I. Chemotherapy-Induced Cardiomyopathy: What every physician needs to know.

As cancer treatment has advanced, there has been a great improvement in long-term survival of patients. However, this has been associated with an increased recognition of adverse cardiovascular effects associated with aggressive anticancer treatment.

One of the most common adverse effects is cardiotoxicity, which has an important impact on the patient’s survival and quality of life independent of the oncologic prognosis. “Cardiotoxicity” related to chemotherapy is not limited to left ventricular dysfunction, and it can include a much broader spectrum of cardiovascular side effects such as arrhythmias, Q–T prolongation, hypertension, thrombosis, or even pericardial disease.

Left ventricular dysfunction and heart failure (HF) are known consequences associated with exposure to several chemotherapy agents. The classic description of cardiomyopathy related to chemotherapy results from anthracyclines.

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With this particular class of drugs, the onset of cardiomyopathy can occur acutely (during or shortly after treatment), subacutely (days or weeks after treatment), or chronically (months to years after treatment). On the other hand, newer agents such as trastuzumab appear to have a different pattern of cardiac dysfunction that are not necessarily dose-related and thought to be due to alterations in myocardial signaling without apoptosis, which in many cases is reversible.

A newer class of chemotherapy drugs that target and inhibit vascular endothelial growth factor (VEGF) very commonly can result in severe hypertension. Typically this precedes the development of cardiomyopathy and diastolic heart failure may be an early clinical manifestation. In this chapter, we will focus on chemotherapy induced cardiomyopathy related to anthracyclines, trastuzumab, and anti-VEGF agents.

II. Diagnostic Confirmation: Are you sure your patient has Chemotherapy Induced Cardiomyopathy?

In 2002 the Cardiac Review and Evaluation Committee in the trastuzumab clinical trials established a definition of chemotherapy-induced cardiomyopathy (CIM). The following criteria established a diagnosis of CIM:

Multi Gated Acquisition Scan

1. Decrease in left ventricular ejection fraction (LVEF) globally or more severe in the septum

2. Symptoms of congestive heart failure (CHF) (i.e., paroxysmal nocturnal dyspnea [PND], orthopnea, dyspnea, lower extremity swelling)

3. Signs of CHF (i.e., S3, tachycardia)

4. Five percent decline in LVEF to less than 55% AND signs/symptoms of CHF OR 10% decline in LVEF to less than 55% without signs/symptoms of CHF

However, a more updated definition that is being used by more recent clinical trials and accepted by the general consensus includes a decrease in LVEF by more than 15% (absolute change) irrespective of whether it fell below or above the institutional lower limits of normal OR less than or equal to 15% decrease to below the lower limits of normal. This definition allows for detecting patients who remain asymptomatic and with a “normal EF” who have similar overall cardiac outcome to those who exhibit a low LVEF.

Table I demonstrates the common thresholds and definitions for change in EF that is used by major clinical trials.

Table I.
Classification Systems Grade 1 Grade 2 Grade 3 Grade 4
NYHA No limitation of activities Mild limitation of activity Marked limitation of activity Confined to bed or chair
ACC/AHA Stage A: at high risk but without structural heart disease Stage B: structural heart disease but without signs or symptoms Stage C: structural heart disease with prior or current symptoms Stage D: refractory CHF requiring intubation
Common terminology criteria for adverse events version 4.0 Resting ejection fraction (EF) 50%-40%; 10%-19% drop from baseline Resting ejection fraction (EF) 50%-40%; 10%-19% drop from baseline Resting ejection fraction (EF) 39%-20%; >20% drop from baseline Resting ejection fraction (EF) <20%
N9831 Intergroup Decrease in LVEF by more than 15% OR less than or equal to 15% to a level below the facility’s lower limits of normal
Breast Cancer International Research Group Relative LVEF reduction of more than 10% from baseline or at the last follow-up evaluation

NYHA: New York Heart Association

ACC/AHA: American College of Cardiology/American Heart Association

A. History Part I: Pattern Recognition;

The clinical manifestation of CIM can range from asymptomatic with abnormalities seen on imaging or cardiac biomarkers to immediate life-threatening symptoms or even sudden cardiac death.

Common clinical findings detected in asymptomatic subclinical phase can be as subtle and include:

1. Mild blood pressure changes

2. Arrhythmias

3. Transient or temporary LV function decline

4. Subtle ECG changes

5. Abnormal cardiac biomarkers (elevated BNP or Troponin I)

Patients in the symptomatic phase can present with much more life-threatening symptoms such as:

1. Thrombosis

2. Myocarditis

3. Pericarditis

4. Myocardial infarction

5. Cardiomyopathy and congestive heart failure

The pattern of disease presentation can be quite different relative to specific chemotherapeutic agents. For example, cardiomyopathy related to use of trastuzumab can develop over the course of the treatment typically after the initial 3 months of exposure. This is thought to be due to mostly reversible myocardial dysfunction, which may respond to conventional heart failure therapy.

