INTRODUCTION — The anthracyclines and related compounds (doxorubicin, daunorubicin, idarubicin, epirubicin, and the anthraquinone mitoxantrone) are among the chemotherapeutic agents implicated in cardiotoxicity. Anthracycline therapy is associated with an increase in the risk for developing heart failure with significant associated morbidity and mortality [1]. While anthracyclines are associated with increased risk of cardiomyopathy, they are also important components of many chemotherapy regimens. 

Management of anthracycline-induced cardiotoxicity will be reviewed here. The mechanism, clinical manifestations, monitoring, and diagnosis of anthracycline-induced cardiotoxicity and cardiovascular complications of other classes of chemotherapy agents are discussed separately. (See "Clinical manifestations, monitoring, and diagnosis of anthracycline-induced cardiotoxicity" and "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines" and "Cardiotoxicity of trastuzumab and other HER2-targeted agents".)

PREVENTIVE MANAGEMENT

Approach to prevention — Optimum preventive management of cardiotoxicity requires a multidisciplinary approach with close collaboration between the treating oncologist, internist, and cardiologist. Limited data from small trials are available to guide prevention and management of cardiotoxicity.

The following approach represents consensus among the authors based upon the limited data and their clinical experience. All patients should receive a baseline clinical cardiovascular assessment, including physical examination and an echocardiogram prior to initiation of anthracyclines. Although guidelines have not included baseline electrocardiogram in their recommendations, some UpToDate contributors find it helpful to obtain a baseline electrocardiogram to compare with future studies, in the event of new-onset cardiac signs or symptoms.

The decision to use an anthracycline is based on the baseline cardiac function, overall health status, and the availability of equivalent non-anthracycline-based alternative regimens. The baseline assessment is also used to identify patients proceeding with anthracycline therapy who should receive neurohormonal inhibition. (See "Clinical manifestations, monitoring, and diagnosis of anthracycline-induced cardiotoxicity", section on 'Approach to baseline assessment and monitoring' and "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Acceptable alternatives to anthracycline-based treatment' and "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Non-anthracycline-based therapy' and "Initial treatment of advanced stage diffuse large B cell lymphoma", section on 'Patients with cardiac disease'.)

The following strategy outlines our risk stratification for patients in whom anthracyclines are being considered:

●Heart failure with reduced ejection fraction (HFrEF) or LVEF ≤40 percent – For patients with current or past HFrEF (LVEF ≤40 percent), HF with borderline reduced LVEF (LVEF >40 but <50), or baseline LVEF ≤40 percent, anthracycline chemotherapy should generally be avoided. However, decisions in this regard should be individualized, and factors including the availability of other therapeutic options as well as the projected benefit (percent increase in cure rate, or absolute improvement in median survival) should be considered. If the benefit is felt to outweigh the risks, informed and shared decision-making with the patient to proceed should be done with monitoring as outlined below.

Patients with HFrEF should receive standard evidence-based therapy for HF. In addition, we suggest angiotensin converting enzyme (ACE) inhibitor (or angiotensin II receptor blocker [ARB]) plus beta blocker therapy for patients with asymptomatic LV dysfunction with LVEF ≤40 percent. (See "Treatment and prognosis of heart failure with preserved ejection fraction" and "Management and prognosis of asymptomatic left ventricular systolic dysfunction" and "Overview of the management of heart failure with reduced ejection fraction in adults", section on 'Pharmacologic therapy' and "Overview of the management of heart failure with reduced ejection fraction in adults".)

●Asymptomatic and LVEF >40 and <50 percent – For patients who have an LVEF >40 and <50 percent and no current or past HF, a risk-benefit analysis of available treatment options (anthracyclines and any alternatives) should be performed. If a decision is made to proceed with anthracycline therapy in a patient with LVEF<50 percent at baseline, then we suggest the following measures:

•Optimizing cardiovascular status including good blood pressure control in hypertensive patients. (See 'General measures' below.)

•Initiation and titration of an ACE inhibitor (or ARB) plus beta blocker prior to starting anthracycline therapy. (See 'General measures' below and 'Neurohormonal inhibition' below.)

•Careful monitoring of the LVEF and discontinuation of anthracyclines if the LVEF decreases by more than 10 absolute percentage points from baseline [2]. (See "Clinical manifestations, monitoring, and diagnosis of anthracycline-induced cardiotoxicity", section on 'Approach to baseline assessment and monitoring' and 'Management of heart failure or subclinical cardiac dysfunction occurring after treatment initiation' below.)

