An extremely wide QRS complex tachycardia induced by anamorelin

Anamorelin, a ghrelin receptor agonist, is used for cancer-related cachexia but can induce life-threatening arrhythmias. A case study illustrates an extremely wide QRS tachycardia, posing diagnostic challenges. Anamorelin cessation led to normalization, highlighting the importance of ECG monitoring, particularly in liver-compromised patients, and hemodynamic support are crucial during suspected toxicity. Anamorelin is a selective ghrelin receptor agonist that is widely used to increase appetite and promote weight gain in patients with cancer or cancer-related cachexia. The drug has been associated with sodium and L-type calcium channel blockade, which may theoretically cause serious adverse effects such as sinus arrest, atrio-ventricular block, wide QRS duration, and QT interval prolongation.1-3 However, there are limited reports on the clinical manifestation of anamorelin-induced arrhythmias.3, 4 Here, we present a case of an anamorelin-related extremely wide QRS complex tachycardia that posed difficulty in decision-making during diagnosis and treatment. A 54-year-old woman presented with a history of rectal cancer and postoperative liver metastasis. She had a normal 12-lead electrocardiogram (ECG) and no known history of cardiac disease (Figure 1A). She had Child–Pugh class A with a score of 5; therefore, she was prescribed anamorelin (100 mg/day) for cancer cachexia, which remarkably improved her appetite. However, she complained of fatigue, loss of appetite, and dizziness 2 months later. Two days later, she experienced a transient loss of consciousness and chest tightness with cold sweats at 9:30 a.m. after taking anamorelin at 7 a.m. Upon examination by a primary care physician at 11 a.m., a 12-lead electrocardiography was performed for the first time since the introduction of anamorelin. It revealed an irregular tachycardia with remarkably wide QRS complexes (QRS duration, 254 ms; QTc interval, 740 ms; Figure 1B). She was transferred to the emergency department 1 h later. Upon arrival, she was clearly conscious, and her vital signs were as follows: blood pressure, 87/62 mmHg; body temperature, 36.5°C; and heart rate, 126 beats/min. The 12-lead ECG showed findings similar to those of the previous one (Figure 1C). However, wide P waves (140 ms) regularly preceded every three almost identical wide QRS complexes (237 ms) with a prolonged PR interval (353 ms), suggesting sinus rhythm followed by atrial premature contraction (APC) couplet with severe conduction disturbances throughout the heart. The transthoracic echocardiography revealed no structural abnormalities with a left ventricular ejection fraction of 60% except for left ventricular dyssynchrony, which we assumed was caused by severely delayed ventricular conduction. No electrolyte abnormalities were observed; however, the laboratory data showed high lactate levels (107 mg/dL) and indicated that the patient had Child–Pugh class B with a score of 9. Anamorelin was strongly suspected to be responsible for her condition considering her medical history, medication use, and the 12-lead ECGs. We discontinued anamorelin and closely monitored the ECG without administering any antiarrhythmic drugs in the hospital. As expected, we observed gradual QRS narrowing and QT interval shortening, and APCs disappeared 11 h after admission (Figure 2A). The ECG obtained on Day 3 showed that the parameters almost normalized to baseline values except the negative T wave (Figure 2B), and the patient was discharged on Day 6 without any complications. This case underscores the infrequent but potentially life-threatening adverse effect of anamorelin, which is similar to flecainide toxicity.3, 4 A previous randomized control trial including 83 patients on anamorelin reported that five patients experienced first-degree atrioventricular block and two patients developed tachycardia.1 A recent meta-analysis demonstrated that anamorelin does not increase adverse effects when compared with placebo in patients with cancer cachexia.2 The drug was approved in Japan in 2020 but not in the United States or Europe, partially owing to inadequate safety data. Two case reports of three patients are currently available to demonstrate anamorelin-induced severe conduction disturbance.3, 4 Two patients developed wide QRS tachycardias, which normalized 1 and 4 days after discontinuing the drug, respectively.3 Another patient showed hemodynamically unstable ventricular tachycardia, which required electrical cardioversion to terminate. The ECG parameters normalized after approximately 24 h of taking anamorelin.4 None of the three patients experienced loss of consciousness. The unusually wide QRS duration owing to sodium channel blockade can complicate diagnoses. The initial ECG obtained by the primary physician (Figure 1B) revealed an extremely wide QRS tachycardia. According to the diagnostic Brugada algorithm,5 the ECG parameters met supraventricular tachycardia criteria except for RS interval >100 ms in the precordial leads. However, the long RS interval may be attributed to remarkable intrinsic QRS widening caused by anamorelin toxicity. The QRS morphology was almost identical to that in the second ECG (Figure 1C), which suggests a sinus rhythm with the APC couplet with a delayed ventricular conduction. Considering the above observations, the primary ECG (Figure 1B) is likely to show a supraventricular arrhythmia rather than a ventricular arrhythmia. Notably, the patient experienced transient loss of consciousness shortly before contacting the primary care physician. The remarkably elevated lactate level recorded at the emergency department suggested that the patient underwent hemodynamic collapse shortly before arrival. It is possible that life-threatening arrhythmias such as torsade de pointes, rapid ventricular tachycardia, and sinus arrest may have occurred. Anamorelin is rapidly metabolized by CYP3A4, primarily in the liver. A 100 mg oral dose of anamorelin peaks at 0.75 h, with a half-life of 8.8 h. Thus, the optimal strategy may be waiting for the clearance of the drug while ensuring the patient's hemodynamics when anamorelin cardiac toxicity is suspected. In fact, this approach worked well in the present case as well as the three other reported cases.3, 4 Meanwhile, liver dysfunction slows anamorelin metabolism; thus, the drug is contraindicated in patients with moderate–severe liver dysfunction. The patient had Child–Pugh class A with a score of 5 when anamorelin was initiated. However, as the disease progressed, her liver dysfunction advanced to Child–Pugh class B with a score of 9 upon admission, potentially contributing to anamorelin toxicity, as evidenced by the extreme conduction abnormality. This case emphasizes the importance of regular monitoring of 12-lead ECG as well as liver function after introducing anamorelin, especially in patients with existing liver disease. In conclusion, anamorelin-induced conduction disturbance should be carefully monitored as it can be life-threatening. The authors received no financial support for the research, authorship, and publication of this article. Authors declare no conflict of interests for this article. Approval of the research protocol: N/A. Informed consent: Written informed consent was obtained from the patient for the publication of this case report and accompanying images. Animal studies: N/A. The data that support the findings of this study are available from the corresponding author, IM, on reasonable request.