pharmacoepidemiology and drug safety 2008; 17: 1033–1035w.interscience.wiley.com) DOI: 10.1002/pds.1624

Published online 9 July 2008 in Wiley InterScience (ww

BRIEF REPORT

Syncope and sinus bradycardia from combined use ofthalidomide and b-blockery

Takashi Yamaguchi MD*

Department of Internal Medicine, Teine Keijinkai Hospital, Japan

SUMMARY

We present a case of a 76-year-old Japanese man with hypertension and multiple myeloma (MM) presented with syncope andsinus bradycardia. Thalidomide therapy for MM was added to longstanding atenolol therapy one month prior to presentation.His heart rate (HR) was around 70 beats per minute (bpm) before addition of Thalidomide. His HR on presentation was lessthan 30 bpm. He was treated with intravenous atropine followed by temporary pacemaker and taken off atenolol. His HRreturned to around 70 bpm few days after discontinuation of atenolol, even though he was still taking thalidomide, permittingoutpatient management without a pacemaker. Both thalidomide and atenolol have been reported to cause bradycardia.Neither agent caused bradycardia when used alone in this patient, but simultaneous use caused symptomatic bradycardia. Asthalidomide is prescribed more frequently, clinicians should be aware of the possibility of drug-induced sinus bradycardiadue to the interaction of thalidomide and b-blockers. Copyright # 2008 John Wiley & Sons, Ltd.

key words— thalidomide; b-blocker; syncope; sinus bradycardia; multiple myeloma

Received 6 March 2008; Revised 2 May 2008; Accepted 3 May 2008

INTRODUCTION

Both thalidomide and b-blocker are known to causebradycardia in certain patients.1,2 From post-marketing data, the incidence of bradycardia due toatenolol and thalidomide are 1.57 and 0.12%,respectively. In this case bradycardia and syncopewere caused by the combination of thalidomide andatenolol in a patient who had not experiencedbradycardia with either agent alone.

CASE

A 76-year-old Japanese man with hypertension andmultiple myeloma (MM) had an episode of syncope

* Correspondence to: Dr T. Yamaguchi, Department of InternalMedicine, Teine Keijinkai Hospital, 1-12-1-40, Maeda, Teine-KuSapporo, Japan 006-8555. E-mail: ikagoro@pop06.odn.ne.jpyNo conflict of interest was declared.

Copyright # 2008 John Wiley & Sons, Ltd.

while attending an outpatient haematology clinic for aroutine appointment. His heart rate (HR) during theepisode was less than 30 beats per minute (bpm).

His medications included atenolol 50 mg daily, aswell as hydrochlorothiazide and furosemide forhypertension. He had taken the atenolol for the past2 years, during which he had no episode ofbradycardia, syncope or pre-syncope (his baselineHR was 70–80 bpm and blood pressure was about 120/70 mmHg). Thalidomide 100 mg daily was added tohis regimen one month prior to admission. He had noother significant past medical history. He did not takeany over the counter drug or herbal medicine and usetobacco, but consumed occasional beer. His fatherdied from sudden death of unknown cause at the age of70.

At presentation, his vital signs were significant for aHR of 30 bpm and a blood pressure of 90/50 mmHgwithout fever and abnormal respiratory rate. Cardiacexamination revealed no S3 or S4 gallops and no otherheart murmurs. Both lower extremities had mild

1034 t. yamaguchi

pitting edema. The remainder of the physicalexamination was unremarkable, including the neuro-logical examination.

A complete blood count (CBC) showed mildpancytopenia (WBC 2760/ml, Hgb 11.0 g/dl, Hct31.3%, platelet count 106 000/ml), all of which wasnot unchanged from baseline CBC. Renal functionand electrolytes were normal. TSH was 1.96mU/ml(normal range 0.27–4.20mU/ml). An electrocardio-gram (ECG) showed sinus bradycardia without AVblock or any ischemic changes. Cardiac ultrasono-graphy showed mild left ventricular hypertrophy withnormal systolic function and an ejection fraction of70%, with no wall motion abnormalities.