●Asymptomatic and LVEF ≥50 percent – For patients with no history of HF with baseline LVEF ≥50 percent, we suggest optimizing the patient’s cardiovascular status, particularly control of hypertension. (See 'General measures' below.)

The 2015 American Society of Echocardiography and European Association of Cardiovascular Imaging guidelines classify a 2D echocardiographic LVEF of <52 percent in men and <54 percent in women as abnormal (ie, more than two standard deviations below the mean LVEF for adults without cardiovascular disease) [3]. In our practice, we do not routinely treat patients with LVEF ≥50 percent with neurohormonal blockade at this time; however, that may change as prognostic studies with these new guidelines are designed.

If a cardioprotective strategy is pursued for either primary or secondary prevention for patients receiving anthracyclines, we suggest the use of an ACE inhibitor (or ARB if patient has angioedema or cough with ACE inhibitor) and use of carvedilol or nebivolol for beta blockade. (See 'Neurohormonal inhibition' below.)

For patients receiving doxorubicin, we generally limit the lifetime dose to 450 to 550 mg/m² (table 1), although higher doses may be delivered on an individualized basis, particularly for those being treated with anthracyclines to induce a remission and who have not developed HF or a decline in EF. Although data in adults are limited, some experts initiate dexrazoxane when lifetime doses of anthracycline exceed 300 mg/m².

Discussion of the use of dexrazoxane in adults and in children is found below. (See 'Dexrazoxane' below and 'Modification of anthracycline chemotherapy' below.)

General measures — For all patients planning to receive anthracycline chemotherapy, we recommend optimal management of cardiovascular risk factors prior to anthracycline exposure. This includes optimizing management of hypertension, preexisting HF, and other cardiac conditions (eg, angina), and metabolic disorders as well as counseling regarding smoking cessation, weight loss, and physical activity when possible. Risk stratification using biomarkers or echocardiographic data may help identify patients who benefit from a cardioprotective approach, though the impact of such strategies on clinical outcomes has not been established, as discussed below. (See 'Cardioprotective strategies' below.)

Modification of anthracycline chemotherapy — Patients may consider non-anthracycline alternatives that may be close to being equally efficacious. For example, in breast cancer the adjuvant regimen docetaxel and cyclophosphamide effectively reduces the risk of recurrence. These regimens are discussed in detail elsewhere. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Choosing a regimen'.)

The risk of anthracycline-associated cardiotoxicity should be weighed against the potential benefits of anthracycline chemotherapy given the patients' prognosis and likely clinical benefit [4]. For example, the risk of HF with standard regimens for breast cancer, the most common use of anthracycline in solid tumors, is typically less than 0.5 percent [5]. Thus, in a patient with normal baseline cardiac function, the benefits of anthracycline likely outweigh the risk for patients especially in higher-risk breast cancers. However, some patients with HF, low baseline LVEF, or significant heart disease will not be appropriate for anthracyclines.

●The risk of cardiotoxicity has long been recognized to correlate with the cumulative anthracycline dose (table 1) [6-8]. For patients receiving doxorubicin, we generally limit the lifetime dose to 450 mg/m², although higher doses may be delivered on an individualized basis, particularly for those with limited other options who are being treated with anthracyclines to induce a remission and who have not developed HF or a significant decline in EF. For patients who may be treated with multiple anthracycline agents, the fraction of allowable lifetime anthracycline dose contributed by each agent is calculated and summed when determining whether further anthracyclines are contraindicated.

●There are few high-quality studies on whether anthracycline dose modification offers cardiac protection with equal efficacy. Therefore, for patients with preexisting cardiac dysfunction or significant cardiovascular risk factors, we often opt for a non-anthracycline-based regimen if a comparable one exists rather than dose reduction of an anthracycline-containing regimen. For example, in breast cancer, multiple non-anthracycline-based adjuvant regimens exist. (See "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Non-anthracycline-based therapy' and "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Acceptable alternatives to anthracycline-based treatment'.)

●A cardioprotective strategy that has been employed in hematologic malignancies and in certain sarcoma protocols is infusional rather than bolus dosing of anthracycline; for example, with 24-hour dosing of etoposide, doxorubicin, and vincristine through a central venous catheter in the EPOCH chemotherapy regimen. Infusional dosing has also demonstrated low rates of HF in breast cancer [9,10], although it is not typically used given that it requires an indwelling catheter and the fact that the cumulative doses of anthracycline exposure in breast cancer are typically lower (240 mg/m²).

