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Iatrogenic heart failure 

Iatrogenic heart failure

Chapter:
Iatrogenic heart failure
Author(s):

Martin Denvir

DOI:
10.1093/med/9780199577729.003.0009
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Introduction

Heart failure (HF) can result from adverse or unwanted effects of treatment for unrelated conditions. Iatrogenic literally means an illness or condition generated by the physician (from the Greek iatros, a physician, and genic meaning ‘induced by’). In the acute setting, the physician can induce HF—in a patient without any clinically overt cardiac disease—by the inadvertent use of high volumes of fluid, or drugs known to depress cardiac function; or during cardiac surgery when the left ventricle experiences injury (either directly or indirectly) while on cardiopulmonary bypass. Chronic HF, on the other hand, is more common in patients treated for lymphoma, breast cancer, or more rarely lung cancer. In this clinical setting, the patient may present many months or years after the initial injury to the heart resulting from chemotherapeutic agents and/or radiotherapy. This chapter outlines the main causes of HF induced by the physician in the acute setting, and focuses on the epidemiology, presentation, and treatment of chronic HF syndromes resulting from treatment of childhood and adult cancers.

Iatrogenic heart failure in the acute setting

Occurrences of acute HF resulting from treatment or management are generally quite common scenarios in the hospital setting, and yet these are poorly described and documented in the published literature. A typical clinical example is the overzealous use of fluid in the perioperative period in elderly patients undergoing surgery for acute events such as traumatic hip fracture or abdominal sepsis. In these settings, it is common for the medical team caring for the patient to attempt to maintain tissue perfusion by infusing large quantities of crystalloid or colloid, particularly if the patent is shocked or hypotensive. Even in a patient with no previous clinical history of cardiac disease, this can result in volume overload and a clinical picture of acute HF with breathlessness, elevated venous pressure, pulmonary rales, and chest radiograph evidence of pulmonary oedema. Such adverse outcomes may now become increasingly rare as anaesthetists adopt strategies for careful preoperative planning of fluid management,1 and implement the routine use of echocardiography for monitoring left ventricular performance during noncardiac surgery.2

Acute HF may also result from the use of drugs that are recognized to depress cardiac contractility. Thankfully, many drugs that are known to produce profound cardiac contractile depression are now rarely used. However, myocardial depression sufficient to result in clinical HF may result from the use of some evidence-based drugs at accepted clinical doses where the patient appears sensitive to the drug or where there is concomitant liver or renal impairment resulting in accumulation and subsequent toxicity. Such drugs include calcium antagonists, β-blockers, anaesthetic agents, and antiarrhythmic drugs (Table 9.1). HF may also result when using these drugs where the patient is systemically compromised for other reasons such as in severe sepsis. Careful consideration and clinical assessment is required when using these drugs in the intensive care unit. Acute severe left ventricular systolic dysfunction (LVSD) may also result from long-term use of intravenous inotropic agents such as noradrenaline or adrenaline in this setting, although these drugs are reserved for patients in a precarious haemodynamic situation. The mechanisms for this are thought to relate to progressive down-regulation of β-adrenoreceptor responsiveness due to chronic overstimulation of cardiomyocytes,4 or direct cardiomyocyte cell death due to necrosis and apoptosis resulting from high-dose catecholamine exposure.5,6

Table 9.1 Iatrogenic causes of heart failure

Surgical

Drugs

Fluid overload

Calcium antagonists:

Nifedipine

Verapamil

Amlodipine

Acute or chronic prosthetic heart valve regurgitation

β-blockers

Iatrogenic AV fistula formation

Antiarrhythmic drugs:

Quinidine

Procanamide

Lignocaine

Anaesthetic induction agents:

Etomidate

Propofol

Fentanyl

Centrally acting sympatholytic drugs:

Clonidine

α-methyl DOPA

Adrenaline

Noradrenaline

Chemotherapeutic and immunosuppressant agents:

Cytarabine arabinoside

Gemcitabine

Interleukin

Methotrexate

Mitomycin

Muromonab-CD3

Pentostatin

Tretinoin

Adapted from Zausig YA, Busse H, Lunz D, Sinner B, Zink W, Graf BM. Cardiac effects of induction agents in the septic rat heart. Crit Care 2009;13(5):R144.

