracyclines

9 RCTs9 RCTs 692 adult patient received dexrazoxane692 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 cancer8 studies: solid tumors with majority being breast cancer 1 study: leukemia1 study: leukemia

Occurrence of HFOccurrence 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 rateResponse rate RR = 0.88, 95% CI (0.77 to 1.01) P = 0.06RR = 0.88, 95% CI (0.77 to 1.01) P = 0.06

Patients treated with dexrazoxane might have a lower anti-tumor response Patients treated with dexrazoxane might have a lower anti-tumor response rate rate

Meta-analysis of survival showed no significant difference between the Meta-analysis of survival showed no significant difference between the dexrazoxane and control group dexrazoxane and control group

Conclude that if the risk of cardiac damage is expected to be high, it might 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 be justified to use dexrazoxane in patients with cancer treated with anthracyclines. anthracyclines.

Dalen E. Cochrane Database Syst Rev 2005;(1): CD003917

ASCO Guideline 2008ASCO 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 therapyCaution should be exercised in the use of dexrazoxane in settings in which doxorubicin-based therapy has been shown to improve survival

CarvedilolCarvedilol Adrenergic blockade Adrenergic blockade Non-selective Beta-blockerNon-selective Beta-blocker FDA approved forFDA approved for

Heart failureHeart failure HypertensionHypertension Impaired left ventricular function – Myocardial infarctionImpaired left ventricular function – Myocardial infarction

Non-FDA labeled indicationsNon-FDA labeled indications Chronic anginaChronic angina Atrial arrhythmiaAtrial arrhythmia Cardiac dysrhythmiaCardiac dysrhythmia Congestive cardiomyopathyCongestive cardiomyopathy CHF, nitrate toleranceCHF, nitrate tolerance Disease of liverDisease of liver Prophylaxis for gastroesophageal varicesProphylaxis for gastroesophageal varices Surgical procedureSurgical procedure

CarvedilolCarvedilol Proposed mechanism for prevention of AT-induced Proposed mechanism for prevention of AT-induced

cardiomyopathycardiomyopathy Potent anti-oxidant Potent anti-oxidant

10x more potent than alpha-tocopherol10x more potent than alpha-tocopherol Metabolites 1,000 more potentMetabolites 1,000 more potent Accumulates in myocardium plasma membraneAccumulates in myocardium plasma membrane

10,000x more in cell membrane than in extracelluar medium10,000x more in cell membrane than in extracelluar medium Inhibit formation of reactive oxygen radicalsInhibit formation of reactive oxygen radicals

Prevent lipid peroxidationPrevent lipid peroxidation Prevent formation of vacuolesPrevent formation of vacuoles

Scavenger for oxygen free radicalsScavenger for oxygen free radicals Prevent depletion of endogenous anti-oxidants Prevent depletion of endogenous anti-oxidants

Vit EVit E GlutathioneGlutathione

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 AT-induced cardiac myocyte in rat modelmodel

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

RCT: Protective effects of carvedilol against RCT: Protective effects of carvedilol against anthracycline-induced cardiomyopathyanthracycline-induced cardiomyopathy

Patient diagnosed with malignancy and planned AT Patient diagnosed with malignancy and planned AT therapy with doxorubicin or epirubicintherapy with doxorubicin or epirubicin

Exclusion criteria:Exclusion criteria: Previous chemotherapy or radiotherapyPrevious chemotherapy or radiotherapy Presence of CHF symptoms or established CMPPresence of CHF symptoms or established CMP Hx of CADHx of CAD Presence of moderate to severe mitral or aortic valve diseasePresence of moderate to severe mitral or aortic valve disease Any CI to carvedilolAny CI to carvedilol Bundle branch blockBundle branch block Thyroid function disorderThyroid function disorder Other comorbid diseaseOther comorbid disease Taking other drugs that affect cardiac functionTaking other drugs that affect cardiac function

RCT: Protective effects of carvedilol against RCT: Protective effects of carvedilol against anthracycline-induced cardiomyopathyanthracycline-induced cardiomyopathy

Design of studyDesign of study RandomizedRandomized Single-blindedSingle-blinded Placebo-controlledPlacebo-controlled

Arms of studyArms of study 25 patients received 12.5mg once daily carvedilol before start of 25 patients received 12.5mg once daily carvedilol before start of

CTCT 25 patients received placebo25 patients received placebo

DurationDuration 6 months during CT6 months during CT

Primary end pointPrimary end point Systolic functionSystolic function

RCT: Protective effects of carvedilol against RCT: Protective effects of carvedilol against

anthracycline-induced cardiomyopathyanthracycline-induced cardiomyopathy

Kalay N. J Am Coll Cardiol. 2006 Dec 5;48(11):2258-62.

RCT: Protective effects of carvedilol against RCT: Protective effects of carvedilol against anthracycline-induced cardiomyopathyanthracycline-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

RCT: Protective effects of carvedilol against RCT: Protective effects of carvedilol against anthracycline-induced cardiomyopathyanthracycline-induced cardiomyopathy

Kalay N. J Am Coll Cardiol. 2006 Dec 5;48(11):2258-62.