Evidence for the cardioprotective effect of infusional dosing comes from a meta-analysis including seven studies with different infusion durations. Among a total of 803 participants, the risk of HF (risk ratio 0.27, 95% CI 0.09-0.81) and subclinical evidence of cardiotoxicity (risk ratio 0.36, 95% CI 0.15-0.90) was reduced with longer-duration infusion compared with more rapid infusion [11]. No significant difference in cancer response rate was observed on analysis of the two studies that included response rate data. Early studies demonstrated that prolonging infusion times over 48 to 96 hours resulted in less injury to the myocardium on endomyocardial biopsy, less clinical HF, and preserved antitumor responses [12]. In adult patients, slower infusion of anthracyclines lowers the peak plasma level (C_max), which correlates with the propensity to develop cardiotoxicity, but it does not affect the area under the curve, which correlates with antitumor activity [13].

●For patients who are likely to need high cumulative doses of anthracyclines, a liposomal formulation of anthracycline may limit cardiotoxicity. For example, liposomal doxorubicin is United States Food and Drug Administration (FDA) approved for metastatic breast cancer, advanced/refractory ovarian cancer, multiple myeloma, and AIDS-related Kaposi sarcoma. These agents preferentially enter and accumulate in malignant tissues as a result of the tumor’s leaky microvasculature and impaired lymphatics, whereas drug extravasation into cardiomyocytes in the heart is limited [14]. Several clinical trials have confirmed comparable or nearly comparable antitumor efficacy and reduced cardiotoxicity observed with liposomal formulations [15-18]. However, compared with traditional anthracyclines, the use of liposomal formulations has been associated with an increased risk of mucositis and hand-foot syndrome [19].

While it has long been thought that epirubicin confers a lower risk of cardiotoxicity compared with doxorubicin [20], this is likely only true on a mg-for-mg basis. Most regimens employ a higher dose of epirubicin than doxorubicin, and therefore there are no clinical differences in safety or efficacy between the two agents. A Cochrane review demonstrated no difference between epirubicin and doxorubicin with regard to the development of clinical HF [15].

Cardioprotective strategies — We suggest cardioprotective therapy to patients with preexisting mild LV dysfunction (LVEF 40 to 49 percent). We typically do not offer these therapies to patients with baseline LVEF ≥50 percent unless a high-dose of anthracyclines is being considered. For patients with cardiovascular risk factors such as hypertension or diabetes, we optimize the management of these conditions.

A network meta-analysis of 16 randomized controlled trials for primary prevention of anthracycline-associated cardiotoxicity in a total of 1918 patients evaluated dexrazoxane, angiotensin antagonists, beta blockers, combination angiotensin antagonist and beta blocker, statins, coenzyme Q-10, prenylamine, and N-acetylcysteine [21]. As discussed below, the risk of HF was significantly reduced only by dexrazoxane and by angiotensin antagonists. However, nearly 70 percent of the patients in the intervention groups were treated with dexrazoxane and limited numbers of patients were treated with the other interventions.

Neurohormonal inhibition — The evidence supporting use of agents such as beta blockers and ACE inhibitor or ARB in treatment of HFrEF as well as following myocardial infarction has prompted study of the potential efficacy of such agents in management of cardiotoxicity. However, clinical trials have been small and frequently relied upon the surrogate endpoints such as change in LVEF. While these interventions are not routinely indicated as preventive measures for patients who lack cardiac risk factors or disease, they may be appropriate for select patients, as discussed elsewhere. Further indications for patients who develop HF are discussed below. (See 'Approach to prevention' above and 'Management of heart failure or subclinical cardiac dysfunction occurring after treatment initiation' below.)

