1. Chapter 4: Management of Chemotherapy-Associated Cardiomyopathy
Lauren Gilstrap
Mike Harrison
Gretchen Kimmick
Anju Nohria
Cardio-Oncology
Eds: Kimmick, Lenihan, Sawyer, Mayer, Hershman

2. Cancer Therapies Associated with Cardiomyopathy
Class of Chemotherapy
Examples
Anthracycline
Daunarubicin
Doxorubicin
Epirubicin
Mitoxantrone
Alkalating Agents
Cyclophosphamide
Cisplatin
Microtubule-targeting agents
Paclitaxel
Docetaxel 
Topoisomerase II inhibitors
Etoposide
Biologic response modifiers
Interferon
Interleukin-2 
Antimetabolites
Florouracil
Antibodies
Trastuzumab
Pertuzumab
T-DM1
Bevacizumab
Alemtuzumab 
Tyrosine kinase inhibitors
Sunitinib
Sorafenib
Imatinib
Lapatinib
Trametinib 
Proteosome Inhibitors
Carfilzomib
Cancer Therapies Associated with Cardiomyopathy 

3. Proposed mechanisms of anthracycline-mediated cardiotoxicity
Increased myocardial oxidative stress via redox-cycling of the quinone moiety of anthracyclines and through the formation of anthracycline-iron complexes.
Disruption of cellular and mitochondrial calcium homeostasis.
Disruption of mitochondrial energetics.
Degradation of ultrastructural proteins including titin and dystrophin.
Direct DNA damage via inhibition of topoisomerase 2β.
Inhibition of pro-survival pathways such as neuregulin 1 and ErbB.
Direct cytotoxic effects on cardiac progenitor cells diminishing repair potential after myocardial injury.
Hahn, Lenihan and Ky. JAHA 2014;3:e000665
Lyu et al. Ca Res 2007;67:
Yeh and Bickford. JACC 2009;53:

4. Anthracycline Cardiotoxicity: Clinical Presentation
Acute
Early-onset chronic progressive
Late-onset chronic progressive

5. Risk factors for early- and late-onset anthracycline cardiotoxicity
Cumulative anthracycline dose
Concurrent mediastinal radiation
Extremes of age
Female gender
Cardiac risk factors or pre-existing heart disease
Von Hoff . Am J Med. 1977;62:

6. Prevention of Anthracycline-induced Cardiomyopathy
Adjust dosing schedule
CIVI and smaller more frequent doses are less cardiotoxic
Consider liposomal preparations
Epirubicin and mitoxantrone are less cardiotoxic
Dexrazoxane
Iron-chelator: binds free iron and prevents the formation of anthracycline-iron complexes that contribute to oxygen free radical formation.
Consider starting when doxorubicin dose is ≥ 300mg/m2, or the equivalent with other anthracyclines
Possible association with increase risk of MDS and AML
Legha et al. Ann Int Med 1982;96:
Smith et al. BMC Cancer 2010;10:337
van Dalen et al. Cochrane Database 2010:CD005006
Swain et al. JCO 1997;15:
Tebbi et al. JCO 2007;25:

7. Prevention of Anthracycline-induced Cardiomyopathy
Also consider prophylaxis with:
ACE-inhibitor
Beta-blocker
Combination
Georgakopoulos et al. Am J Hematology. 2010;85:
Kalay et al. JACC 2006;48:
Kaya et al. Int J Cardiology ;167:
Bosch et al. JACC. 2013;61:
Gulati et al. 2015

8. Risk factors for trastuzumab cardiotoxicity
Age greater than 50 years
Previous or concurrent anthracycline use
Other cardiovascular risk factors:
Hypertension
Obesity
Prior diagnosis of heart disease
Diabetes
Ewer and Ewer . Drug Safety 2008;31:
Smith et al. Lancet 2007;369:29-36
Procter et al. JCO 2010;28:
Piccart-Gebhart et al. N Engl J Med 2005;353:
Romond et al. JCO 2012;30:
Serrano et al. Ann Oncol 2012;23:

9. Recommended Monitoring for Trastuzumab-related cardiomyopathy
Check LVEF prior to the initiation of trastuzumab therapy.
When trastuzumab therapy follows anthracycline treatment, LVEF should be assessed after the completion of anthracycline therapy and prior to the initiation of the trastuzumab.
If normal baseline LVEF, begin trastuzumab therapy.
If mildly reduced (LVEF 40-50%), consider risks and benefits before initiating trastuzumab
In the adjuvant setting, check baseline and every 3 months during therapy.
If LVEF declines more than 15% from baseline or 10% from baseline to below 50%, trastuzumab should be held for a month before the LVEF is reassessed.
If LVEF remains low or there is evidence of symptomatic heart failure, trastuzumab should be discontinued.
In the metastatic setting, check baseline, and thereafter as clinically indicated.
If LVEF declines, consider benefits and risks of continuing therapy.
Plana et al. J Am Soc Echocardiography. 2014;27:
Serrano et al. Ann Oncol 2012;23:
Fox. Br J Ca 2006; 95:1454
Romond et al. New Engl J Med 2005;353:

10. Prevention of Trastuzumab-induced Cardiomyopathy
Also consider prophylaxis with:
Beta-blocker
Pituskin et al. SABCS Abstract S1-05.