In contrast, cardiomyopathy related to use of anthracyclines can be subclinical for many years and typically it is unmasked by some other insult such as severe illness. Additionally, anthracyclines are known to cause myocardial cell death, which may result in a more permanent effect if not recognized early.

On the other hand, patients who receive anti-VEGF agents may present with predominately systolic blood pressure elevation and potentially rapid onset after initiation of chemotherapy. Hypertension (HTN) can be the first clinical sign of toxicity from anti-VEGF therapy and long-standing blood pressure elevation can eventually lead to diastolic heart failure, although there have been some reports of systolic dysfunction and resultant heart failure as well.

B. History Part 2: Prevalence:

The incidence of chemotherapy-induced cardiomyopathy varies with each chemotherapy agent and the exact incidence is not known. The wide range in reported incidences can be partly due to variation in definition of cardiotoxicity among different trials.

It has been suggested that anthracycline-induced cardiomyopathy accounts for 1% of all cases of cardiomyopathy. This may be an underestimation as there is only limited data available on long-term follow up (10 to 20 years) of these patients during which there have been reports of development of cardiomyopathy.

For example, 65% of patients who receive anthracycline for childhood leukemia show evidence of LV dysfunction up to 15 years after completion of chemotherapy. Several factors such as cumulative dose, rate of drug administration, concomitant mediastinal radiation, age, female gender, and preexisting heart disease have been reported to be associated with higher incidence of CIM due to anthracyclines.

The incidence of cardiomyopathy associated with trastuzumab is reported to be 7% to 33%, and a significant portion of these patients can have asymptomatic LV dysfunction. Age, prior exposure to anthracycline, borderline EF before treatment, and presence of cardiovascular risk factors seem to be the most important risk factors for trastuzumab-induced cardiomyopathy.

For anti-VEGF drugs, the incidence of hypertension varies according to characteristics of patients (age, history of HTN, comorbidities), location of the primary tumor (higher incidence with renal cancer and breast cancer), as well as dose and type of drug.

In major clinical trials, the incidence of severe HTN ranged from 3% to 40% with higher incidences associated with the highly potent VEGF receptor inhibitors. Incidence of heart failure associated with bevacizumab has been relatively low and in the range of 0.8% to 2.2%, but up to 11% in patients being treated with sunitinib.

C. History Part 3: Competing diagnoses that can mimic Chemotherapy-Induced Cardiomyopathy.

Several disease processes can mimic heart failure; however, the constellation of history, physical exam, cardiac biomarkers, and other clinical data can usually help differentiate.

The differential diagnosis of acute heart failure can be as follows:

  • Acute coronary syndrome

  • Pulmonary embolism

  • Pneumonia

  • Asthma

  • Atrial fibrillation

  • Chronic obstructive pulmonary disease

  • Supraventricular tachycardias

  • Interstitial pulmonary fibrosis

  • Renal insufficiency

  • Anemia

  • Sleep apnea

D. Physical Examination Findings.

The most specific physical exam findings in acute heart failure are the presence of an S3 gallop, hepatojugular reflux, and jugular venous distention with positive likelihood ratios of 11, 6.4, and 5.1, respectively.

Other physical exam findings that can be present are: pulmonary rales, lower extremity edema, heart murmur, ascites, and chest wheezing but with much lower specificity.

Monitoring for early signs of hypertension can also be helpful in detecting cardiotoxicity related to anti-VEGF chemotherapy.

E. What diagnostic tests should be performed?

The diagnosis of heart failure is a clinical diagnosis. As mentioned above, physical exam findings that are highly sensitive include S3 gallop, jugular venous distention, and hepatojugular reflux; these can help identify a patient in acute decompensated heart failure.

Other diagnostic tests such as basic metabolic panel, complete blood count, chest x-ray, electrocardiogram (ECG), urinalysis for detection of protein, V/Q scans, and pulmonary function test can also help rule out other common competing diagnosis. Once other common diagnosis are excluded, patients should have a complete evaluation for comorbidity and common risk factors for cardiovascular disease, such as hyperlipidemia and thyroid disorders.

Echocardiography remains the best overall tool for assessing LV function. However, other modalities such as multigated acquisition (MUGA) scan and cardiac magnetic resonance imaging (MRI) can also been used depending on other factors such as body habitus and image quality.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

There has been a trend in more recent years to use cardio-specific biomarkers as a valid tool for early identification, assessment, and monitoring of cardiotoxicity associated with chemotherapy. Biomarkers such as B-type natriuretic peptide (BNP) and troponin (I and T) are increasingly being used to risk stratify patients.