Beta blockers — Based on extensive literature supporting the use of beta blockers in treatment of HFrEF, a few small, randomized clinical trials have been performed to examine the role of beta blockers for primary prevention of anthracycline-induced LV dysfunction (table 2). Initial trials of carvedilol [22] and nebivolol [23] suggested a benefit, though subsequent larger trials of metoprolol did not [24,25]. In a randomized, double-blind, placebo-controlled trial of 192 women with HER2-negative breast cancer, carvedilol conferred no benefit with regard to LVEF decline and a possible benefit with regard to secondary end points, including troponin levels, LV dimensions, and diastolic function. Notably, the decline in LVEF was minimal in both treatment and placebo groups in this trial [26]. Another randomized trial of 468 patients with HER2-positive breast cancer treated with trastuzumab showed a benefit of both carvedilol and lisinopril on the decrease of LVEF only in patients previously treated with anthracyclines [27]. It is unclear whether the positive effects seen with carvedilol and nebivolol are an artifact of the small sample sizes of initial studies or whether they represent true differences in biologic action compared with metoprolol. In particular, carvedilol has been proposed to attenuate anthracycline-mediated cardiac injury by mitigating oxidative stress, preventing mitochondrial dysfunction, and maintaining calcium homeostasis [28]. Prior to routine incorporation of beta blockade into primary prevention strategies for anthracycline-mediated cardiotoxicity, larger randomized controlled trials are needed to determine if cardioprotection is a class effect of beta blockers and to examine efficacy and safety in the cancer patient population.

Angiotensin inhibitors — While large, randomized trials support the use of ACE inhibitor or ARB in treatment of HFrEF, only a few small studies are available on the use of either agent for primary prevention of anthracycline-mediated cardiotoxicity (table 2). The network meta-analysis of randomized controlled trials of primary prevention of anthracycline cardiotoxicity cited above included three studies with a total of 124 patients treated with anthracycline cardiotoxicity. Angiotensin antagonists significantly reduced the risk of HF (odds ratio [OR] 0.18, 95% CI 0.05-0.55) but not a composite of HF or LV dysfunction (OR 0.53, 95% CI 0.12-2.30) [21]. Results from the PRADA trial (PRevention of cArdiac Dysfunction during Adjuvant breast cancer therapy) in 130 patients treated with epirubicin with or without trastuzumab suggest that use of the ARB candesartan mitigates the decline in LVEF by under two percentage points, though the clinical significance of this observation remains unclear [25].

Combined beta blockade and angiotensin inhibition — Treatment of HF with combined beta blocker and ACE inhibitor therapy is more effective than the use of either therapy alone (see "Initial pharmacologic therapy of heart failure with reduced ejection fraction in adults", section on 'Beta blocker'), but the role of combined therapy to prevent HF due to cardiotoxicity is uncertain. Evidence for a combined approach of beta blockade and angiotensin inhibition in preventing anthracycline-induced cardiotoxicity comes largely from the OVERCOME trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies) (table 2) [29]. Although there was a significant difference in the incidence of death or HF in this trial (6.7 percent in the enalapril/carvedilol group and 22 percent in the control group), the average decline in LVEF during the treatment period was small, and the majority of patients in both groups retained an LVEF greater than 50 percent by the end of the trial. Larger randomized, controlled studies with more extensive follow-up will be necessary to determine the long-term impact of a combined approach for primary prevention in this setting.

Dexrazoxane — Dexrazoxane is the only drug that is FDA approved specifically to prevent anthracycline-mediated cardiotoxicity. Although much of the evidence supports the safety of dexrazoxane as a cardioprotectant, its effect on cancer-related outcomes remains controversial [30]. As a result, the FDA has restricted its use to patients with metastatic breast cancer who have received at least 300 mg/m² of doxorubicin with an ongoing indication to receive doxorubicin-based chemotherapy. The recommended dose ratio of dexrazoxane to doxorubicin is 10:1 (eg, 500 mg/m² of dexrazoxane to 50 mg/m² of doxorubicin). Solution is administered as an infusion up to 15 minutes in duration with a 30-minute fixed interval from the completion of dexrazoxane infusion to the initiation of doxorubicin.

Mechanistically, dexrazoxane is believed to chelate intracellular iron, block iron-assisted oxidative radical production, and inhibit the topoisomerase II-beta isoenzyme, which has been implicated in anthracycline cardiotoxicity [31-34]. Several trials have supported the use of dexrazoxane as a cardioprotectant (table 2) [35-38], although there are concerns that it might reduce the antitumor activity of anthracyclines. The network meta-analysis of randomized controlled trials of primary prevention of anthracycline cardiotoxicity cited above included eight studies with a total of 666 patients treated with dexrazoxane. Dexrazoxane therapy significantly reduced the risk of HF (OR 0.12, 95% CI 0.06-0.23) as well as a composite of HF or LV systolic dysfunction (OR 0.26, 95% CI 0.11-0.74) [21].