Heart failure resulting from cancer therapy

Survival following treatment of many solid and haemopoetic tumours has improved dramatically over the last 20 years, mainly due to better pharmacological agents given in well-tested regimens. However, the trade-off for better survival has been the long-term consequences of therapies containing highly toxic systemic agents, frequently combined with radiotherapy. The toxic effects of chemotherapeutic agents on the heart are well described in the basic and clinical scientific literature,7,8 although there are differences in the epidemiology of long-term cardiotoxicity in the treatment of adult and childhood cancers. Table 9.2 summarizes some of the long-term sequelae of cancer therapy in which HF features strongly.

Table 9.2 Relative risk of developing secondary health conditions among cancer survivors, as compared to siblings

Condition

Survivors

Siblings

Relative risk

(N = 10 397)

(N = 3034)

(95% CI)

(%)

(%)

Major joint replacement

1.61

0.03

54.0 (7.6–386.3)

Congestive heart failure

1.24

0.10

15.1 (4.8–47.9)

Second malignant neoplasm

2.38

0.33

14.8 (7.2–30.4)

Cognitive dysfunction, severe

0.65

0.10

10.5 (2.6–43.0)

Coronary artery disease

1.11

0.20

10.4 (4.1–25.9)

Cerebrovascular accident

1.56

0.20

9.3 (4.1–21.2)

Renal failure or dialysis

0.52

0.07

8.9 (2.2–36.6)

Hearing loss not corrected by aid

1.96

0.36

6.3 (3.3–11.8)

Legally blind or loss of an eye

2.92

0.69

5.8 (3.5–9.5)

Ovarian failure

2.79

0.99

3.5 (2.7–5.2)

Adapted from Oeffinger KC, Mertens AC, Sklar CA, et al. Childhood Cancer Survivor Study. Chronic health conditions in survivors of childhood cancer. N Engl J Med 2006;355(15):1572–82, with permission.

Anthracyclines and the heart

Clinical pharmacology of anthracyclines

Anthracyclines were initially isolated from the bacteria Streptomyces peucetius, and the compound first used in humans for the treatment of cancer was daunorubicin. Subsequently, the 14-hydroxy version was developed and named doxorubicin (also known as adriamycin or hydroxydaunorubicin; Fig. 9.1). It is used for the treatment of a number of solid tumours including gastric, breast and ovarian cancer, non-Hodgkin’s and Hodgkin’s lymphoma, thyroid carcinoma, neuroblastoma, small cell carcinoma of the lung, and Wilms’ tumour. It is also extremely effective in the treatment of acute lymphoblastic leukaemia in children.

Fig. 9.1 Chemical structure of doxorubicin.

Fig. 9.1
Chemical structure of doxorubicin.

Doxorubicin is administered intravenously as a series of slow, single-dose, single-agent boluses no more than 60–75 mg/m2 every 3–4 weeks, or 30 mg/m2 every 2 weeks, up to a total cumulative dose not exceeding 550 mg/m2. Early studies suggested that the incidence of congestive HF with doxorubicin was approximately 5% at this dose and that this represented the balance point for oncological efficacy versus cardiotoxicity. A reduction of the cumulative total dose is recommended in patients at higher risk of cardiotoxicity. Risk factors for the development of cardiotoxicity are summarized in Box 9.1.

Cellular mechanism of anthracycline cardiotoxicity

Cardiomyocyte mitochondrial injury is a key feature of the cardiotoxicity induced by anthracyclines. Numerous studies in animal models and cell culture have suggested that free-radical formation by cardiomyocyte mitochondria causes widespread cellular damage due to the production of reactive oxygen species, including superoxide.1013 The mitochondria subsequently undergo structural changes including vacuolation, swelling, and fragmentation of cristae.13 A number of other ultrastructural changes typically occur in the myocyte including loss of myofibrils, deformation of the nucleus, and dilatation of the sarcoplasmic reticulum.14 Apoptosis also plays a role in myocyte cell loss and appears to be stimulated by free-radical production.15,16