Elevated troponin levels during chemotherapy seem to correlate with increased risk of developing cardiotoxicity. Troponin I elevation soon after high-dose chemotherapy is also a poor prognostic indicator for development of LV dysfunction and poor cardiac outcome.

Persistent elevation of BNP in the first 72 hours after administration of high-dose chemotherapy has also correlated with a significant decrease in systolic and diastolic LV parameters during the follow-up period, whereas this was not seen in patients who only had a transient increase or no increase in BNP levels. However, one must keep in mind that these markers can be elevated in other conditions and results of these tests should be interpreted in the entire clinical scenario.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Diagnosis of chemotherapy-induced cardiomyopathy can be challenging. Patients can remain asymptomatic with an LVEF in the normal range while cardiac dysfunction is developing at the cellular level with myocardial cell death. Transthoracic echocardiography remains the best tool in assessing the LV function and regular assessment is recommended by oncology guidelines.

Generally, for patients undergoing chemotherapy with anthracycline-based therapy, LVEF assessments should be repeated after a cumulative dose of 250 to 300 mg/m2 and thereafter at 450 mg/m2 if the patient has no other risk factors. Since cardiomyopathy from trastuzumab can occur at any point during therapy, it is recommended that patients have an LVEF assessment every 3 months.

The down side to this approach is that by the time reduced LVEF is detected there typically has been advanced myocyte damage to overcome the recruitable contractive reserve. Conversely, evidence of normal LV function does not exclude subclinical myocardial dysfunction.

Additionally, a reduction in LVEF is an imperfect marker of LV function that can be influenced by volume status, blood pressure, heart rhythm, and variation in reporting standards. In light of these findings, cardiac biomarkers are considered complimentary information to improve decision making.

III. Management.

The best strategy for management is early detection and prompt initiation of prophylactic medication. There has been evidence that the only predictors of LVEF recovery are baseline New York Heart Association functional class and time to initiation of heart failure medications.

Conventional heart failure medications, if initiated within 2 months of completion of anthracycline-based chemotherapy, has shown to significantly restore LV function. Other measures to consider are limiting cumulative chemotherapy doses, using less toxic analogues, and adding cardioprotectant agents, such as ACE-inhibitors and beta-lockers.

There is also an inclination to discontinue chemotherapy as soon as LV dysfunction is detected. However, this decision is not always in the best interest of the patient.

In a study done by the Breast Cancer International Research Group, it was demonstrated that the addition of trastuzumab and anthracycline to a chemotherapy regimen resulted in lower incidence of the recurrence of breast cancer and mortality but an increased risk of severe heart failure. Although, there was no description of the treatment of HF in these patients, this strongly suggests that if aggressive HF therapy had been promptly initiated, these HF outcomes would be improved.

With an individualized approach to patient care, one may be able to continue treatment with chemotherapy while initiating conventional heart failure therapy and assessing for change in functional status or worsening LV function.

The best treatment for chemotherapy-induced cardiomyopathy is prevention. There is some data that suggests that carvedilol (a beta-blocker [BB]) may prevent the development of cardiac dysfunction during anthracycline based therapy at a dose up to 12.5 mg b.i.d. Additionally, enalapril (an angiotensin-converting enzyme inhibitor [ACE-I]) at a dose up to 10 mg b.i.d. has also been helpful in preventing serious cardiac events during high-dose chemotherapy.

It is unlikely that all patients who are going to be treated with anthracycline-based or high-dose chemotherapy would benefit from treatment with BB or ACE-I, but certainly those at high risk for cardiac toxicity (such as those with previous cardiac issues, including HTN or prior chemotherapy) would benefit.

A. Immediate management.

The immediate management of the treatment of HF includes reducing pulmonary edema, improving oxygenation, and relieving cardiac ischemia if present.

B. Physical Examination Tips to Guide Management.

The physical findings to monitor in a patient with CIM include heart rate, blood pressure, and evidence of worsening volume overload.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Cardiac biomarkers (BNP and Troponin I) are cost-effective laboratory values to follow in a patient with CIM. Serial assessments of LVEF are periodically necessary but are not cost- effective.

D. Long-term management.

Although the long-term survival of these patients has improved, there is no consensus on the long-term monitoring of these patients. It is generally recommended that these patients have periodic monitoring; however, there is no data on how frequently or what tests or findings are necessary. There should be aggressive cardiovascular risk factor modification as cancer patients may be less active due to comorbid conditions and overall poor health.