In one trial of patients with advanced breast cancer, a decreased objective response rate was observed in patients treated with dexrazoxane versus placebo (46.8 versus 60.5 percent) [38]. However, time to progression and survival were not significantly affected, and patients treated with placebo had a much higher rate of LVEF decline or HF compared with those treated with dexrazoxane (hazard ratio 2.63, 95% CI 1.61-4.27). Subsequent trials have not suggested any decrease in antitumor efficacy with the use of dexrazoxane, and similar oncologic response rates were reported in a large Cochrane meta-analysis [35]. Another study raised concern that dexrazoxane may increase the risk of secondary malignancies in survivors of Hodgkin lymphoma [39]. However, two subsequent reports of childhood survivors of acute lymphoblastic leukemia did not suggest any increase in the rate of secondary malignancies [40,41].

Investigational therapy — There is growing interest in the use of statins for primary prevention of anthracycline-mediated cardiotoxicity based on their antioxidant and anti-inflammatory properties, although a cardioprotective effect has not been established (table 2). An initial small, randomized trial of atorvastatin was favorable with regard to echocardiographic parameters [42], and a retrospective observational study of breast cancer patients that prescribed statins for other indications demonstrated a significantly decreased risk of HF hospitalization compared with propensity-matched control patients [43]. Statins may also exert antitumor effects [44], and several randomized clinical trials are ongoing to examine their efficacy as cardioprotectants in patients treated with anthracyclines.

ROLE OF CARDIOLOGY CONSULTATION — Cardiologist involvement in the care of patients at risk for anthracycline cardiotoxicity may vary among different practice settings. A cardiology consultation is suggested in the following clinical settings:

●Patients with increased risk for anthracycline-related cardiotoxicity warrant consultation to ensure that hemodynamic status has been optimized with appropriate medications or interventions. Risk factors in adults include older age (ie, age >65 years), preexisting cardiovascular disorders (eg, left ventricular ejection fraction [LVEF] percent or hypertension) or risk factors (smoking, hyperlipidemia, obesity, or diabetes), high cumulative anthracycline exposure (eg, >300 mg/m²), as well as radiation therapy involving the chest or use of trastuzumab. (See "Clinical manifestations, monitoring, and diagnosis of anthracycline-induced cardiotoxicity", section on 'Risk factors'.)

●If baseline or follow-up cardiac function is uncertain (eg, suboptimal or discordant cardiac imaging results).

●If the primary physician is seeking advice on initiation or titration of angiotensin inhibitor or beta blocker therapy for primary or secondary prevention.

●If a decision is made to proceed with therapy in a patient with baseline LVEF ≤50 percent.

●If a patient receiving anthracycline therapy develops HF or LVEF ≤40 percent or fall in LVEF ≥15 absolute percentage points to LVEF <50 percent.

MANAGEMENT OF HEART FAILURE OR SUBCLINICAL CARDIAC DYSFUNCTION OCCURRING AFTER TREATMENT INITIATION

Approach to new LV systolic dysfunction or heart failure — Given the limited evidence available, we suggest the following consensus-based approach to patients who develop a new significant decline in left ventricular (LV) systolic dysfunction (measured as LV ejection fraction [LVEF]) and/or heart failure (HF) symptoms. The thresholds indicated are similar to those used by the by the Cardiac Review and Evaluation Committee for the use of trastuzumab, another cardiotoxic agent [45]. However, lesser degrees of fall in LVEF and markers of cardiotoxicity beyond LVEF should raise concern for cardiotoxicity. (See "Clinical manifestations, monitoring, and diagnosis of anthracycline-induced cardiotoxicity", section on 'Endomyocardial biopsy'.)

Our approach is as described for those with:

●For symptomatic HF with a decline in LVEF (see "Heart failure: Clinical manifestations and diagnosis in adults"):

•We suggest holding anthracycline therapy and assessing the risk-benefit of alternate treatment options.

•HF with reduced ejection fraction should be treated according to standard evidence-based guidelines, with the exception that we favor instituting such therapy for patients with LVEF <50 percent (in contrast to the traditional threshold of ≤40 percent). (See "Overview of the management of heart failure with reduced ejection fraction in adults" and "Overview of the management of heart failure with reduced ejection fraction in adults", section on 'Pharmacologic therapy'.)

