Anthracycline Cardiomyopathy

Anthracycline cardiomyopathy is dose dependent myocardial injury from doxorubicin, daunorubicin, epirubicin, idarubicin and mitoxantrone, leading to left ventricular dysfunction and heart failure. It is a form of cancer therapy related cardiac dysfunction.

Severity is graded:

• Mild: ejection fraction 50% or more with a fall in global longitudinal strain of over 15% from baseline, or a new rise in troponin or natriuretic peptide.
• Moderate: ejection fraction fall of 10 points or more to 40% to 49%, or a fall under 10 points to 40% to 49% with strain or biomarker change.
• Severe: ejection fraction under 40%, or symptomatic heart failure.

Toxicity is acute (during infusion, rare arrhythmia or pericarditis myocarditis), early (within the first year, in most patients) or late (years to decades after treatment, notably in childhood cancer survivors).

Heart failure incidence with doxorubicin rises with cumulative dose: about 3 to 5% at 400 mg/m2, 7 to 26% at 550 mg/m2 and 18% to 48% at 700 mg/m2. Usual cumulative limits are 450 to 550 mg/m2 of doxorubicin, and 400 mg/m2 with risk factors. Other anthracyclines are converted to doxorubicin equivalents.

Risk factors are age under 18 or over 65 years, female sex, previous chest radiotherapy, co-administration of trastuzumab, cyclophosphamide or taxanes, hypertension, diabetes, kidney disease, obesity, smoking, pre-existing cardiac disease and genetic variants.

Pathophysiology. Doxorubicin binds topoisomerase II beta in cardiomyocytes, causing DNA breaks, mitochondrial dysfunction, iron mediated oxidative stress and apoptosis. Myocyte loss is permanent. Remaining myocytes compensate until reserve is exhausted, so dysfunction can appear years later.

Recovery is most likely when treatment starts early.

• Many patients are asymptomatic and the abnormality is found on surveillance imaging.
• Exertional dyspnoea, fatigue, orthopnoea, oedema, palpitations, syncope.
• Arrhythmia: atrial fibrillation, supraventricular tachycardia, ventricular ectopy. Acute pericarditis myocarditis during infusion.
• Signs of heart failure in advanced disease. Hepatic congestion and cachexia can mask them.
• Childhood cancer survivors present decades later with heart failure, often with growth failure of the ventricle and restrictive features.

Red flags.

• Ejection fraction fall of 10 points or more, or to under 50%
• Symptoms of heart failure during or after chemotherapy
• New arrhythmia, syncope or raised troponin
• Cumulative doxorubicin dose over 250 mg/m2 with a risk factor, or over 400 mg/m2
• Combination with trastuzumab or previous chest radiotherapy
• Childhood cancer survivor with new dyspnoea or palpitations

• Baseline risk assessment before treatment: blood pressure, ECG, echocardiography with global longitudinal strain, troponin and natriuretic peptide, lipids, glucose, creatinine and cardiovascular risk factors.
• Surveillance in adults: echocardiography with strain and troponin during treatment (after a cumulative dose of 200 mg/m2 and before each further cycle in high risk patients), at completion, and at 3 to 6 months and 12 months, then every 2 to 5 years in survivors.
• In children, echocardiography before treatment, every 2 to 5 years afterwards with the interval set by the cumulative dose, and lifelong.
• Echocardiography. Ejection fraction by three dimensional or biplane method, strain (a relative fall over 15% from baseline is abnormal), diastolic function, effusion.
• Cardiac MRI when echocardiography is inadequate or discordant. Endomyocardial biopsy only for diagnostic doubt.
• Troponin and natriuretic peptide. A rise in troponin over the 99th percentile during treatment predicts later dysfunction.
• Exclude other causes: coronary disease, trastuzumab and checkpoint inhibitor toxicity, radiation, thyroid disease, anaemia, sepsis, tumour involvement and pulmonary embolism.

Differential diagnosis.

• Trastuzumab, checkpoint inhibitor and other drug related cardiotoxicity
• Radiation induced heart disease
• Pericardial effusion or tamponade from tumour
• Ischaemia, including fluoropyrimidine coronary vasospasm
• Tachycardia induced cardiomyopathy
• Sepsis, anaemia and thyroid dysfunction
• Pulmonary embolism
• Myocarditis and takotsubo syndrome
• Pre-existing cardiomyopathy

Prevention.