Cardiotoxicity of anthracyclines in childhood

Cardiotoxic drugs used in childhood cancers are broadly similar to those used in adults. Anthracyclines, with a cumulative dose used of up to 550 mg/m2, have played a significant therapeutic role in improving the 5-year survival in acute lymphoblastic leukaemia from less than 10% to over 80% in the last 30 years.17 A number of long-term follow-up studies of children treated for haematological malignancies demonstrate a range of systolic, diastolic, and wall thickness abnormalities, as assessed by echocardiography or radionuclide ventriculography, in at least half of all subjects treated with anthracyclines during childhood.18 However, these are almost exclusively retrospective cross-sectional studies and so there is considerable variation in reported subclinical cardiac toxicity. The incidence of clinically apparent CHF varies from as low as 0% to 16% in 30 studies published between 1966 and 2000.19 In a single site study, clinical CHF was reported in 8% of children at 1 year20 and in another 2.8% at 6 years.21 This group estimated the risk in their cohort of 5% after 15 years for children treated with a cumulative dose of doxorubicin greater than 300 mg/m2 between 1976 and 1997. A more recent study of 116 children treated for acute lymphoblastic leukaemia with doses of doxorubicin less than 300 mg/m2 provided follow-up for a mean of 8.2 years. This study suggested that even at these apparently ‘safe’ cumulative doses the incidence of significantly reduced left ventricular wall thickness and increased left ventricular end-diastolic diameter was increased compared with age-matched controls.22

The variation in incidence of clinical CHF is also partly due to differing durations of follow-up, the heterogeneous populations studied and possibly due to the different ways in which CHF was defined in these studies. However, with an estimated 20 000 children now surviving cancer into adulthood in the United Kingdom, the potential for a substantial burden of cardiac disease, including HF, requiring future clinical care is evident.

Cardiotoxicity of anthracyclines in adults

There are many studies reported in the literature of follow-up of patients after treatment with cardiotoxic drugs, mainly anthracyclines. It would be fair to say that many of these studies are reports of a small number of patients being followed up after treatment in a clinical setting where the authors have carefully documented the clinical details and correlated these with the findings on echocardiography. While these are valuable studies there are a number of questions that arise in terms of their validity. First, the patients included represent survivors and exclude patients dying before any cardiac assessment was reported. Few studies give an indication of the total number from which their published population is derived. Secondly, many of the reported studies fail to state how many survivors were excluded and for what reasons. For example, patients with recurrence of their primary disease or metastases or with other comorbidities may have been excluded. Hence, the rigour in defining the population being assessed and presented within the published article is uncertain. Thirdly, and related to the first and second points above, very few studies have performed prospective longer-term follow-up studies in a large enough cohort to examine true incidence of clinical HF and associated mortality. Throughout the literature it is clear that while cumulatively many patients are followed up, the heterogeneity of the patients and uncertainty of methods used in follow-up make a true prediction of echocardiographic and clinical outcomes difficult. However, in adults treated with doxorubicin the earliest reports suggested that 4% of patients receiving a dose of 500–550 mg/m2 developed cardiotoxicity, rising to 18% at doses between 551–600mg/m2.23

More recent studies have indicated that the risk of cardiotoxicity may be higher than previously estimated at lower total cumulative doses. After doses of 240 mg/m2 there is evidence for significant reductions in left ventricular function24 and at 400 mg/m2 the incidence of congestive HF may actually be closer to that previously thought to occur at 550 mg/m2, namely 5%.25 Overall, low cumulative doses appear to be associated with a lower risk of cardiotoxicity, but once above 450 mg/m2 then the incidence of CHF starts to rise and probably rises exponentially above 500 mg/m2. There is some evidence that infusions of doxorubicin rather than bolus injections may result in less cardiotoxicity26 although some studies have not confirmed this.27 A more recent systematic review suggested that infusions of 6 h or more duration may be associated with reduced cardiotoxicity in adults.28 These authors strongly recommend further studies in children to assess the potential to reduce cardiotoxicity using infusion rather than bolus dosing.

