a b s t r a c t

Varenicline (Champix(R), Chantix(R)) is a partial agonist of the ?4?2 nicotinic acetylcholine receptor (nAChR) and a full agonist of the ?7 nAChR. It has been used for smoking cessation since 2006. Varenicline has been associated with adverse cardiovascular (CV) events, including myocardial infarction, which may be caused by activation of the ?7 nAChR receptor that in turn stimulates parasympathetic output from the brainstem to the heart, release of catecholamines, and has a prothrombotic effect. However, among the adverse CV events, the issue related to the varenicline-induced pulmonary thromboembolism (PTE) has not being addressed. We report a case of PTE with pulmonary infarction presenting as right flank pain that resulted from the use of varenicline (the total score of Adverse drug reaction probability scale, 6; probable association between varenicline and pulmonary PTE) in a pa- tient without underlying CV disease and in whom low probability of PTE (Wells score was zero) was identified.

(C) 2017

A healthy 47-year-old man of normal-weight (body mass index, 23.3 kg/m²) presented to our emergency department (ED) with com- plaints of several days of right flank pain. He had no previous medical history, including previous deep venous thromboembolism or pulmo- nary thromboembolism (PTE), heart failure, or kidney disease. There was no history of recent infection, trauma, hypertension, diabetes mellitus, or hyperlipidemia. The patient reported taking varenicline

0.5 mg twice daily for one month to quit smoking. He was an ex-smoker (30 pack-years) and had stopped smoking after starting varenicline fol- lowing his first health-check-up one month before. During the initial health-check-up, he underwent a chest X-ray, Electrocardiogram , low-dose chest computed tomography , and abdominal CT with Contrast enhancement. All examination results were unremark- able. Except for taking varenicline, his Drug history was unremarkable. Vital signs were within normal limits (125/71 mmHg-78 beats/ min-18 breaths/min-36.8 ?C). Physical examination was unremark- able except for focal, dull tenderness at the right costovertebral angle. The Wells score was zero. Laboratory findings, including whole blood count, electrolytes, liver function, renal function, erythrocyte sedimen- tation rate, and C-reactive protein level, were normal. Initial abdominal X-ray, chest X-ray (Fig. 1A), and EKG (Fig. 1B) were normal. Urine anal- ysis showed no microscopic hematuria, pyuria, proteinuria, or bacteri- uria. An abdominal contrast-enhanced CT was performed to further investigate the cause of the right flank pain.

* Corresponding author.

E-mail address: [email protected] (S.J. Yun).

Abdominal CT showed unremarkable findings for the abdominal or- gans. However, multifocal, central, intraluminal Filling defects in the pulmonary arteries of both lower lobes with Ground glass opacities were identified, which indicated acute pulmonary emboli with suspected pulmonary infarction (Fig. 2A and B). Emergent arterial blood gas analysis of room air showed mild hypoxemia (pH: 7.36; PaCO₂: 40 mmHg; PaO₂: 78.3 mmHg; HCO₃: 24 mmHg). A pulse oxim- etry monitor indicated oxygen saturation level (SpO₂) of 92% on room air. For clarification, chest CT angiography was performed, which con- firmed acute PTE in the segmental branches of both lower lobe pulmo- nary arteries with pulmonary infarction (Fig. 2C and D). Subsequent lower extremity CT angiography revealed no evidence of deep vein thrombosis. After comprehensive comparison with the abdominal CT scan obtained one month previously at the health check-up (Fig. 2E and F), varenicline-induced PTE with pulmonary infarction was highly suspected. The patient was managed with oxygen (2 L/min) and heparinization was started in the ED. The patient was admitted to the Intensive care unit and stopped taking varenicline. On follow up chest CT angiography after 2 weeks, PTE completely resolved, and he was discharged with no flank pain and respiratory symptom. According to the adverse drug reaction (ADR) probability scale [1], the total score was 6 (means probable association between varenicline and pulmonary PTE). After considering patient’s history, treatment, and ADR probability scale, we finally diagnosed varenicline-induced pulmonary PTE with infarction.