He received 0.5 mg of intravenous atropine sulfate,which increased his HR to 60 bpm. Syncope did notrecur as long as his HR was kept above 40 bpm.However, syncope was recurred, when his HR was lessthan 30 bpm. He was admitted to the hospital andreceived a temporary transvenous pacemaker. Afteradmission, atenolol was stopped but thalidomide wascontinued. His HR gradually increased to more than60 bpm and the temporary pacemaker was removed onthe 6th hospital day. Holter ECG after removal ofpacemaker showed no abnormality. He was dischargedon the 7th hospital day. He continued to takethalidomide after discharge, and had no furtherepisodes of bradycardia.

Figure 1. The relation of heart rate and drug use. Heart rate is 70 bpmuse of atenolol and thalidomide, heart rate decreased less than 30 bpm.hospital day

Copyright # 2008 John Wiley & Sons, Ltd. Pha

DISCUSSION

Thalidomide and atenolol have both been implicatedas causes of bradycardia. Post-marketing data reporteda 0.12% rate of thalidomide-induced bradycardia, butother recent reports indicate that thalidomide-inducedbradycardia may be far more frequent, up to 5–53%.3–6

In this case, ECG and cardiac ultrasonographyshowed no evidence of other cardiac aetiology, such asischemia. Electrolytes were also normal. Althoughdiuretics use can cause syncope which related toorthostatic hypotension, syncope in this case hap-pened when the patient was sitting. We think thecombination of thalidomide and atenolol causedprofound bradycardia and syncope. Naranjo’s prob-ability index indicates probable association in thiscase (score is 7).

Bradycardia related to the combined use ofthalidomide and a b-blocker is rare and only onecase has been reported,7 in which the patient hadalready been bradycardic on a b-blocker alone. In thatcase, after starting thalidomide, his bradycardiaworsened, and dizziness developed as the dose ofthalidomide was increased. After discontinuation ofb-blocker, thalidomide was discontinued on accountof persistent dizziness. In contrast, our patientdeveloped bradycardia and syncope only with the

or more with atenolol or thalidomide alone. Only with combinationHR: heart rate, bpm: beat per minute, PTA: prior to admission, HD:

rmacoepidemiology and Drug Safety, 2008; 17: 1033–1035DOI: 10.1002/pds

KEY POINT

� We should carefully observe the change of HRafter starting Thalidomide to the patients whohave already taken beta-blocker, especially afterthe first few months.

syncope and sinus bradycardia 1035

additive effects of both thalidomide and a b-blocker,and was able to continue using thalidomide alonewithout recurrent bradycardia or syncope (Figure 1).

The mechanism by which thalidomide causesbradycardia has not been determined yet. AlthoughBadros and his colleagues reported secondaryhypothyroidism in myeloma patients treated withthalidomide,8 our patient’s normal thyroid functiontests make hypothyroidism an unlikely explanation forthe bradycardia. Emch and his colleagues reported thatTNF-a inhibits activity of the dorsal motor nucleus(DMN) of the vagus nerve, which supplies visceralparasympathetic fibres to both the heart and the gut.9

By decreasing the production of TNF-a, thalidomidemight increase the activity of the DMN, and increaseparasympathetic tone. Adding the effects of increasedparasympathetic tone (thalidomide) to b-blockerinduced sympathetic nervous system inhibition couldbe a plausible explanation for the severe bradycardiaand syncope observed in this patient.

Thalidomide is proving to be useful for anincreasing number of haematologic and oncologicdisorders. Use of thalidomide is no longer restricted topatients with refractory MM. As thalidomide is usedmore frequently, the opportunities for interactionswith b-blockers and other negative chronotropes areincreased. Clinicians should consider the possibility ofsevere bradycardia related to combination use ofthalidomide and b-blockers.

Copyright # 2008 John Wiley & Sons, Ltd. Pha

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9. Emch GS, Hermann GE, Rogers RC. Tumor necrosis factor-ainhibits physiologically identified dorsal motor nucleus neuronsin vivo. Brain Res 2002; 951: 311–315.

rmacoepidemiology and Drug Safety, 2008; 17: 1033–1035DOI: 10.1002/pds