Liposomal preparations of doxorubicin may also be associated with a reduced incidence of cardiotoxicity,29 although long-term follow-up studies comparing free doxorubicin with pegylated versions are awaited. Epirubicin, a derivative of doxorubicin, has also been reported to have a low incidence of cardiotoxicity. After a median of 7 years follow-up (range 1 month to 15 years), Fumoleau et al.30 reported a combined early and late occurrence of LVSD in 1.4% of patents treated with epirubicin compared to 0.2% in patients not treated with epirubicin. Clinical CHF developed in only 0.2% of patients treated with epirubicin. This compares with an expected incidence of CHF, if treated with equivalent doses of doxorubicin, of over 7%.

Diastolic dysfunction resulting from anthracyclines

Various echocardiographic measurements of relaxation change during acute infusion of anthracyclines including increased end-diastolic wall thickness, prolonged isovolumic relaxation time, and decreased E:A ratio.31 Doppler tissue measurements also change following administration of cardiotoxic chemotherapeutic agents with a rise in E:A ratio and a lengthening of isovolumic relaxation time.32

A number of studies have examined long-term changes in diastolic function in survivors of childhood cancers treated with anthracyclines. Diastolic abnormalities, as measured by changes in inflow patterns and isovolumic relaxation times, can be identified in up to 50% of survivors.19 However, longer-term follow-up studies of children with a variety of malignancies failed to suggest any significant longer-term diastolic abnormalities in survivors followed up for an average of almost 14 years after diagnosis.33,34 Furthermore, a further study of diastolic abnormalities found both increases and decreases in E:A ratio compared with controls but showed no specific association with the development of clinically overt HF or mortality.35 Some caution should be used in interpreting cross-sectional retrospective follow-up data of survivors as the impact of early and medium-term diastolic abnormalities on longer-term symptoms and development of clinical HF is unknown. The prevalence of diastolic abnormalities in nonsurvivors is also unknown.

Strategies to avoid anthracycline cardiotoxicity

Clinical strategies to avoid cardiotoxicity associated with anthracyclines include using the minimum efficacious dose for oncological response, and delivering the drug as an infusion rather than as a bolus thus reducing the peak dose of the drug. Currently doxorubicin is commonly given in doses of approximately 60–70 mg/m2 repeated every 3 weeks on 4–6 occasions. This approach to administration is now widely used although there is some evidence that it makes little difference to the risk of developing cardiac dysfunction and HF compared to doses exceeding 45 mg/m2 per week.27

The use of the antioxidant drug dexrazoxane indicated reductions in troponin release up to 180 days after treatment with doxorubicin in children with acute lymphoblastic leukaemia.36 Disappointingly, this reduction in myocardial injury in the short term did not result in any difference in clinical endpoints over a 3-year follow-up period. Longer-term follow-up of these patients to assess development of chronic left ventricular dysfunction and clinical HF is not yet reported.

Careful clinical assessment before and during treatment are also important aspects to help reduce the risk of anthracycline cardiotoxicity. Interestingly, none of the clinical guidelines for treatment of breast cancer recommend simple baseline cardiac investigations before starting chemotherapy unless the patient is thought to be at high risk. The minimum investigation recommended by most cardiologists would be an ECG, but additionally an echocardiogram or multiple gated acquisition (MUGA) scan to assess left ventricular function should also be done. Baseline assessment provides a comparison with any future investigations in the event that complications arise during or after treatment. Table 9.3 shows a suggested algorithm for guiding management of patients with breast cancer. Although there is no guaranteed way of avoiding cardiotoxicity, the clinician should explain to the patient that some degree of judgement is required in assessing the risk–benefit ratio for efficacy of cancer treatment balanced against cardiotoxicity. Such discussions are clearly more important where the patient has a pretreatment risk of cardiotoxicity which is deemed to be medium or high or where the selected cumulative dose of anthracycline is high.