E. Common Pitfalls and Side-Effects of Management

Commonly during chemotherapy, the patient may experience many episodes of BP fluctuation. Ongoing adjustments to the dose of ACE-I or BB may need to be made. However, long-term discontinuation is associated with worsening HF and even sudden death. Attempts to maintain at least some tolerable doses are important.

IV. Management with Co-Morbidities

It is imperative for the oncologist and cardiologist treating a patient with cancer to have open communication and cooperation to improve the quality of life of these patients. Cardiologists need to use their expertise to identify and manage cardiac injury to maximize the potential for successful chemotherapy.

V. Patient Safety and Quality Measures

A. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

1. Daily weights and BP measurement

2. Increase regular exercise

3. Avoid sodium consumption

B. What's the Evidence for specific management and treatment recommendations?

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Perez, EA, Suman, VJ. “Effect of doxorubicin plus cyclophosphamide on left ventricular ejection fraction in patients with breast cancer in the North Central Cancer Treatment Group N9831 Intergroup Adjuvant Trial”. J Clin Oncol. vol. 422. 2004. pp. 3700-4.

Gottdiener, JS, McClelland, RL. “Outcome of congestive heart failure in elderly persons: influence of left ventricular systolic function”. The cardiovascular health study. Ann Intern Med. vol. 137. 2002. pp. 631-9.

Owan, TE, Hodge, DO. “"Trends in prevalence and outcome of heart failure with preserved ejection fraction”. N Engl J Med. vol. 355. 2006. pp. 251-9.

Yeh, ET, Tong, AT. “Cardiovascular complications of cancer therapy: diagnosis, pathogenesis, and management”. Circulation. vol. 109. 2004. pp. 3122-31.

Khakoo, AY, Kassiotis, CM. “Heart failure associated with sunitinib malate: a multitargeted receptor tyrosine kinase inhibitor”. Cancer. vol. 112. 2008. pp. 2500-8.

des Guetz, G, Uzzan, B. “Cardiovascular toxicity of anti-angiogenic drugs”. Targeted Oncol. vol. 6. 2011. pp. 197-202.

Felker, GM, Thompson, RE. “Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy”. N Engl J Med. vol. 342. 2000. pp. 1077-84.

Lipshultz, SE, Colan, SD. “Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood”. N Engl J Med. vol. 324. 1991. pp. 808-15.

Guglin, M, Hartlage, G. “Trastuzumab-induced cardiomyopathy: not as benign as it looks? A retrospective study”. J Cardiac Fail. vol. 15. 2009. pp. 651-57.

Curigliano, G, Mayer, EL. “Cardiac toxicity from systemic cancer therapy: a comprehensive review”. Prog Cardiovasc Dis. vol. 53. 2010. pp. 94-104.

Chu, TF, Rupnick, MA. “Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib”. Lancet. vol. 370. 2007. pp. 2011-19.

Wang, CS, FitzGerald, JM. “Does this dyspneic patient in the emergency department have congestive heart failure”. JAMA. vol. 294. 2005. pp. 1944-56.

Cardinale, D, Sandri, MT. “Role of biomarkers in chemotherapy-induced cardiotoxicity”. Prog Cardiovasc Dis. vol. 53. 2010. pp. 121-9.

Ewer, MS, Lenihan, DJ. “Left ventricular ejection fraction and cardiotoxicity: is our ear really to the ground”. J Clin Oncol. vol. 26. 2008. pp. 1201-3.

Cardinale, DA, Colombo. “Anthracycline-induced cardiomyopathy: clinical relevance and response to pharmacologic therapy”. J Am Coll Cardiol. vol. 55. 2010. pp. 213-20.

Slamon, D, Eiermann, W. “Adjuvant trastuzumab in HER2-positive breast cancer”. N Engl J Med. vol. 365. 2011. pp. 1273-83.

Kalay, N, Basar, E. “Protective effects of carvedilol against anthracycline-induced cardiomyopathy”. J Am Coll Cardiol. vol. 48. 2006. pp. 2258-62.

Cardinale, D, Colombo, A. “Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition”. Circulation. vol. 114. 2006. pp. 2474-81.

C. DRG Codes and Expected Length of Stay.

V67.5 – High Risk Rx NEC Exam

794.39 – Abn Cv Funct Study Nec

794.31 – Abnormal Electrocardiogram

402.01 – Hypertensive heart disease, malignant, with heart failure

402.11 – Hypertensive heart disease, benign, with heart failure

428.0 – Congestive heart failure, unspecified

428.1 – Left heart failure

428.20 – Unspecified systolic heart failure

428.30 – Unspecified diastolic heart failure

428.40 – Unspecified combined systolic and diastolic heart failure