azitromizina y muerte cardiaca subita

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540 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 80 NUMBER 9 SEPTEMBER 2013

AZITHROMYCIN AND SUDDEN CARDIAC DEATH

All physicians

should consider

risk factors for

QT prolongation

and torsades

de pointes

when

prescribing

azithromycin

yt, o, 65 ses, sudde d det(TABLE 1).6

At e vlue, te ube o FAERS e-pots ppes to be sl betee te vousolde tbots. Hoeve, t s pottto eebe tt tese dus de subst-tlly te ube o pesptos tteo te, t ztoy be pesbedoe ote. Also, te FAERS ubes esubjet to ube o ell-ko lttossu s ooud vbles, ueve qultyd opleteess o epots, duplto, dudeepot. Tese lttos peludete use o su dvese epot dtbses lult d teeby op te tuedee o dvese evets ssoted tte vous olde tbots.69

RAY ET AL FIND A HIGHER RISKOF CARDIOVASCULAR DEATH

Despte tese eet s, tl post-ket suvelle epots st eou doubto te lo-std oto tt ztoy- s te sest olde tbot to poptRy et l to ssess ts sety obsevto-l, odozed study o people eolled te Teessee Medd po.

Tey oud tt, ove te typl 5 dys otepy, people tk ztoy d teo dovsul det .88 tes e t people tk o tbot, d .49 tes -

e t people tk oxll (TABLE 2).

Hoeve, te bsolute exess sk o-ped t oxll ved osdeblyod to bsele sk soe o do-vsul dsese, t exess dovsu-l det pe 4, te est-sk deleoped t exess dovsul detpe , te loest-sk dele.,

Moeove, te ese dets dd otpesst te te 5 dys o tepy. Ts te-lted ptte detly oelted t ex-peted pek ztoy pls levels du- stdd 5-dy ouse.

Ry et l used ppopte lyt et-ods to ttept to oet o y ooudbs ts to te obsevtol, o-dozed study des. Neveteless, te p-tets ee Medd beefes, o ve e pevlee o oobd odtosd e otlty tes t te eelpopulto. Teeoe, lette questos

ee sed bout ete te esults o testudy ould be eelzed to popultos tsubsttlly loe bsele sk o dovs-ul dsese d deees te bseletests o te tetet oups eedequtely otolled.,

THE FDA REVISES AZITHROMYCINSWARNINGS AND PRECAUTIONS

Te stk obsevtos by Ry et l, ou-pled t te oes sed by postket-

suvelle epots, opelled te FDA

TABLE 1

Comparison of commonly prescribed macrolide antibiotics

Macrolideantibiotic hERG IC50(M)a CYP3A4substrate CYP3A4inhibitor Adverse eventsin FAERSb Fatal eventsin FAERS

Azithromycin35 1,091 No No 203 65

Clarithromycin4,5 45.7 Yes Yes 246 66

Erythromycin4,5 38.9 Yes Yes 50 17

Telithromycin4,5 42.5 Yes Yes 107 29

CYP3A4 = cytochrome P450 3A4; FAERS = Food and Drug Administration Adverse Event Reporting System; hERG = human ether

-go-go-related gene (a potassium channel involved in myocyte repolarization) ; IC50 = hal maximal inhibitory concentrationaThese represent experimental values obtained under dissimilar experimental conditions. As such, use o these values to directly

compare the propensity o each drug to prolong the QT interval and cause torsades de pointes should be avoided.b

Adverse event reporting rom postmarketing surveillance does not account or prescription volume and is oten subjected to signif-cant bias rom conounding variables, quality o reported data, duplication, and underreporting o events.

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CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 80 NUMBER 9 SEPTEMBER 2013 541

GIUDICESSI AND ACKERMAN

Although

azithromycin

may increase

the relative risk

of a cardiovas-

cular event,

for most

otherwise-

healthy

patients theabsolute risk

is miniscule

to eve te lbels o ztoy d oteolde tbots.

Ulttely, te FDA opted to evse te d peutos seto o teztoy du lbel to lude bout te potetl sk o tl yts,speflly QT tevl poloto dtosdes de potes. I M setyoueet, t lso ued elt e po-essols to use uto e pesbztoy to ptets ko to ve sktos o du-elted yts, ludoetl lo QT sydoe, qued QTtevl poloto, ypokle, ypo-es, bdyd, d ouet use o oteedtos ko to polo te QT te-vl, speflly te lss IA (e, qude dpode) d lss III (e, odoe,sotlol, d doetlde) tyts.

SVANSTRM ET AL FINDNO INCREASED RISK

Hoeve, just e te edl outyppeed edy to ept tt ztoyy ot be s se s e tout t s, lepospetve study by Svst et l, pub-lsed ely My , oud o esedsk o dovsul det ssoted tztoy (TABLE 2).4

Te ptets ee epesettve popul-to o you to ddle-ed Ds dults tlo bsele sk o udely dovsuldsese.