Table 9.3 Clinical algorithm for guiding management and monitoring of cardiac risk associated with use of anthracyclines

Clinical risk levela

Example

Total cumulative dose of doxorubicin

〈300 mg/m2

300–450 mg/m2

〉450 mg/m2

Low

No cardiovascular history, middle aged, no previous anthracycline exposure

ECG and echo/MUGA at baseline

ECG and echo/MUGA at baseline + 3 months after completion of chemotherapy

ECG and Echo/MUGA at baseline and after every cycle of chemotherapy + 3 months after completion + yearly thereafter

Medium

Stable hypertension or ischaemic heart disease managed with medication

ECG and echo/MUGA at baseline + every 1–2 cycles of chemotherapy + 3 months after completion of chemotherapy

ECG and echo/MUGA at baseline and after every cycle of chemotherapy + 3 months after completion + yearly thereafter

Avoid anthracyclines

High

Previous anthracycline therapy, hypertension, elderly

ECG and echo/MUGA at baseline and after every cycle of chemotherapy + 3 months after completion + yearly thereafter

Avoid anthracyclines

Avoid anthracyclines

a For assessment of clinical risk see Box 9.1.

ECG

The ECG has largely been overlooked as a potential screening tool for either baseline cardiac disease prior to starting chemotherapy or as a method of monitoring for cardiotoxicity. However, given its powerful negative predictive value in the diagnosis of HF in breathless patients presenting with suspected HF, there is certainly scope for further research.37 One study of children with cancer suggested that the QT interval may help in the assessment of cardiotoxicity in conjunction with echo-derived shortening fraction in identifying reduced ejection fraction following chemotherapy.38 A more recent study suggested that an abnormal ECG was a powerful predictor of cardiotoxicity in patients treated for a variety of cancers and after adjustment for confounders was as predictive as the biomarkers B-type natriuretic peptide (BNP) and troponin.39 Further large-scale prospective trials are needed.

Echocardiography

Echocardiography has been widely used to monitor cardiac function before during and after chemotherapy in both adults and children. The advantages are that it is cheap, does not involve ionizing radiation, and provides additional information regarding cardiac structure and function over and above ejection fraction. Increasingly, with modern technology the quality of imaging has improved substantially and limitations related to body shape and size are less problematic.

Radionuclide ventriculography

This technique, commonly referred to as a MUGA scan, is widely used to measure ejection fraction in patients being treated for cancer. Technetium-99 is commonly used as the radioactive tracer, and the radioactivity over the heart is collected throughout a number of cardiac cycles. The ejection fraction is estimated from the difference between the radioactive counts in end-diastole and end-systole. Although the technique has limitations it is acknowledged to be a reasonably accurate and highly reproducible way to assess the systolic function. However, contemporary data suggest that with modern equipment there is no significant difference between methods of assessing ejection fraction.40 Therefore, variations in the use of different imaging modalities probably reflects differences in clinical opinions, availability of techniques, and expertise from one region or one country to another.

Biomarkers (BNP and troponins)

Plasma biomarkers are a potentially valuable method of identifying cardiotoxicity in patients undergoing chemotherapy. In particular, the use of BNP to diagnose and monitor LVSD in patients with non-chemotherapy-related HF has is now widely accepted.41 In patients with chemotherapy-related cardiotoxicity there have been numerous studies but to date these have been small, and few have provided long-term outcomes.

In children, one study identified elevated NT-proBNP, but not troponin, in 13% of survivors followed up for an average of 14 years after treatment for various childhood cancers using anthracyclines.33 However, another study found no elevation in natriuretic peptide levels despite the presence of detectable echocardiographic abnormalities of systolic and diastolic function.42 Our current understanding of the value of biomarkers in assessing cardiotoxicity in childhood cancers is poor.43 This is mainly because the studies published to date have been predominantly observational cohort studies (with the exception of one study using troponin T),36 with small numbers, no clear inclusion criteria, considerable variation in types of cancers, inconsistencies in the control groups used, and no long-term follow-up data. Further studies addressing these inconsistencies are clearly needed.

In the adult, there are also few studies with sufficient power to address the value of biomarkers in identifying and monitoring for cardiotoxicity. One study, involving 54 breast cancer patients, suggested that 2.5–6.5 years after treatment with higher doses of doxorubicin, patients had increased levels of plasma natriuretic peptides compared with those receiving lower doses.44 However, only 2 patients developed clinical HF during follow-up in this study. In a more recent study, 5 patients (from 70 treated for breast cancer) developed clinical CHF during follow-up and BNP remained elevated in these patients while in other patients that developed a rise and then a fall in BNP levels there was no clinically overt CHF after a mean follow-up of 880 days.45 In terms of long-term monitoring of cardiac function there is still little evidence that BNP/NT-proBNP can replace measurement of ejection fraction, as a recent study suggested that there was no correlation between fall in ejection fraction during treatment for breast cancer and associated changes in plasma BNP.46