●For symptomatic HF without a decline in LVEF, treatment of HF with preserved ejection fraction (HFpEF) includes management of any concurrent conditions (such as hypertension) and fluid management with diuretic therapy as needed. A causal link between anthracycline therapy and HFpEF has not been established and may be related to volume status, so development of HFpEF is not necessarily an indication for stopping anthracycline therapy, and an individualized approach is appropriate. Some experts alter chemotherapy in selected patients with new HFpEF depending upon clinical factors such as the severity of HF, response to anthracycline therapy, and availability of alternatives to anthracycline chemotherapy. (See "Treatment and prognosis of heart failure with preserved ejection fraction".)

●For asymptomatic decline to an LVEF <40 percent or at least 15 percentage points to LVEF <50 percent (see 'Management of subclinical dysfunction' below), we suggest holding anthracycline therapy for most patients and assessing the risk-benefit of alternate treatment options. A choice to continue therapy may be made for individual patients, particularly those who are being treated for curative intent or for whom other appropriate options are not available.

●If a patient develops an asymptomatic (no symptoms of HF) decline in LVEF to <50 percent but >40 percent (see 'Management of subclinical dysfunction' below):

•We favor a discussion regarding the risks and benefits of continuing anthracycline therapy. A decline in EF should raise the index of suspicion for cardiotoxicity, and more frequent echocardiography and/or cardiology consultation may be appropriate.

•We suggest treatment with an angiotensin converting enzyme (ACE) inhibitor (or angiotensin II receptor blocker [ARB]) plus beta blocker for secondary prevention. Of note, this recommendation differs from our general recommendation to treat asymptomatic LV systolic dysfunction at a threshold of ≤40 percent. A threshold <50 percent is considered reasonable in this setting since patients in this setting may experience further decline in LVEF, regardless of whether they continue on anthracyclines or not. (See 'Neurohormonal inhibition' above and "Management and prognosis of asymptomatic left ventricular systolic dysfunction", section on 'Management'.)

All patients with HF and/or a significant decline in LVEF should undergo evaluation to exclude causes other than anthracycline cardiotoxicity such as myocardial infarction, stress cardiomyopathy, myocarditis, or infiltrative disease, since specific therapies may be required for certain causes. (See "Determining the etiology and severity of heart failure or cardiomyopathy".)

Management of anthracycline-induced heart failure

Treatment — Patients with anthracycline-induced HF should be treated according to standard evidence-based guidelines for the management of HF including initiation and titration of ACE inhibitor (or ARB or angiotensin receptor neprilysin inhibitor [ARNI]), beta blocker, and mineralocorticoid receptor antagonist, as appropriate. The role of device therapies such as implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy (CRT) as well as therapies for refractory HF such as mechanical circulatory support and cardiac transplantation is assessed based upon the cancer prognosis and other comorbidities in consultation with the primary oncologist [46]. (See "Management of refractory heart failure with reduced ejection fraction" and "Overview of the management of heart failure with reduced ejection fraction in adults" and "Overview of the management of heart failure with reduced ejection fraction in adults", section on 'Pharmacologic therapy'.)

If pharmacologic management results in resolution of HF, reintroduction of anthracycline may be attempted, depending on the intent of treatment (curative versus palliative), the efficacy of non-anthracycline alternatives, and the risk posed by stopping anthracycline treatment. Multidisciplinary involvement from both oncology and cardiology is necessary for the management of such patients.

Follow-up — Patients with suspected anthracycline-induced cardiomyopathy should be followed closely by a cardiologist for management of HF including titration of neurohormonal blocking agents and management of volume status. The frequency of repeat imaging depends on the severity of the clinical presentation, the clinical course, and need to assess criteria for therapies such as an ICD and/or CRT, as appropriate in relation to the overall prognosis. (See "Overview of the management of heart failure with reduced ejection fraction in adults".)

