01148601 seminar; 18/03/15

Azithromycin an increased Risk CV Death ?

Presenter : Mr. THEERASIN YOMA ID .54191014

School of Pharmacy; Eastern Asia University

AGENDA

2012

Azithromycin and
Risk of Cardiovascular Death

Introduction

Background

Case Report 2006-2007

Case Report 2527-2555

THEERASIN YOMA

CONCLUSION

FAD: Safety Announcement

2013

Cardiovascular Events and

Safety Outcomes Associated 2014
with Azithromycin Therapy

INTRODUCTION
U.S FDA APPROVE

Azithromycin
ZITHROMAX (Azithromycin)
capsules 250 mg: 1 Nov. 1991
( Discontinued Drug Products)

Tablets 250 mg&600mg : Feb.

&Jun 1996
Tablets 500 mg : May 2002
THAI FDA APPROVE ZITHROMAX (Azithromycin)

Capsules 250 mg : 21 Nov 2004

THEERASIN YOMA

Outline

INTRODUCTION
MOA
Azithromycin binds to the 23S rRNA of
the bacterial 50S ribosomal subunit.
It blocks protein synthesis by inhibiting
the transpeptidation/translocation step
of protein synthesis and by inhibiting the
assembly of the 50S ribosomal subunit.

THEERASIN YOMA

INTRODUCTION
Susceptibility Gram-positive bacteria (+)
Staphylococcus aureus
Streptococcus agalactiae
Streptococcus pneumoniae
Streptococcus pyogenes
Gram-negative bacteria (-)
Haemophilus ducreyi
Haemophilus influenzae
Moraxella catarrhalis
Neisseria gonorrhoeae
Other bacteria
Chlamydophila pneumoniae
Chlamydia trachomatis
Mycoplasma pneumoniae
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INTRODUCTION
Indication (U.S FDA)
Acute bacterial sinusitis
Community-acquired pneumonia
Mycoplasma pneumoniae
&Streptococcus pneumoniae

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INTRODUCTION
Indication
[National List of Essential Medicines (Thailand)]
1. Treat LRI for Pt. cant use others drug
2. Treat. non-tuberculous mycobacterium (NTM)
3. Azithromycin Dose 2 g O.D For Pt. early syphilis
cant use penicillin or Doxycycline or Ceftriaxone
National List of Essential Medicines (Thailand) :

30 2556
THEERASIN YOMA

INTRODUCTION
DOSE & Administration

THEERASIN YOMA

INTRODUCTION
ADR
More 1 % : diarrhea/loose stools (4-5%), nausea (3%) and
abdominal pain (2-3%)
1% or less : Cardiovascular: Palpitations, chest pain.
Gastrointestinal: Dyspepsia, flatulence, vomiting, melena
Genitourinary: Monilia, vaginitis and nephritis.
Nervous System: Dizziness, headache, vertigo
General: Fatigue.
Allergic: Rash, pruritus, photosensitivity and angioedema.

THEERASIN YOMA

INTRODUCTION
ADR
Post-Marketing Experience:
Allergic: Arthralgia, edema, urticaria and angioedema
Cardiovascular : Arrhythmias including ventricular
tachycardia and hypotension. There have been rare
reports of QT prolongation and torsades de

pointes.
Gastrointestinal: Anorexia, constipation, dyspepsia,

General: Asthenia, paresthesia, fatigue, malaise and anaphylaxis

Genitourinary: Interstitial nephritis and acute renal failure
THEERASIN YOMA

BACKGROUND

Azithromycin-induced QT prolongation
in elderly patient.

Russo V, Puzio G, Siniscalchi N.

Acta Biomed. 2006 Apr;77(1):30-2.

Presenter Mr. THEERASIN YOMA ID: 54191014

School of Pharmacy; Eastern Asia University

BACKGROUND
P: male patients 65 years old
HPI: idiopathic dilated cardiomyopathy.
CC: community-acquired pneumonia
Ceftriaxone IV 1 g O.D
Azithromycin IV 0.5 g
azithromycin oral 0.25 g
6 hr
slightly and disappear

ECG showed QT prolongation

off AZT

2 Day
QT interval returned to the normal value
THEERASIN YOMA

BACKGROUND

Azithromycin as a cause of QT-interval prolong

ation and torsade de pointes in the absence of
other known precipitating factors

Kezerashvili A, Khattak H, Barsky A, Nazar

i R, Fisher JD.
J Interv Card Electrophysiol. 2007
Apr;18(3):243-6. Epub 2007 Jun 2

Presenter Mr. THEERASIN YOMA ID: 54191014

School of Pharmacy; Eastern Asia University

BACKGROUND
P: Female patient aged 55 Year
HPI: hypertension and a pacemaker for intermittent
symptomatic bradycardia.
CC: Staphylococcus aureus
gentamicin and vancomycin

severe acute renal failure &hemodialysis

off genta.