Plasma troponin has been assessed prospectively as a poten-tial marker of acute cardiac injury during chemotherapy and radiotherapy. In a series of over 700 patients with a variety of cancer types, Cardinale, et al, 47 identified a sub-population with no elevation of troponin during and after chemotherapy who were very unlikely to develop cardiac events, principally an asymptomatic reduction in ejection fraction of 25%, or more, during a mean of 20 months follow-up. Despite these important findings, there remains uncertainty regarding the optimal timing of troponin sampling and the longer term prediction of cardiac outcomes. In addition, further prospective studies are required to assess modern high sensitivity troponin assays in oncology patients.

Troponin may, however, be emerging as a potentially more useful test than natriuretic peptides for identifying early cardiac injury associated with chemotherapy.

Trastuzumab

Trastuzumab (Herceptin) is a monoclonal antibody that blocks the human epithelial growth factor receptor 2 (HER2). The receptor protein is overexpressed or the gene is amplified in the tumour tissue of 15–25% of women with breast cancer and tends to be associated with more aggressive disease. When used in combination with other chemotherapy regimes, trastuzumab reduces the risk of relapse by approximately 50% and reduces the risk of death by 30% when given in conjunction with cytotoxic chemotherapy.48,49 Therefore, trastuzumab is currently recommended as a treatment option for early-stage HER2-positive breast cancer following surgery, when combined with a sequential regimen of chemotherapy (neoadjuvant or adjuvant) and radiotherapy (if applicable). Patients should have a baseline assessment of left ventricular ejection fraction (LVEF) and only those above 55% should receive the drug.50 This has caused considerable concern among the oncology and cardiology communities since 55% is well above the normal cut-off range for many cardiology departments. The consequences of applying this rigorously is that many women who are suitable for treatment would not receive it because their ejection fraction is normal but measures below 55%. The sensible clinical approach to this issue is for cardiologists and oncologists in centres treating breast cancer to agree the normal range for their locally agreed method of assessing LVEF. These agreed cut-off values rather than a fixed lower limit of 55% should guide both initiation and monitoring of cardiac function associated with trastuzumab therapy.51

The concerns regarding cardiac status stem from an unexpectedly high incidence of HF in early trials in using trastuzumab. Symptoms of HF were particularly common when trastuzumab was administered concurrently with chemotherapy. In the pivotal trial, paclitaxel monotherapy was associated with a 1% incidence of CHF, concurrent use of trastuzumab with paclitaxel was associated with a 13% incidence of CHF, and patients receiving the combination of anthracycline and trastuzumab concurrently had a 27% incidence of HF including 16% with NYHA class III or IV symptoms.52

A later series of trials published as a single study of open-label trastuzumab plus chemotherapy versus chemotherapy alone was designed more cautiously. The adjuvant chemotherapy was administered before starting trastuzumab and patients developing symptoms or signs of cardiotoxicity or a fall in ejection fraction during initial cytotoxic chemotherapy were excluded from receiving trastuzumab.53 Although, trastuzumab was given in conjunction with paclitaxel, the resulting incidence of NYHA III or IV HF in the trastuzumab treatment group was 4.1% compared with 0.8% in the control group after 3 years follow-up. A second trial designed to include a drug-free time period between finishing cytotoxic chemotherapy (including doxorubicin and cyclophosphamide) and starting a 1-year regime of trastuzumab infusions every 3 weeks resulted in a much lower incidence of HF of 1.7% compared with less than 0.1% in the control group.49

Cellular mechanisms of trastuzumab cardiotoxicity

The HER2 receptor is one of a family of four receptors linked to a signalling pathway that protects the cardiomyocyte from a variety of stresses including anthracycline toxicity, hypertension, ischaemia, and hypertension. Blocking this pathway results in a loss of this protective mechanism. This is supported by work using a mouse model with a cardiac ventricle specific knockout of the HER2 (ERbB2) receptor. These mice initially develop normally, but as adults they develop dilated cardiomyopathy and isolated cardiomyocytes are more susceptible to anthracycline toxicity.54

This pathway clearly represents an important potential therapeutic target for cardiac protection and possibly treatment of HF. However, a recent study of pacing induced cardiomyopathy in dogs suggested that while there was activation of the ErbB2 (HER2) receptor and its ligand (neuregulin) during development of HF, other downstream messengers in the pathway, ERK1 and 2, remained inactivated.55 Further studies assessing changes in the ligands and receptors in this pathway in human HF are needed.