Management of subclinical dysfunction

Treatment

Our approach — Although direct evidence from randomized controlled trials is lacking in cancer patients, we suggest neurohormonal inhibition with beta blockade and angiotensin inhibition for patients treated with anthracyclines who demonstrate evidence of subclinical LV systolic dysfunction (LVEF <50 percent), based on results from other causes of LV dysfunction. These treatments should be started as soon as an LVEF <50 percent is detected, ideally within six months after completion of anthracycline-based chemotherapy. Of note, the threshold LVEF that triggers therapy in this setting is higher than that generally suggested for patients with asymptomatic LV systolic dysfunction (LVEF ≤40 percent) (see "Management and prognosis of asymptomatic left ventricular systolic dysfunction"). The rationale for using a higher threshold in the setting of anthracycline cardiotoxicity is to prevent further deterioration in LV function since progressive depression in LVEF has been observed even when anthracycline therapy does not continue [6]. (See 'Neurohormonal inhibition' above.)

Additionally, we suggest holding or discontinuing anthracycline therapy in asymptomatic patients when LVEF drops below 40 percent. If the EF rises on subsequent echocardiography, reintroduction of anthracycline may be attempted, depending on the intent of treatment (curative versus palliative), the efficacy of non-anthracycline alternatives, and the risk posed by stopping anthracycline treatment.

Observational data suggest that early detection and treatment of asymptomatic reduction in LVEF with carvedilol plus ACE inhibition may improve cardiac function among patients treated with anthracyclines [6,47]. A single-center study of 201 anthracycline-treated patients showed that for every doubling in time to detection and HF treatment, there was a fourfold decrease in the chance of complete recovery of LVEF. No response was observed in those treated more than six months after chemotherapy. Responders showed a lower rate of cumulative cardiac events than partial responder and nonresponder groups, suggesting that early detection/treatment of cardiac dysfunction may improve outcomes [47].

In a subsequent report from the same center, 2625 patients receiving anthracycline chemotherapy underwent echocardiography every three months during anthracycline therapy and for one year after completion of anthracycline therapy, and every six months for four additional years [6]. ACE inhibition (eg, enalapril) and beta blocker treatment was initiated immediately after an impaired LVEF (decrease by >10 absolute points and <50 percent) was detected in 226 patients. Eleven percent of the patients totally recovered a normal LVEF and 71 percent of the patients improved their LVEF by more than 5 percent. Over a median follow-up of five years, cardiac death was 0 percent in patients with totally recovered LVEF, 1 percent in patients with partial recovery, and 10 percent in patients without LVEF recovery (table 3).

Studies suggest that echocardiographic-derived myocardial deformation indices (strain) can predict later LV dysfunction [48]. At this time, some of the contributors to this topic (AA, TN, MS-C) monitor strain on a case-by-case basis in conjunction with LVEF; in the case of a discrepancy with LVEF (strain decrease of greater than 15 percent with unchanged LVEF), cardiac function is monitored more closely.

Approaches of others — Our approach for prevention and management of anthracycline cardiotoxicity is in broad agreement with major society guidelines, although some guidelines or statements also discuss a potential role for biomarker monitoring [49,50]. The 2012 European Society of Medical Oncologists clinical practice guidelines for cardiovascular toxicity noted that it is not yet established whether routine monitoring of cardiac biomarkers is useful while including a weak recommendation for monitoring biomarkers such as troponin I and brain natriuretic peptide as a potential means of identifying patients who may require further assessment [49]. The 2015 European Society of Cardiology position paper on cancer treatments and cardiovascular toxicity states that initiation of cardioprotection (ie, neurohormonal inhibition) may be considered in patients who are at a high baseline risk or who develop a troponin increase during treatment with high-dose anthracycline therapy [5]. This weak recommendation is based upon a randomized trial that found that administration of an angiotensin converting enzyme inhibitor (enalapril) prevented decline in LVEF [50].

Follow-up — Patients with evidence of subclinical LV dysfunction in the setting of anthracyclines should be followed closely by a cardiologist. Once cardioprotective therapy is initiated, it should be titrated to therapeutic doses as tolerated. The frequency of follow-up testing (generally echocardiography) depends upon the severity of cardiac dysfunction observed and whether the patient receives additional anthracycline-based or other cardiotoxic therapy.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Heart failure in adults" and "Society guideline links: Management of symptoms and toxicities of anticancer therapy".)

SUMMARY AND RECOMMENDATIONS

●Optimum preventive management of cardiotoxicity requires a multidisciplinary approach with close collaboration between the treating oncologist, internist, and cardiologist. (See 'Approach to prevention' above.)

●For all patients planning to receive anthracycline chemotherapy, we recommend optimization of cardiovascular risk factors prior to anthracycline exposure. This includes management of hypertension, preexisting heart failure (HF) and other cardiac conditions (eg, angina), and metabolic disorders as well as counseling regarding smoking cessation, weight loss, and physical activity when possible. (See 'General measures' above.)

