Heart failure can be drug-induced. Cardiotoxicity by a specific drug can be a direct cause of cardiomyopathy and heart failure. In other cases, a cardiovascular drug may destabilize patients with preexisting ventricular dysfunction. The mechanism of drug-induced heart failure may be a direct negative inotropic effect or an adverse hemodynamic effect, such as an increase in preload or afterload. Drugs that induce arrhythmias or conduction disturbances may also exacerbate chronic heart failure. These dangers underline the need for a detailed drug history when attempting to explain destabilization. We discuss below the main classes of drugs responsible for cardiomyopathy.
Anthracyclines are antibiotics that owe their anticancer activity to their ability to inhibit nucleic acid synthesis by binding to both parts of the deoxyribonucleic acid (DNA) helix and thereby blocking the normal function of ribonucleic acid (RNA) and DNA polymerases. The incorporation of anthracyclines into chemotherapy regimens has significantly improved survival in cancer patients, with daunoru-bicin and doxorubicin being the most commonly used agents. However, cardiotoxicity is a major dose-limiting side effect.
Pathogenic mechanisms involved in cardiotoxicity include the production of free radicals (derived from the chemical reduction of anthracyclines through metabolic pathways catalyzed by iron), abnormalities of mitochondrial energy metabolism, and intracellular calcium overload. The anthracyclines and/or their metabolites may also alter adrenergic balance and trigger the release of endogenous substances such as histamine, arachidonic acid metabolites, platelet activators, and calcium, all of which are potentially toxic to the myocardium. Typical findings in endomyocardial biopsies from patients with anthracycline cardiomyopathy include mitochondrial edema, onion-ring mitochondrial crests, cytoplasmic vacuolization due to dilatation of sarcoplasmic tubules, and myofibrillar loss of actin and myosin.
Cardiotoxicity is dose-dependent. Doxorubicin is administered by intravenous bolus at doses of 50 to 75 mg/m2 every 3 weeks, alone or in combination with other chemotherapeutic agents. A total dose of 550 mg/m2 induces heart failure in about 10% of patients, increasing to 30% at higher doses. For this reason most protocols set a ceiling at 450 mg/m2. The least cardiotoxic mode of administration is continuous infusion over 72 hours, since this provides lower and steady plasma levels. The chemotherapy protocol is also important: if the anthracycline is administered in combination with other anticancer agents, it may induce cardiotoxicity at doses below 550 mg/m2, in which case the dose is limited in practice to a maximum of 360 mg/m2. Combination with cyclophosphamide lowers the threshold cardiotoxic dose to 400 mg/m2. With palliative use in advanced disease, higher doses can be given, increasing the incidence of cardiotoxicity, although the risk is clinically less important in this context. The use of a fixed, cumulative dose of anthracycline is common, but has clinical consequences. Some studies in patients remitting at 450 to 550 mg/m2 suggest that remission could be prolonged using higher doses; patients able to tolerate higher doses may be advantaged in terms of tumor-killing effect or duration of response.
Although all anthracyclines are cardiotoxic, epirubicin is rather less so than doxorubicin. In a recent retrospective study in over 450 patients receiving epirubicin for metastatic breast cancer, the risk of developing
Drugs: general considerations heart failure at a dose of 950 mg/m2 was 4%, increasing exponentially to 15% at a cumulative dose of 1000 mg/m2.
Cardiotoxicity may develop at any stage in anthracycline treatment. Acute or early cardiotoxicity develops after a single dose. It is often subclinical, manifested by vasodilatation, hypotension, and reversible electrocardiographic abnormalities, including arrhythmia. It is not associated with myocardial dysfunction. It occurs in 30% of patients within hours of intravenous infusion. Chronic or late cardiotoxicity, probably due to fibrosis following myocyte degeneration, develops in a few weeks, months, or years after the last dose. It presents as dilated-hypokinetic cardiomyopathy with systolic dysfunction. It may occur in patients who had symptoms of heart failure during chemotherapy, but also in those who did not. The most common signs are heart failure and arrhythmia. Breast cancer patients are the most likely to develop late cardiotoxicity, especially when their survival is increased by early tumor diagnosis and a positive tumor response to the anthracycline. This also applies to the increasingly frequent combination with taxanes, especially paclitaxel, in breast cancer chemotherapy.