Reducing the risk of trastuzumab cardiotoxicity

In order to reduce the risk of cardiotoxicity, as well as not being recommended in those with a baseline LVEF of less than 55%, trastuzumab is contraindicated in the following patient groups: patients with angina treated with medication, history of myocardial infarction or HF, evidence of transmural myocardial infraction (Q waves) on resting ECG, high-risk uncontrolled arrhythmias, clinically significant valvular disease, and poorly controlled hypertension.50 One further recommendation is that there is a period of at least 2 weeks between completing cytotoxic chemotherapy and starting trastuzumab.

Monitoring cardiac function during trastuzumab therapy

Monitoring cardiac function during treatment and identifying early subclinical declines in ejection fraction is one way to potentially reduce the incidence of serious adverse cardiac events resulting from trastuzumab therapy (Fig. 9.2). The current recommendation in the United Kingdom is that LVEF is assessed by either echocardiography or radionuclide ventriculography (MUGA) every 3 months during treatment and 3 months after treatment has concluded.50 If there is no significant reduction in ejection fraction during treatment then no further follow-up is required. However, if ejection fraction falls by 10% or more during the course of treatment, then therapy should be withheld for 4–6 weeks. Following this, a further assessment of cardiac function and review by a cardiologist should occur before restarting the drug. If ejection fraction returns to pretreatment levels then trastuzumab treatment can be restarted with a further assessment of ejection fraction after 1 month. If ejection fraction remains reduced then a discussion with the patient regarding risk–benefit ratio should allow a balanced decision to be reached on whether treatment should be stopped completely. However, this approach has generated a considerable number of referrals to cardiologists of women with no symptoms of HF and where the ejection fraction, despite apparently falling by 10%, remains within the normal range. This high level of concern for potential cardiotoxicity is appropriate and understandable when using a new class of drug but has resulted in some clinicians calling for a more pragmatic approach to monitoring.51,56

Fig. 9.2 A method for cardiac monitoring of patients during treatment with trastuzumab.

Fig. 9.2
A method for cardiac monitoring of patients during treatment with trastuzumab.

Adapted from Suter TM, Procter M, van Veldhuisen DJ, et al. Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trial. J Clin Oncol 2007;25:3859–65.

Long-term outcomes following trastuzumab cardiotoxicity

In the case of trastuzumab the reduction in cardiac function, at least in the early phase, appears to be reversible. It is estimated that over 80% of patients who develop trastuzumab cardiotoxicity show significant symptomatic recovery after treatment is withdrawn.57 In a series of 38 patients who were referred to a cardiology service after treatment with trastuzumab caused a mean fall in ejection fraction of 18%, 37 demonstrated a significant recovery of ejection fraction from 43% to 56% 1.5 months after withdrawal of treatment. Although 6 patients recovered without any treatment, the majority required temporary HF medication: 25 patients were retreated with trastuzumab and only 3 of these developed recurrent ventricular dysfunction.59 Therefore, in most patients, treatment withdrawal combined with standard HF medications such as angiotensin converting enzyme (ACE) inhibitors and β-adrenoreceptor antagonists is effective in restoring normal cardiac function and improving symptoms. Furthermore, at least half of patients that develop a fall in ejection fraction with trastuzumab and then recover can go on to complete the full treatment schedule, with HF medication used as a precautionary measure throughout the period of trastuzumab treatment.