●Prior to initiation of anthracycline therapy, all patients should receive a baseline clinical cardiovascular assessment. (See 'Approach to prevention' above and 'Neurohormonal inhibition' above.)

•For patients with current or past HF with reduced (≤40 percent) or borderline reduced (>40 but <50) ejection fraction (EF), or baseline LVEF ≤40 percent, anthracycline chemotherapy should generally be avoided.

●For patients who have an LVEF >40 and ≤50 percent and no current or past HF, a risk-benefit analysis of available treatment options (anthracyclines and any alternatives) should be performed. If a decision is made to proceed with anthracycline therapy, we suggest initiation and titration of an angiotensin converting enzyme (ACE) inhibitor (or angiotensin II receptor blocker [ARB]) plus beta blocker prior to starting anthracycline therapy and careful monitoring of LVEF.

•For patients with no history of HF with baseline LVEF >50 percent with no risk factors, we do not routinely offer preventive treatment.

●For patients receiving doxorubicin, the total lifetime dose should generally be limited to 450 mg/m² (table 1). However, individual patients may be treated with larger doses, particularly if they are being treated to induce remission and have not developed symptoms of HF or a significant decline in EF.

●Infusional rather than bolus regimens of anthracyclines have been found to reduce cardiotoxicity and are used routinely in certain hematologic malignancies and for some sarcoma protocols. (See 'Modification of anthracycline chemotherapy' above.)

●For patients who are likely to need high cumulative doses of anthracyclines, a liposomal formulation of anthracycline may limit cardiotoxicity. However, compared with traditional anthracyclines, the use of liposomal formulations has been associated with an increased risk of mucositis and hand-foot syndrome. Dexrazoxane is approved for use in metastatic breast cancer to lower the risk of cardiomyopathy in patients who have received more than 300 mg of doxorubicin and are felt to derive significant benefit from continuing therapy. (See 'Modification of anthracycline chemotherapy' above.)

●Given few high-quality studies to inform whether dose modification offers cardiac protection with equal efficacy, we generally avoid dose reduction of anthracyclines, instead opting for non-anthracycline-based alternatives for patients with reduced baseline EF (<40 percent), significant cardiac risk factors, or for those who require modification of their treatment due to significant decline in LVEF after having started anthracycline based treatment. (See 'Modification of anthracycline chemotherapy' above.)

●Our approach for patients with a significant decline in LVEF and/or HF after initiation of anthracycline therapy is as follows (see 'Approach to new LV systolic dysfunction or heart failure' above and 'Neurohormonal inhibition' above):

•For patients who develop HF with LVEF <50 percent, or a decline in LVEF to under 40 percent, or a significant decline in EF (15 absolute percentage points) to <50 percent, we hold anthracyclines, treat with an ACE inhibitor (or ARB) plus beta blocker, and treat according to standard evidence-based guidelines for HF with reduced EF. For such patients, we typically utilize a non-anthracycline-based regimen for future treatment cycles. (See 'Approach to new LV systolic dysfunction or heart failure' above and 'Neurohormonal inhibition' above and 'Management of anthracycline-induced heart failure' above.)

•A causal link between anthracycline therapy and HF with preserved LVEF (>50 percent) has not been established, so development of HF with preserved EF (HFpEF) is not necessarily an indication for stopping anthracycline therapy, and an individualized approach is appropriate. Some experts alter chemotherapy in selected patients with new HFpEF depending upon clinical factors such as the severity of HF, response to anthracycline therapy, and availability of alternatives to anthracycline chemotherapy.

•For asymptomatic patients with a decline in LVEF of at least 10 percentage points to <50 percent but >40 percent, we suggest treatment with an ACE inhibitor (or ARB) plus beta blocker for secondary prevention. We also undertake a risk-benefit discussion regarding continued anthracyclines. (See 'Management of subclinical dysfunction' above.)

●All patients with HF and/or a significant decline in LVEF should undergo evaluation to exclude causes other than anthracycline cardiotoxicity such as myocardial infarction/ischemic heart disease, stress cardiomyopathy, myocarditis, or infiltrative disease, since specific therapies may be required for certain causes. (See 'Management of anthracycline-induced heart failure' above and "Determining the etiology and severity of heart failure or cardiomyopathy".)