• Limit cumulative dose, use continuous infusion over 48 to 96 hours in place of bolus when feasible, and consider liposomal doxorubicin or epirubicin in high risk patients.
• Dexrazoxane at a dose ratio of 10:1 to doxorubicin (for example 500 mg/m2 with 50 mg/m2), given by intravenous infusion over 15 minutes, with doxorubicin started within 30 minutes of finishing.
• Indicated in children and in adults with high baseline risk, or when cumulative doxorubicin reaches 300 mg/m2 and treatment continues.
• Reduce the dexrazoxane dose by 50% (ratio 5:1) at creatinine clearance under 40 mL/min. Monitor full blood count, because it adds to myelosuppression.
• Treat hypertension, diabetes and dyslipidaemia.
• For patients at high risk, an ACE inhibitor and beta blocker (enalapril 2.5 mg orally twice daily, increased to 10 mg twice daily, maximum 40 mg daily; carvedilol 3.125 mg twice daily, doubled every 2 weeks to 25 mg twice daily) reduce ejection fraction decline.
• A statin (atorvastatin 40 mg orally once daily, with liver enzymes at baseline and 3 months) is considered in high risk patients.

Established dysfunction.

• Hold anthracycline for ejection fraction under 40%, or a fall of 10 points or more to under 50%. Agree continuation with the oncologist (cardio oncology review). Continue with cardiac protection when ejection fraction is 40% to 49%, and the oncological benefit is high.
• Start heart failure therapy at once. Recovery is much more likely when treatment is started within 2 to 6 months of onset.
  • Sacubitril/valsartan 49/51 mg orally twice daily, doubled at 2 to 4 weeks to the target 97/103 mg twice daily (maximum 194/206 mg daily).
  • Start 24/26 mg twice daily if not on an ACE inhibitor or angiotensin receptor blocker, on low doses, with eGFR under 30 mL/min/1.73 m2, or with moderate liver impairment. Stop any ACE inhibitor 36 hours before.
  • Contraindicated with previous angio oedema, severe liver impairment and pregnancy. Check potassium and creatinine 1 to 2 weeks after each change.
  • Where this is unavailable, use enalapril 2.5 mg orally twice daily, increased to 10 mg twice daily, maximum 40 mg daily (contraindicated in pregnancy and bilateral renal artery stenosis).
  • Carvedilol 3.125 mg orally twice daily, doubled every 2 weeks to the target 25 mg twice daily (50 mg twice daily if over 85 kg), maximum 100 mg daily. Reduce in liver impairment. Contraindicated in decompensated heart failure, asthma, severe bradycardia and high grade AV block without a pacemaker.
  • Or bisoprolol 1.25 mg once daily, increased every 1 to 4 weeks to 10 mg once daily.
  • Spironolactone 25 mg orally once daily (12.5 mg at eGFR 30 to 49 mL/min/1.73 m2), up to 50 mg daily. Check potassium and creatinine at 1 week and 4 weeks, then every 3 months. Withhold at potassium over 5.5 mmol/L and avoid at eGFR under 30 mL/min/1.73 m2.
  • Dapagliflozin 10 mg orally once daily, long term. Start at eGFR 25 mL/min/1.73 m2 or more. Withhold during acute illness with poor oral intake. Contraindicated in type 1 diabetes.
  • Furosemide 40 mg orally once daily in the morning, increased to 80 to 120 mg daily as needed (higher doses in renal impairment under specialist care). Monitor sodium, potassium and creatinine.
• Continue therapy for at least 12 months after recovery, and long term in many, because withdrawal can lead to relapse.
• Atrial fibrillation and thrombosis: anticoagulation by stroke risk and cancer related risk, with apixaban 5 mg orally twice daily.
• Reduce to 2.5 mg twice daily when at least two of age 80 years or over, weight 60 kg or under and serum creatinine 133 micromol/L or over are present.
• Also 2.5 mg twice daily at creatinine clearance 15 to 29 mL/min, and avoided under 15 mL/min. Maximum 10 mg daily. Check platelets and interactions with chemotherapy.
• Devices and advanced therapy. Defibrillator for ejection fraction of 35% or less after 3 months of optimal therapy, with an expected survival over 1 year. Mechanical support and transplantation in cancer free patients (usually 2 to 5 years of remission).

Special groups.

• Children and survivors: lifelong surveillance, attention to blood pressure, lipids and glucose, and avoidance of heavy isometric exertion without assessment. Echocardiography before and during any pregnancy, because peripartum cardiomyopathy is more likely. Stop sacubitril/valsartan, ACE inhibitors and spironolactone before conception.
• Resource limited settings: where dexrazoxane or strain imaging is unavailable, enforce cumulative dose limits, measure ejection fraction at baseline and after 200 mg/m2 and at completion, and start enalapril and carvedilol early.

Monitoring. Troponin and echocardiography with strain at the baseline, after a cumulative dose of 200 mg/m2, at completion, and at 3 to 6 months and 12 months. After heart failure therapy starts, echocardiography at 3 and 6 months, then yearly. Potassium, creatinine and blood pressure after each titration.

Referral and escalation. Refer to a cardio oncology service. Urgent for ejection fraction under 40%, symptomatic heart failure, ventricular arrhythmia, or raised troponin during treatment.