Reversible versus nonreversible cardiotoxicity

Better understanding of the mechanisms and the clinical patterns of cardiac dysfunction that result from cancer-based chemotherapy has clarified our understanding of clinical management. Ewer and Lippman60 proposed two types of cardiac damage that can result during and in the months and years after cancer treatment. Type 1 damage typically results from doxorubicin chemotherapy and is usually chronic and irreversible. Type 1 is typically cumulative, dose dependent and results in ultrastructural changes within cardiomyocytes involving myofibrils and mitochondria. In contrast, type 2 damage, caused by Trastuzumab, is unrelated to dose, produces no ultrastructural changes and is reversible in the majority of cases. While this paradigm of myocardial injury types in cancer therapy is appealing, recent studies have indicated that trastuzumab cardiotoxicity can result in small elevations of troponin58 suggesting that there must be some direct cardiomyocyte injury possibly not yet identified by biopsy studies.

Management of chemotherapy-related cardiomyopathy

Diagnosis

The diagnosis of HF in the cancer patient should be made with standard approaches but with careful consideration given to the details of which cancer therapies have been used and when. This may seem obvious, but it is not uncommon to see a patient many years after treatment for cancer where the clinical case record is unavailable for a number of reasons. Previous use of anthracyclines may be likely if the patient remembers being given a bright red coloured injection or infusion. Tattoos on the precordium may indicate previous mantle radiotherapy in the case of lymphoma.

In a cancer patient, the detection of cardiac involvement may occur in a number of ways. Asymptomatic LVSD may be picked up by routine follow-up in the outpatient setting by echocardiography or radionuclide imaging. However, symptoms of breathlessness on exertion together with objective evidence of LVSD on echocardiography are highly suggestive of the diagnosis of cardiomyopathy. Where these features are combined with clinical signs of fluid overload including peripheral oedema, lung crepitations, and raised jugular venous pressure then the diagnosis of clinical HF may be made. Acute severe HF with symptoms of breathlessness and fluid retention may occur rarely either during chemotherapy or shortly afterwards,61 although it is important to exclude other causes of breathlessness commonly found in cancer patients such as pulmonary embolism and pericardial effusion.

It is also important to consider the possibility of coronary heart disease as a cause for cardiac dysfunction. The absence of any risk factors for coronary heart disease and the absence of an obvious regional wall motion abnormality on cardiac imaging make this diagnosis unlikely, although a number of chemotherapeutic agents can produce coronary spasm or predispose to coronary thrombotic events including 5-fluorouracil and new agents such as capecitabine.6264 Modern evaluation with cardiac magnetic resonance imaging (CMR) and CT are also likely to provide important useful information about diagnosis and aetiology.65

Treatment of cancer therapy related cardiomyopathy and heart failure

There are no large randomized trials of standard HF therapy in patients with anthracycline or trastuzumab cardiomyopathy. However, there are a few reports of improved cardiac function following treatment using standard HF medications in children.66,67 There are also recent reports of improvements with device therapy.68 In the most severe form, anthracycline cardiomyopathy can be treated with cardiac transplantation69 or left ventricular assist devices.70

The largest preventive study reported is a double-blind randomized trial of enalapril in 135 long-term survivors of childhood cancer with an identified baseline abnormality in cardiac systolic function following anthracycline chemotherapy. No patients had evidence of clinical HF at enrolment. Mean age at diagnosis of cancer was 8 years old and all had completed cancer therapy at least 2 years previously. Patients were randomized to placebo or enalapril and followed up for a mean of 2.9 years. There was no difference in the primary outcome measure which was rate of change of maximal cardiac index and left ventricular end-systolic wall stress assessed by echocardiography.71

Despite the lack of direct evidence for use of standard HF medications in cancer patients, there are pragmatic reasons and a general consensus among experts that ACE inhibitors and β-blockers should be used in the treatment of anthracycline-induced cardiomyopathy with or without clinically overt HF.51,72,73

Conclusions

Iatrogenic HF may appear to be an inevitable consequence of modern approaches to cancer therapy and cardiac surgery. However, careful assessment of patients prior to these interventions and modification of management based on the associated risks is an important way of reducing the incidence of this condition. With increasingly aggressive management of many cancers it is likely that there will be new challenges in dealing with the potential cardiotoxicity of such therapies. There is a need for careful and continuous assessment of patients receiving cancer therapy and for adverse cardiovascular outcomes to be clearly identified within all clinical trials of new treatment modalities.

References

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