7 Day

Atypical pneumonia

azithromycin 500 mg O.D

7 Day

QT prolongation and TdP.

Off AZT

found to cause TdP again

THEERASIN YOMA

BACKGROUND

Spontaneous Reports of Adverse

Drug Reaction 2527-2555

BACKGROUND

Agents Associated with Drug-Use Mentions for Chronic

Sinusitis and Bronchitis, According to U.S. Office-Based
Physician Practices (January 2002December 2011)

Cardiovascular Risks with Azithromycin and Other Antibacterial Drugs; Andrew D. Mosholder,(/2013)

THEERASIN YOMA

01148601 seminar

Azithromycin and Risk of

Cardiovascular Death
Wayne A. Ray, Ph.D., Katherine T. Murray,
M.D., Kathi Hall, B.S., Patrick G. Arbogast,
Ph.D., and C. Michael Stein, M.B., Ch.B.
N Engl J Med 2012;366:1881-90.

Impact factor2014 : 54.42

Presenter Mr. THEERASIN YOMA ID: 54191014

School of Pharmacy; Eastern Asia University

BACKGROUND
Erythomycin&Clarithromycin

Azithromycin

(1996-2002)

Accumulating evidence
suggests AZT also may
have proarrhythmic
effects

Increase the risk of serious

venticular arrhytmia
associated with an increased
risk of Sudden cardiac death

BG
Azithromycin (2009)
FDA Adverse Event
Reporting System
includes 20 reports of
torsades de pointes

Azithromycin (2001-2007)
There are reports of pt. with normal
baseline QT intervals in whom AZT had
arrhytamia-related adverse cardiac
effects
QT prolongation
Torsades de pointes
polymorphic ventricular tachycardia

ALLPPT.com _ Free Powerpoint Templates, Diagrams and Charts

OBJECTIVE &RESEARCH QUESION

To assess the knowledge of patients who

took Azithromycin as compared with persons
who did not take Antibiotic and with patients
who took other selected Antibiotic, have an
increased risk of cardiovascular death,
particularly sudden cardiac death.

THEERASIN YOMA

RESEARCH METHODOLODY

Study Type

Retrospective Study , Non-Randomized

Comparison Gr.
: Cohort Study

Data Source

Persons enrolled in Tennessee Medicaid

Program ; Medicaid pharmacy files

Duration

Patients who had been prescribed

Azithromycin
between 1992 through 2006 (14 years)
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RESEARCH METHODOLODY(con.)
Study Design

Screen prescribed cohort of persons

enrolled in Tennessee Medicaid
Computerized Medicaid Data

Matched control periods & Frequency matched

propensity score

Azithromycin
(347,795)

Control

VS

No ATB
(1,391,180)

Others ATB
Amoxy
(1,348,672)

(264,626)
THEERASIN YOMA

(193,906)

Ciproflox
.
Levoflox.

RESEARCH METHODOLODY(con.)

Retrospective: Computerized Medicaid Data

control propensity score
AZT VS NO ATB & other ATB

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RESEARCH METHODOLODY(con.)

InCLUSION CRITERIA

Eligibility

30 74 years of age
No life- threatening non-cardiovascular
Had Not Received a diagnosis of drug abuse
Had Not Resided in Nursing Home in last year
Had not been hospitalized in the prior 30 day
Required at least 365 days at Medical enrollment
Regular use of Medical care
** Control (No ATB) add :Could not have uses any
study ATB During the period 30 Days.
ALLPPT.com _ Free Powerpoint Templates, Diagrams and Charts

RESEARCH METHODOLODY(con.)

ExCLUSION CRITERIA

Eligibility

Persons at high risk for death from causes

unrelated to a
short term effect of proarrhythmic medication

RESEARCH METHODOLODY(con.)
Study End Points The primary study End points
were Cardiovascular Death
and Dearth from any cause

Means of the
product-limit
method

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STATISTIC ANALYSIS

Cox
regression
models; HR
Relative risk

Poisson
regression
model
Risk score
for CVD

All analyses with SAS software, Ver.3.9

All Report P values are 2-side

RESULTS

Cumulative incidence of Death among Patients during 5-Day Cou

rse of Azithromycin, as Compared with Persons Who Received N
o ATB Treatment and Pt. who took Amoxicillin, According to C
ause of Death

Sig.
No sig.