Varenicline (Champix(R), Chantix(R)) is a partial agonist of ?4?2 nico- tinic acetylcholine receptor (nAChR) and a full agonist of the ?7 nAChR

http://dx.doi.org/10.1016/j.ajem.2017.02.044

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Fig. 1. (A) Chest X-ray showing normal vasculature without evidence of lung consolidation, pleural effusion, or cardiomegaly. (B) A 12-lead electrocardiogram (EKG) recorded on the day of emergency department admission. The EKG shows normal sinus rhythm without evidence of ST elevation or T wave change in precordial leads, S1 QIII TIII pattern (Deep S wave in lead I, Q wave in III, inverted T wave in III), or bundle-branch block pattern.

[2]. It was approved as a smoking cessation agent in 2006. Varenicline is used either alone as a first-line therapy or in conjunction with other smoking cessation agents [3]. Although this drug is effective for smoking cessation, adverse effects have been reported. The most common ad- verse effect is nausea (28.8-29.4%). Other side effects include insomnia (14.2%), headache (12.8-14.2%), abnormal dreams (11.7-13.1%), and constipation (7.2-9.0%) [4,5]. In 2013, the Food and Drug Administra- tion reported that this drug was associated with adverse cardiovascular (CV) events (a combined outcome of CV-related death, nonfatal heart attack, and nonfatal stroke) [6]. However, among adverse CV events, the issue related to the varenicline-induced PTE has not being addressed.

Varenicline-induced PTE is an extremely rare side effect of the drug, although the exact incidence is unclear. According to one national postmarketing surveillance study [7], only one case of varenicline-in- duced PTE was identified among 8446 full follow-up patients (0.011%). PTE was a more unusual complication than varenicline-in- duced myocardial infarction (11 among 8446 full follow-up patients, 0.13%). The exact mechanism by which varenicline causes PTE is un- known. One potential mechanism is linked to modulation of parasym- pathetic output from the brainstem to the heart, release of catecholamines, and a prothrombotic effect during therapy [8], which may be related to ?7 nAChR activation. A study in mice concluded that varenicline caused progression of atherosclerotic plaque formation

S.H. Lee et al. / American Journal of Emergency Medicine 35 (2017) 1037.e3-1037.e6 1037.e5

Fig. 2. (A, B) contrast-enhanced abdominal computed tomography (CT) with mediastinal window setting (A) obtained on the day of emergency department admission (taking varenicline for one month) showing a multifocal, central, intraluminal filling defect (arrows, A) in the pulmonary arteries with mild enlargement of the involved arteries in both lower lobes. In lung window setting (B), ill-defined ground glass opacities in both lower lobes are seen. The scans indicate acute pulmonary thromboembolism with infarction. (C, D) Chest CT angiography obtained on the day of emergency department admission (after taking varenicline for one month) confirms multifocal acute thromboembolism (arrows, A) in segmental branches of the pulmonary arteries. The scanty amount of the right pleural effusion is also seen (arrowheads, B). (E, F) Contrast-enhanced abdominal CT with mediastinal window setting (E) and lung window setting (F) obtained on the day of the health-check-up (obtained one month before the emergency department admission, when not taking varenicline) showing no evidence of intraluminal filling defect in the pulmonary arteries and ground glass opacity in both lower lobes.

through activation of ?7 nAChR, thereby increasing the risk of thrombotic events [9]. Although further cross-national cohort studies may be required, our case indicated the potential for varenicline to precipitate PTE (probable association), and thus, it should be listed as a potential, but rare, cause of acute, clinically ap- parent, drug-induced PTE.

In conclusion, emergency physicians should be aware of varenicline-induced PTE with pulmonary infarction, although ex- tremely rare, when treating patients taking varenicline for smoking cessation. Varenicline-induced acute PTE should also be considered

in patients with right flank pain, to prevent late diagnosis and fatality.

Grant or other financial support

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Previous presentation

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1037.e6 S.H. Lee et al. / American Journal of Emergency Medicine 35 (2017) 1037.e3-1037.e6

Conflicts of interest

None declared.

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