Iteestly, Svst et l ee eul to

pot out tt te study s oly poeed to

ule out odete-to- (> 55%) ese te eltve sk o dovsul det. Fu-teoe, pooud deees exsted tebsele sk o det d dovsul sktos betee te ptets d te Tees-see Medd ptets studed by Ry et l.4Teeoe, te utos suested tt te studyopleets te t otdts te studyby Ry et l. Tey ttbuted te deees te fds to tetet-eet eteoeety, te sk o ztoy-ssoteddovsul otlty s lely lted to-sk ptets, ely tose t ultplepeexst dovsul sk tos.4

ACC/AHA RECOMMENDATION:IDENTIFY THOSE AT RISK

Colletvely, te dt eveed bove po-vde opell evdee tt ztoys ot opletely ee o te QT-polod tosdoe eets tt ve lo beessoted t ote olde tbots.

Hoeve, te fds o bot te study byRy et l d tt o Svst et l suesttt peexst dovsul sk tos ply poet ole dete te deeo ztoy-ssoted dovsul det ve populto (TABLE 2).,4

Tese fds sould popt pyssto eully essess te sks d beefts oztoy use te ll ptes.Tey lso eoe eet ll by te Ae- Het Assoto (AHA) d AeCollee o Cdoloy (ACC) to bette de-

ty, ely o, ptets t sk o du-dued

TABLE 2

Risk of cardiovascular death in Tennessee Medicaid patients and youngto middle-aged Danish adults taking a 5-day course of azithromycin

Population Azithromycin vsno antibiotic use

Azithromycin vsbeta-lactam usea

Overall cardiovascularmortality rate(per 1 million azithromycincourses)Risk ratio 95% CI Risk ratio 95% CI

Tennessee10 2.88 1.252.75 2.49 1.384.50 85.2b

Denmark14 2.85 1.137.24 0.93 0.561.55 15.4

aAmoxicillin was used or comparison in the Tennessee Medicaid population, whereas penicillin V was used or comparison in the

Danish population.bIncreases to 245 deaths per 1 million azithromycin courses or those patients with the highest decile cardiovascular risk scores.



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vetul yts d sudde det dto subsequetly pove o tese ptets eotoed e te use o QT-polo dtosdoe dus s edlly eessy.5

AN ELECTRONIC MEDICAL RECORDFLAGS QTc 500 MS

O te eels o tese AHA/ACC suestos,

ou osptl s dopted sttuto-de

QT let syste. Hee, te eleto edleod syste (Cetty EMR; GE Helt-e) uses popety lot to detetd eletolly let ode pyss

e ptet s poloed QT tevl,d ves oto bout te potetlll sfe o ts eletodo-p fd.6 Pyss lso eeve e ode QT-polo dus ptets t sk.

Ts syste s stll ts y, but t sledy ofed tt poloed QT te-vl (QT 5 s) s poeul pedto odet o y use d s deosttedtt otlty tes tose t poloedQT tevls ese dose-depedet

so t te ptets ube o odf-ble sk tos (e, eletolyte dstubeso QT-polo edtos) d ood-fble sk tos (e, eet dsposto, e-le sex, stutul et dsese, dbeteselltus).6 We ve lso oud evdee ttodfble sk tos y ve oe po-oued eet o otlty sk t o-odfble sk tos.6

Tese fds suest tt ototeoloy-bsed QT let systes y oedy povde pyss t pott toolto efetly dety d possbly eve od-y te sk o dovsul det ptetst sk, o exple, by oet ele-tolyte boltes o edu te budeo QT-polo edtos.

CONSIDER RISK OF QT PROLONGATIONWHEN PRESCRIBING AZITHROMYCIN

Fo ost sttutos d ll ptes,su eleto QT let systes e stll yes

ot dedes y. Hoeve, lt o teoto suzed bove, ll pysssould be osde sk tos o QTpoloto d tosdes de potes (su-zed TABLE 3) d e te sks dbeefts o pesb ztoy vs lte-tve tbots t l QT lblty.Ts sould be eltvely sple to do. Tsto keep d: Altou ztoy y ese te

eltve sk o dovsul evet, oost otese-elty ptets, te bso-

lute sk s sule.

TABLE 3

Risk factors for QT prolongationand torsades de pointes

Modifable risk actors

Electrolyte disturbancesHypocalcemia (calcium < 4.65 mg/dL)Hypokalemia (potassium < 3.4 mmol/L)Hypomagnesemia (magnesium < 1.7 mg/dL)

QT-prolonging medication polypharmacyConcurrent use o 1 QT-prolonging medication (see www.azcert.org)

Nonmodifable risk actors

Common diagnosesAcute coronary syndrome

Anorexia nervosa or starvationBradyarrhythmias < 45 bpmCardiac heart ailure (ejection raction < 40%; uncompensated)Congenital long QT syndrome or other genetic susceptibilityChronic renal ailure requiring dialysisDiabetes mellitus (type 1 and 2)Hypertrophic cardiomyopathyHypoglycemia (documented and in absence o diabetes)

Pheochromocytoma

Status post cardiac arrest (within 24 hours)

Status post syncope or seizure (within 24 hours)

Stroke, subarachnoid hemorrhage, or other head trauma (within 7 days)

Personal or amily history o QT interval prolongation or suddenunexplained death in the absence o a clinical or genetic diagnosis

Elderly (> 65 years o age)

Female

While no ormal risk scorecard or drug-induced QT-prolongation exists, a pro-QTc

score 4 based on risk actors similar to those listed above was an independent

predictor o mortality in patients with QT interval prolongation.16 Unortunately,

the predictive value o these risk actors in patients with normal or borderline QT

intervals has not been assessed.



