Capecitabine induced acute coronary syndrome

Abstract

Capecitabine is an oral chemotherapeutic agent recommended by the National Institute for Clinical Excellence as first line treatment for metastatic bowel cancer and second line for breast cancer. With the increasing prevalence and diagnosis of these common malignancies, it is essential that physicians are made aware of the rare, but potentially fatal, cardiac effects of capecitabine. This case report demonstrates a typical presentation of suspected acute coronary syndrome with associated ECG changes in a patient who had started capecitabine 2 days before admission. His troponin was mildly elevated and his ECGs resolved on discontinuation of the drug, but a positive exercise tolerance test precipitated coronary angiography; which was essentially normal, as was his echocardiogram and computed tomography scan. Previous literature has highlighted potential cardiac complications of a similar chemotherapeutic agent 5-fluorouracil, which is the active metabolite present in capecitabine. The possible presentations, complications and clinical management are discussed in this case report.

BACKGROUND

In 2003, the National Institute of Clinical Excellence (NICE) issued guidance on the usage of capecitabine as one of the first line treatments for metastatic bowel cancer, and second line treatment for metastatic or locally invasive breast cancer. The drug itself belongs to a new and rapidly expanding class of therapeutic agents that are designed specifically as an oral medication, thus permitting out of hospital administration, unlike intravenous treatment. With increasing prevalence and early diagnosis of these common malignancies, it is essential that physicians are made aware of their rare, but potentially fatal, cardiac effects.

CASE PRESENTATION

A 65-year-old man was admitted to our acute assessment unit with a history of sudden onset of sharp, non-radiating left sided chest pain occurring at rest of approximately 1 h duration. The chest pain was associated with sweating and there were no relieving or aggravating factors.

His past medical history included Duke’s B carcinoma of his sigmoid colon and he had undergone a resection of his rectosigmoid colon with a colostomy formation 6 months previously, and subsequently had been referred for adjuvant chemotherapy. Oral capecitabine had been commenced 2 days before his admission.

The only risk factor for coronary artery disease was being an ex cigarette smoker.

Clinical examination revealed a blood pressure of 125/70 mm Hg, heart rate 90/min, and a soft non-radiating pansystolic murmur on auscultation at the apex.

INVESTIGATIONS

His chest x ray was normal. Blood tests showed a white cell count of 8.1×10⁹/l, C reactive protein (CRP) 5.8 mg/l, potassium 4.2 mmol/l, and a troponin I at 12 h was raised at 0.25 ng/ml (normal range <0.1 ng/ml).

An echocardiogram showed no evidence of pericardial effusion, good left ventricular systolic function with no regional wall abnormalities, a slightly dilated left atrium and mild mitral regurgitation, mild tricuspid regurgitation and mild pulmonary regurgitation, with normal right side heart dimensions.

Electrocardiogram (ECG) on admission demonstrated global saddle ST elevation with peaked T waves in the chest leads V2–V6 (fig 1).

Figure 1.

Patient’s ECG on admission.

A tentative diagnosis of possible viral myopericarditis was made and the patient was initially treated conservatively. A computed tomography (CT) scan of the chest showed normal appearance of lungs and mediastinum, with no evidence of pericardial effusion or thickening.

During admission, after discussion with the oncologists, capecitabine was discontinued. Subsequently, the patient’s chest pain subsided and resolution of his ECG changes was evident. In order to exclude coronary ischaemia, on day 4, an exercise stress ECG was performed utilising the Bruce protocol. The patient achieved stage II (5 min 30 s) without symptoms. However, the ECG reading during the exercise phase was similar to that on admission and the test was terminated (figs 2 and 3). These ECG changes took 14 min and 10 seconds to resolve during the recovery phase.

Figure 2.

Pre-exercise test ECG.

Figure 3.

Stage 2 (Bruce protocol) exercise test at 5 min 30 s.

On account of the positive exercise tolerance test, on day 5 a coronary angiogram was performed. This showed no evidence of significant coronary artery disease with a good left ventricular function. He remained pain-free off his chemotherapy and was discharged home.

OUTCOME AND FOLLOW-UP

At his 6 month cardiology follow-up the patient remained well with no further episodes of chest pain and remained off chemotherapy.

DISCUSSION

This case highlights the importance of recognising the potential side effects of an increasingly popular oral chemotherapeutic medication. Capecitabine undergoes an enzymatic conversion to 5-fluorouracil (5-FU), which accumulates in the target tumour, preventing DNA synthesis and leading to an imbalance in cell growth and ultimately tumour cell death.¹

Cardiotoxicity due to 5-FU is rare, but potentially fatal side effects are reported in 1–18% of patients, higher in those with pre-existing coronary artery disease and in those receiving higher doses.^2,3

The most common symptom of 5-FU associated cardiotoxicity is angina-like chest pain. Other symptoms include cardiac arrhythmias, congestive heart failure, myocardial infarction, dilated cardiomyopathy, cardiogenic shock, cardiac arrest or sudden death.³ Published case reports suggest that chest pain may develop within 48–72 h after commencing capecitabine, as was the case with this patient.²

Serum cardiac enzymes tend to be normal, while ECG changes commonly demonstrate characteristic ischaemic changes in 68–88% of patients. Echocardiography may show transient regional or more often global, left ventricular dysfunction in 24–56% of patients which can last for up to 7 days, hence resembling post-myocardial ischaemic “stunning”.³

Coronary vasospasm due to 5-FU has been documented in oncology journals previously,⁴ and capecitabine induced coronary vasospasm was first reported in 2004.⁵

In 1993, a study by Robben et al analysed 135 patients who received 5-FU, and found that 89% encountered angina, 88% showed ST changes and ischaemia on ECG, 43% had raised cardiac markers, 38% encountered arrhythmias, and 24% had documented left ventricular dysfunction.⁶

In previous reports of 5-FU induced cardiotoxicity, symptoms did not occur after the first dose of capecitabine. In most cases, three doses of capecitabine (7500 mg/m² total dose) and approximately a 12 h delay after the last ingestion was necessary before chest pain developed, hence demonstrating a cumulative dose effect.

The pathophysiology of 5-FU induced cardiotoxicity remains controversial and conclusions are based on clinical studies and case reports rather than on experimental evidence. Theories that include coronary artery spasm, direct toxicity to the myocardium, thrombogenic effects, and an autoimmune phenomenon have all been proposed.⁷

An in vitro study in 1993 by the American Association of Cancer Research demonstrated that 5-FU causes direct, endothelium independent vasoconstriction of the vascular smooth muscle, involving the activation of protein kinase C, and is independent of the cell membrane receptors or the cyclo-oxygenase pathway. In other words, typical membrane receptor blockers such as β-blockers and calcium channel blockers would fail to alter the vasoconstriction which is only likely to be abolished by glyceryl trinitrate.⁶

In our patient, with the small troponin rise, and transient diffuse ST segment elevation on the ECG, it seems possible that he suffered coronary vasospasm rather than an isolated myocardial infarction secondary to a critical atherosclerotic lesion. This theory is supported by a normal coronary angiogram, a good residual left ventricular function, and a normal ECG upon discharge and on follow-up.

LEARNING POINTS

• NICE recommendations ensure increasing usage of oral capecitabine for metastatic bowel and breast cancer.

• Capecitabine should be recognised as a drug with potential cardiotoxic effects.

• Typical presentations include angina and arrhythmias with elevated cardiac enzymes, ECG changes and left ventricular impairment.

• Mechanisms of the cardiac side effects are still debatable.

• Treatment should be discontinuation of capecitabine and administration of glyceryl trinitrate.