Steinherz et al demonstrated very late cardiotoxicity in a follow-up study of 201 children. Sixty percent developed systolic dysfunction more than 10 years after completing anthracycline therapy. The pathogenesis remains unclear, but reinforces the message that all anthracycline recipients should be considered at risk of cardiomyopathy and heart failure. Prevention is crucial to improving quality of life in long-term chemotherapy survivors and constitutes a challenge for research.
Lists the cardiomyopathy risk factors. Since anthracyclines are metabolized by the liver, hepatic disease reduces their clearance and increases the risk of hemo-toxicity and cardiotoxicity. Radiotherapy compounds cardiotoxic risk. Prior exposure of the heart to radiation increases the risk of heart failure and leads to a more rapid fatal outcome.
There are widely used monitoring guidelines for the early diagnosis of cardiomyopathy during and after treatment. Their purpose is to permit early treatment, hence delaying and minimizing symptom severity.
Early recognition, before marked deterioration of the ejection fraction, can identify the patients most likely to benefit from less cardiotoxic strategies. The practice guidelines are based on clinical evaluation of the patients at risk using electrocardiographic and echocardiographic criteria. The ejection fraction should be measured 3 weeks after the last dose and 1 week before the next to avoid the transient response to acute anthracycline administration. The patient should also be normothermic, with a hemoglobin above 9 g/dL. A gradual decline in contractility over several investigations is a more reliable indicator than a single large decrease, for which an interfering factor may be responsible. The parameters currently used are the ejection fraction, fractional shortening, isovolumic relaxation time, and end-systolic wall stress. This monitoring regimen based solely on the evaluation of left ventricular function reduces the incidence of heart failure. As with any chronic disease, multidisciplinary continuity of care is also required. Fuller evaluation, including a functional cardiovascular and autonomic workup, may be useful in high-risk individuals being considered for anthracycline therapy.
Since echocardiography and radionuclide studies are insensitive indicators of incipient cardiomyopathy, alternative techniques are being investigated. Radioimmunoscintigraphy with antimyosin monoclonal antibodies labeled with indium-111 has given poor results due to low specificity. Hashimoto et al recently reported promising results with an echocardiographic method of automatic border detection that identifies early impairment of left ventricular filling. Elevation of serum cardiac troponin T levels also appears promising, although still confined to experimental models: highly significant positive correlations have been found with cardiomyopathy scores based on cardiac biopsy and cumulative doxorubicin dose. Myocytes release troponin T in response to anthracycline injury, both from the cytosolic soluble pool (due to oxidative damage to the sarcolemma) and from the myofibrils.
An alternative indicator, in asymptomatic breast cancer patients with normal systolic function treated with anthracyclines, is autonomic dysfunction. Many patients show altered R-R variability after high-dose therapy, suggesting that this could be an early indication of cardiotoxicity.
Neuroendocrine activation, reflected in increased plasma natriuretic (atrial and brain-type) hormone levels, occurs in early left ventricular dysfunction. It may be a useful marker of subclinical dysfunction rather than of early cardiotoxicity.
Long-term survivors of childhood anthracycline therapy may show echocardiographic diastolic dysfunction during inotropic stimulation with dobutamine 10 (ig/kg/min. In women with breast cancer treated with epirubicin, diastolic dysfunction was present on the echocardiogram at rest at the upper dose limit. These results suggest that diastolic dysfunction could be an early sign of cardiotoxicity, as confirmed by Hashimoto et al.
The treatment of heart failure due to anthracycline cardiomyopathy is no different from that of other causes of heart failure. The efficacy of cardioprotective drugs is under investigation. Dexrazoxane is a prodrug that is hydrolyzed in the cell to form an efficient iron chelator which removes the doxorubicin-iron complex and hence is cardioprotective, as has been shown in randomized trials. The pharmacological spectrum of dexrazoxane includes a cardiomyocyte protective effect against anthracyclines, mitoxantrone, and other chemotherapy agents. Cardioprotection could permit higher doses of anthracyclines, hence augmented anticancer efficacy.