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I ptet t sk (e, t bsele QTpoloto o ultple sk tos ot), ztoy o ote QT-po-lo tbot su s olde o

uooquoloe s edlly eessydue to peeetl btel suseptbltyo ptet llees, evey eot sould bede to oet odfble sk tos (e,eletolyte boltes) d, possble,to vod polypy t ultple QT-polo dus.

Fo ptets o ve ultple sk toso QT poloto o tetet

t ko QT-polo edtos stll deeed te ptets best teest,sto osdeto sould be ve to -ptet dstto d oto u-

tl te tetet s bee opleted.Wt eul osdeto o odfble

d oodfble sk tos s ell s lttleext uto e pesb potetl QT-polo edtos su s ztoy,te ll beeft o tese ote-dvt-eous edtos be xzed d tedee o tese t but e du-duedsudde d dets be edued.

REFERENCES1. Hopkins S. Clinical toleration and saety o azithromycin. Am J Med

1991; 91:40S45S.2. Milberg P, Eckardt L, Bruns HJ, et al . Divergent proarrhythmic

potential o macrolide antibiotics despite similar QT prolongation:

ast phase 3 repolarization prevents early aterdepolarizations and

torsade de pointes. J Pharmacol Exp Ther 2002; 303:218225.

3. Ioannidis JP, Contopoulos-Ioannidis DG, Chew P, Lau J. Meta-analysis

o randomized controlled trials on the comparative efcacy and

saety o azithromycin against other antibiotics or upper respira-

tory tract inections. J Antimicrob Chemother 2001; 48:677689.

4. Owens RC Jr, Nolin TD. Antimicrobial-associated QT interval prolon-

gation: pointes o interest. Clin Inect Dis 2006; 43:16031611.

5. Arellano-Rodrigo E, Garca A, Mont L, Roqu M. Torsade de pointes

and cardiorespiratory arrest induced by azithromycin in a patient

with congenital long QT syndrome. (Article in Spanish.) Med Clin

(Barc) 2001; 117:118119.

6. Raschi E, Poluzzi E, Koci A, Moretti U, Sturkenboom M, De Ponti

F. Macrolides and torsadogenic risk: emerging issues rom the da

pharmacovigilance database. J Pharmacovigilance 2013; 1:104.

7. Shaffer D, Singer S, Korvick J, Honig P. Concomitant risk actors in

reports o torsades de pointes associated with macrolide use: review

o the United States Food and Drug Administration Adverse Event

Reporting System. Clin Inect Dis 2002; 35:197200.

8. Stephenson WP, Hauben M. Data mining or signals in spontaneous

reporting databases: proceed with caution. Pharmacoepidemiol

Drug Sa 2007; 16:359365.

9. Bate A, Evans SJ. Quantitative signal detection using spontaneous

ADR reporting. Pharmacoepidemiol Drug Sa 2009; 18:427436.

10. Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycinand the risk o cardiovascular death. N Engl J Med 2012; 366:1881

1890.

11. Mosholder AD, Mathew J, Alexander JJ, Smith H, Nambiar S. Car-

diovascular risks with azithromycin and other antibacterial drugs. N

Engl J Med 2013; 368:16651668.

12. Louie R. Azithromycin and the risk o cardiovascular death. N Engl J

Med 2012; 367:774775.

13. Koga T, Imaoka H. Azithromycin and the risk o cardiovascular

death. N Engl J Med 2012; 367:774775.

14. Svanstrm H, Pasternak B, Hviid A. Use o azithromycin and death

rom cardiovascular causes. N Engl J Med 2013; 368:17041712.

15. Drew BJ, Ackerman MJ, Funk M, et al; American Heart Association

Acute Cardiac Care Committee of the Council on Clinical Cardiology,

the Council on Cardiovascular Nursing, and the American College of

Cardiology Foundation. Prevention o torsade de pointes in hospital

settings: a scientifc statement rom the American Heart Associationand the American College o Cardiology Foundation. Circulation

2010; 121:10471060.

16. Haugaa KH, Bos JM, Tarrell RF, Morlan BW, Caraballo PJ, Ackerman

MJ. Institution-wide QT alert system identifes patients with a high

risk o mortality. Mayo Clin Proc 2013; 88:315325.

ADDRESS: Michael J. Ackerman, MD, PhD, Mayo Clinic Windland Smith RiceSudden Death Genomics Laboratory, Guggenheim 501, Rochester, MN 55905;e-mail: [email protected]

CME ANSWERS

Answers to the credit tests on page 599 o this issue

Transient ischemic attack 1D 2C Cardiovascular disease in women 1C 2C Cardiac biomarkers 1C 2B

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azitromizina y muerte cardiaca subita

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