11. Management of Cancer Treatment Related Heart Failure
Treatment is based on the recommended guidelines for the management of heart failure with reduced ejection fraction (HFrEF) due to other etiologies.
Circulation 2005;112:1825–52
Arnold et al. Can J Cardilogy ;22:23-45
Yancy et al. JACC 2013;62:e

12. Guidelines for the management of heart failure with reduced ejection fraction (HFrEF)
At Risk for HF
Heart Failure
Stage A
Stage B
Stage C
Stage D
Symptoms
Hypertension
Atherosclerosis, Diabetes, Obesity
Metabolic syndrome OR
Prior cardiotoxin use (including chemotherapy)
Familial cardiomyopathy
Prior MI
LV hypertrophy
Decreased EF
Valve disease (asymptomatic)
Structural disease
AND
Dyspnea
Fatigue
Decreased exercise tolerance
HF symptoms at rest despite maximal medical therapy
Goals of Therapy
Risk Factor Management Including:
Treat hypertension
Smoking cessation
Lipid management
Regular exercise
Decrease/eliminate alcohol
Eliminate illicit drug use
Control metabolic syndrome
Dietary Salt Restriction
Address Goals of Care and Appropriate Level of Care
Standard Drug Therapy
ACEi/ARBs for patients with diabetes and/or known vascular disease
Beta-blockers for patients with prior MI, decreased EF or valve disease (when appropriate)
ACEi
Beta-blockers
Diuretics
Drug Therapy to Consider in Selected Patients
Aldosterone antagonist
ARB’s
Digitalis
Hydralazine/nitrates
Additional Therapies to Consider in Selected patients
Biventricular pacing
Defibrillator
Heart transplant
Chronic inotropes
Permanent mechanical support
Experimental drugs and/or surgeries
Compassionate care/Hospice Care
Adapted from Circulation 2005;112:1825–52

13. Drug Dosages for the Management of Heart Failure with Reduced Ejection Fraction    
Drug Class
Starting Dose
Target Dose
ACE Inhibitors (ACEi)
Captopril
6.25m to 12.5mg TID
25mg to 50mg TID
Lisinopril
2.5mg to 5mg QD
20mg to 40mg QD
Enalapril
1.25mg to 2.5mg BID
10mg to 20 mg BID
Ramipril
1.25mg to 2.5mg QD
10mg QD
Angiotensin Receptor Blockers (ARB)
Candesartan
4mg QD
32mg QD
Valsartan
40mg BID
160mg BID
Losartan
12.5mg QD
150mg QD
Beta Blockers
Carvedilol
3.125mg BID
25mg BID
Metoprolol Succinate
12.5 to 25mg QD
200mg QD
Bisoprolol
1.25mg QD
Aldosterone Antagonists
Spironolactone
50mg QD
Eplerenone
25mg QD
Vasodilators
Hydralazine
10mg TID
75mg TID
Isosorbide dinitrate
40mg TID
Isosorbide mononitrate
30mg QD
120mg QD

14. Summary of Recommendations (1)
Patients undergoing treatment with potentially cardiotoxic chemotherapies are at risk for developing heart failure (Stage A) and measures should be taken to minimize cardiotoxicity.
Limiting the cumulative anthracycline dose, using less cardiotoxic alternatives, and concomitant use of agents such as dexrazoxane should be considered to minimize cardiotoxicity.
Limited data suggests that prophylactic use of ACEi and/or beta-blockers may be cardioprotective in patients undergoing potentially cardiotoxic chemotherapy.
Serial monitoring of LVEF by echocardiography can help identify asymptomatic left ventricular dysfunction (Stage B).
Initiation of ACEi and beta-blockers ± interruption/discontinuation of cardiotoxic chemotherapy can help reverse/prevent further progression of heart failure in patients with Stage B disease.
The general principles of the management of heart failure with reduced ejection fraction apply to chemotherapy-induced cardiomyopathy.
All patients with symptomatic heart failure (Stage C) should receive guideline-based therapy with ACEi/ARB, beta-blockers, and aldosterone antagonists as tolerated.

15. Summary of Recommendations (2)
Diuretics should be used as needed for symptom relief.
Hydralazine plus nitrates and digoxin should be considered in certain patient populations.
Patients with end-stage heart failure (Stage D) can be considered for advanced therapies (home inotropes, mechanical circulatory support and cardiac transplantation).
Patients with end-stage heart failure (Stage D) who are cancer-free for ≥5 years can be considered for cardiac transplantation.
Careful consideration should be given to co-morbidities that might worsen surgical outcomes, especially in patients with prior thoracic irradiation.
Patients undergoing mechanical circulatory support should be carefully evaluated for right ventricular dysfunction to guide appropriate device selection.
In patients who are ineligible for transplant or mechanical circulatory support, home inotropes can be considered for palliation.
Patients with a history of cancer who require advanced cardiac therapy consideration should be referred to a tertiary center with experience dealing with this unique patient population.