Recent evidence-based practice guidelines recommend dexrazoxane in patients with advanced disease highly sensitive to chemotherapy who have already received conventional doses of doxorubicin, and in patients requiring further doxorubicin treatment and/or treatment to doses up to or exceeding 300 mg/m2 (55% of the maximal dose). In patients treated with epirubicin, the first two indications given for doxorubicin are valid. However, there is no firm evidence yet of a target dose. A formula similar to that for doxorubicin could be used, ie, 550 mg/m2 (maximum 1000 mg/m2). Patients at risk of cardiomyopathy may benefit most from dexrazoxane cardioprotection. Dexrazoxane does not have side effects of its own, and does not aggravate those of the anthracyclines (except for a slight increase in neutropenia); nor does it impair antitumor efficacy.
The individual patient context must never be forgotten. Many patients would accept mild myocardial dysfunction in exchange for an increased probability of survival. Deterioration in quality of life induced by anthracycline cardiotoxicity may be important to a young patient with curable disease. Antitumor efficacy may be the primary consideration for palliative therapy in an older patient, or in a patient with advanced disease.
Cyclophosphamide is cardiotoxic via its active metabolites. The most probable mechanisms involve endothelial damage, followed by extravasation of the toxic metabolites, causing myocyte lesions, edema, and interstitial hemorrhage. Heart failure may ensue within 2 weeks of starting treatment, with death in a few weeks. Those at greatest risk may be the most active metabolizers, ie, those with the lowest area under the plasma concentration/time curve (AUC), lowest peak plasma level, and longest exposure to metabolite levels. AUC monitoring is therefore recommended to identify such patients. The clinical presentations of cyclophosphamide cardiotoxicity may be reversible or irreversible, depending on baseline cardiac function, prior chemotherapy, and the dose and mode of cyclophosphamide administration.
The taxanes (paclitaxel and docetaxel) represent a major new class of antineoplastic agent. Paclitaxel promotes tubulin polymerization. Microtubules formed in the presence of paclitaxel are ultrastable and dysfunctional. As such they interfere with the processes of cell division and interphase, resulting in cell death. Paclitaxel induces apoptosis and inhibits angiogenesis, tumor cell motility, invasiveness, and metalloproteinase production. It is increasingly used in advanced ovarian and breast cancer. The most frequent side effect (30% of cases) is transient asymptomatic bradycardia. Clinically significant bradycardia is rare. As for heart failure, there is no firm evidence that it can be induced by paclitaxel alone. It has been used without triggering or aggravating heart failure in patients with risk factors such as preexisting heart failure, severe ischemic heart disease, angina, and ongoing (S-block-er or other antiarrhythmic therapy.
Paclitaxel differs from the anthracyclines in the mechanism of its anticancer activity, with no clear evidence of cross-resistance. Combination therapy thus enhances treatment response and slows disease progression, but does not lower mortality rates. However, heart failure occurs in patients receiving combination doxorubicin at a cumulative dose exceeding 360 mg/m2, most probably due to interference by paclitaxel in the pharmacokinetics of doxorubicin elimination. This effect depends on the dosing interval between the two drugs and the duration of paclitaxel infusion. No such interference is seen with docetaxel: the combination of docetaxel with doxorubicin does not increase the risk of cardiotoxicity.
Mitoxantrone is structurally related to doxorubicin and may increase the risk of myocardial dysfunction. Cardiotoxicity is probably dose-dependent. Further research is needed, but mitoxantrone must be viewed as a potent cardiotoxin. Preclinical studies show no evidence that dexrazoxane is cardioprotective in the presence of drugs such as mitoxantrone; no clinical studies are available. Use of a cardioprotective agent cannot therefore be recommended.