RCT: Protective effects of carvedilol against RCT: Protective effects of carvedilol against anthracycline-induced cardiomyopathyanthracycline-induced cardiomyopathy

ResultsResults Primary outcome: Heart failure (EF < 50%)Primary outcome: Heart failure (EF < 50%)

1 (4%) pt from carvedilol group developed HF1 (4%) pt from carvedilol group developed HF 5 (20%) pt from control group developed HF5 (20%) pt from control group developed HF ARR=16%, RRR=80%, NNT=6ARR=16%, RRR=80%, NNT=6

Systolic diametersSystolic 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

LimitationsLimitations

Limited number of enrolled patients-low powerLimited number of enrolled patients-low power Found less mortality in carvedilol group but was Found less mortality in carvedilol group but was

not significantnot significant Only evaluated early cardiotoxic effect of ATOnly evaluated early cardiotoxic effect of AT

Early CMP depend on cumulative dose of ATEarly CMP depend on cumulative dose of AT Late CMP can occur to patient with any doseLate CMP can occur to patient with any dose

Most patient were solid tumor with other types Most patient were solid tumor with other types not specifiednot specified

Patient were blinded but clinicians were not Patient were blinded but clinicians were not blindedblinded

Carvedilol ADRCarvedilol ADR

Cardiovascular: bCardiovascular: bradyarrhythmia, radyarrhythmia, hypotension peripheral edema, hypotension peripheral edema, atrioventricular blockatrioventricular block

Endocrine metabolic: hEndocrine metabolic: hyperglycemia, yperglycemia, weight gain weight gain

Gastrointestinal: Gastrointestinal: diarrheadiarrheaNeurologic: dNeurologic: dizzinessizzinessReproductive: Reproductive: erectile dysfunction erectile dysfunction Other: Other: fatigue fatigue

ConclusionConclusion

Carvedilol ppx in AT therapy show Carvedilol ppx in AT therapy show promising protective effect against promising protective effect against cardiomyopathycardiomyopathy

However, need larger randomized trial to However, need larger randomized trial to further investigate the protective effectfurther investigate the protective effect

Back to CR

May be an option for CRMay be an option for CRYoung without added risk factorsYoung without added risk factorsUnclear on cumulative dose of ATUnclear on cumulative dose of ATFuture need for further AT therapyFuture need for further AT therapy

Confirmed persistent AML with >70% blast in Confirmed persistent AML with >70% blast in marrow post induction regimenmarrow post induction regimen

Avoid possible malignant protective effect Avoid possible malignant protective effect from Dexrazoxanefrom Dexrazoxane

ReferencesReferences1.1. Anderlini P, Benjamin RS, Wong FC, et al. Idarubicin cardiotoxicity: a retrospective study in Anderlini P, Benjamin RS, Wong FC, et al. Idarubicin cardiotoxicity: a retrospective study in

acute myeloid leukemia and myelodysplasia.acute myeloid leukemia and myelodysplasia. J Clin Oncol. 1995 Nov;13(11):2827-34.J Clin Oncol. 1995 Nov;13(11):2827-34.

2.2. Cardinale D, Colombo A, Lamantia G, et al. Anthracycline-induced cardiomyopathy: clinical 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-relevance and response to pharmacologic therapy. J Am Coll Cardiol. 2010 Jan 19;55(3):213-20.20.

3.3. Dalen E; Caron H; Dickinson H; Kremer L. Cardioprotective interventions for cancer patients Dalen E; Caron H; Dickinson H; Kremer L. Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database Syst Rev 2005;(1): CD003917receiving anthracyclines. Cochrane Database Syst Rev 2005;(1): CD003917

4.4. Hensley ML; Hagerty KL; Kewalramani T; et al. American Society of Clinical Oncology 2008 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 clinical practice guideline update: use of chemotherapy and radiation therapy protectants. J Clin Oncol. 2009 Jan 1;27(1):127-45.Clin Oncol. 2009 Jan 1;27(1):127-45.

5.5. Kalay N; Basar E; Ozdogru I; et al. Protective effects of carvedilol against anthracycline-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.induced cardiomyopathy. J Am Coll Cardiol. 2006 Dec 5;48(11):2258-62.

6.6. Matsui H, Morishima I, Numaguchi Y, et al. Protective effects of carvedilol against 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.doxorubicin-induced cardiomyopathy in rats. Life Sci. 1999;65(12):1265-74.

7.7. Santos DL, Moreno AJ, Leino RL, et al. Carvedilol protects against doxorubicin-induced 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.mitochondrial cardiomyopathy. Toxicol Appl Pharmacol. 2002 Dec 15;185(3):218-27.

8.8. Wouters KA, Kremer LC, Miller TL, et al. Protecting against anthracycline-induced myocardial 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. damage: a review of the most promising strategies. Br J Haematol. 2005 Dec;131(5):561-78. Review.Review.