Other chemotherapy agents
Heart failure has been associated with other chemotherapy agents such as 5-fluorouracil, cytarabine, and trastuzumab (Herceptin®).
5-Fluorouracil is often used for various malignant tumors. Cardiotoxicity is rare (ranging from 1.2% to 18% of cases). The mechanism is unknown. Knowledge is based mainly on case reports. Although the clinical and electrocardiographic data suggest that coronary spasm is involved (toxicity usually presents as myocardial ischemia, more rarely as reversible left ventricular dysfunction, and in one case as severe, probably ischemic, heart failure), the histomorpholo-gy and biochemistry suggest direct cytotoxicity. There are no guidelines to prevention or treatment. Signs generally regress after treatment withdrawal. Risk is greatly increased on rechallenge. Cardiac risk factors and parameters should be carefully monitored during treatment, with definitive withdrawal in the event of cardiotoxicity.
Cytarabine must be considered as potentially cardiotoxic, on the basis of case reports only. Trastuzumab was recently introduced as a combination therapy with doxorubicin and paclitaxel for breast, ovarian, or stomach cancer expressing high levels of pi85 HER2 (the receptor encoded by the HER2 gene, specifically inhibited by trastuzumab). The Food and Drug Administration has approved its use as the only treatment in patients with metastatic breast cancer expressing excessive HER2 protein, patients who have received one or more chemotherapy treatments, and in combination with paclitaxel in chemotherapy-naive patients. However, cardiac dysfunction presenting as an anthracycline-like cardiomyopathy has been observed in one third of patients treated with trastuzumab vs only 6% of those receiving doxorubicin and paclitaxel alone.
Three interferons, a, (3, and y, are used in clinical practice. The first two have antiviral and antiproliferative effects; interferon-y is mainly an immunoregulatory cytokine. Interferon-a has adverse cardiovascular effects such as hypotension and tachycardia in the first few days of treatment in 5% to 15% of patients. Interferon cardiotoxicity presents as arrhythmia, cardiomyopathy, and symptoms of myocardial ischemia. Heart failure has also been attributed to interferon-a, but the underlying mechanism is unknown. Altered myocyte metabolism and an increased oxygen requirement following tachycardia may play an important role. Rats treated with interferon-a show increased endothelial thickening in myocardial capillaries, with a resulting decrease in the capillary lumen. Interferon-P has never been associated with heart failure, and interferon-y only rarely, in patients with preexisting left ventricular dysfunction.
Interleukin-2, which is used to treat metastatic renal carcinoma, can have serious negative cardiovascular effects. Hypotension and tachycardia are frequent, but echocardiography and scintigraphy have also shown reversible left ventricular dysfunction. The mechanism involves inhibition of cellular cyclic adenosine monophosphate (cAMP). Accumulation of eosinophils and mixed eosinophil-lymphocyte material has also been observed and has been attributed to a hypersensitivity reaction.
Clozapine, an effective antipsychotic, has recently been suspected of inducing cardiomyopathy. Its major documented side effects include agranulocytosis (complete blood count monitoring helps to control morbidity and mortality), tachycardia, and orthostatic hypotension (rarely of clinical significance). The observation of 23 cases of myocarditis (some fatal) in 8000 patients in the first month of treatment (mean time to onset: 2 weeks) threw suspicion on clozapine. Intramyocardial eosinophilic infiltrates have been seen at autopsy. An alternative explanation is an IgE-mediated hypersensitivity reaction. Cases of dilated cardiomyopathy (probably due to myocarditis) have been observed an average of 36 months after starting therapy.
Hashimoto I, Ichida F, Miura M, et al. Automatic border detection identifies subclinical anthracycline cardiotoxicity in children with malignancy. Circulation. 1999;99:2367-2370.
Steinherz U, Steinhen PG, Tan C. Cardiac failure and dysrhythmias 6-19 years after anthracycline therapy: a series of 15 patients. Med Pediatr Oncol. 1995;24:352-361.
drug cardiotoxicity; cytostatic agent; chemotherapy; anthracycline; paclitaxel; immunomodulating drug; interferon; interleukin-2