Sig.
No sig.

Sig.
No sig.

No sig.
No sig.

No sig.

Sig.

Cumulative Incidence of Cardiovascular Death and Death from

RESULTS Any Cause among Patients Who Took Azithromycin and Persons
(Con).
Who Did Not Take Study Antibiotics during a 10-Day Period.
Sig.
v
Sig.

Sig.

No.Sig. Sig.

Sig.

No.Sig.
No.Sig.

Cumulative Incidence of Cardiovascular Death and Death from

RESULTS Any Cause among Patients Who Took Azithromycin and Persons
Who Did Not Take Study Antibiotics during a 10-Day Period.
Sig.
v
Sig.

No.Sig.

Cumulative Incidence of Cardiovascular Death

RESULTS and Death from Any Cause for Patients Who Took
Azithromycin or Amoxicillin during a 10-Day Period
Sig.

Sig.

No.Sig.

RESULTS

Cumulative Incidence of Cardiovascular Death

and Death from Any Cause for Patients Who Took
Azithromycin or Amoxicillin during a 10-Day Period
Sig.

Sig.

No.Sig.

RESULTS
Excess Risk of Cardiovascular Death with Azithromycin as Compare
d with Amoxicillin, According to Decile of Cardiovascular Risk Score
.
59%
245 (63-576)

DISCUSSION
Limitations of study

Retrospective study
Matched control periods & Frequency
matched propensity score

Prospective study

CONCLUSION
During 5 days of azithromycin therapy, there was a small
absolute increase in cardiovascular deaths.
As compared with amoxicillin, there were 47 additional
Cardiovascular deaths per 1 million courses of Azithromycin
therapy; for patients in the highest decline of base line risk
of cardiovascular disease, there were 245 additional cardiov
ascular deaths per 1 million

FAD: Safety Announcement

WARNINGS!!!

THEERASIN YOMA

01148601 seminar

Cardiovascular Events and Safety

Outcomes Associated with Azithromycin
Therapy: A Meta-Analysis of Randomized
Controlled Trials

Ziyad S. Almalki, BPharm, PhD student; Je

ff Jianfei Guo, BPharm, PhD

Am Health Drug Benefits.

2014;7(6):318-328

Presentor
Mr. THEERASIN YOMA
54191014

School of Pharmacy; Eastern Asia University

RESEARCH METHODOLODY :METHODS

A meta-analysis
1990 through September 2013.
Identify relevant randomized clinical trials
PT: the risk for CV events : treat. azithromycin therapy or
placebo in Pt. infection or for the secondary prevention
of coronary events.

1 End points: mortality, hospitalization, and coronary i

ntervention

No heterogeneity was observed (I2 = 0%)

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RESEARCH METHODOLODY :METHODS

Flow Diagram of the Articles Reviewed

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CONCLUSION
The findings in this meta-analysis indicate that there
is no increased risk for mortality or for CV events with
the use of azithromycin therapy among patients enrolled
in the treatment or prevention clinical trials included in
this analysis.
Future research considerations are warranted
to study a larger number of patients with preexisting
bacterial infection and CV risk factors, and longer followup duration of trials is needed to detect any potential
long-term negative or positive effects, including CV effects,
of azithromycin therapy
THEERASIN YOMA

RESULTS
Selected Randomized Clinical Trials with Azithromycin Therapy

RESULTS

Effect of Azithromycin Treatment on Total Mortality

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RESULTS

Effect of Antibiotic Treatment on Hospitalization rate

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RESULTS

Effect of Antibiotic Treatment on Coronary Intervention rate

THEERASIN YOMA

01148601 seminar; 18/03/15

Azithromycin an increased

Presenter : Mr. THEERASIN YOMA ID .54191014

Risk CV Death ?

School of Pharmacy; Eastern Asia University

CONCLUSION

Review of Research and case report Azithromycin. it was

found that azithromycin increased the risk of fatal arrhythm
ias, specifically QT Prolongation and TdP, especially patients
Cardiovascular risk factors. affect increased Risk CV Death
although the risk was a small but as a pharmacist It should
antibiotic smart use in patients for decrease risk CV death
and drug resistant. Consider of Indication, Safety, Efficacy,
Cost

THEERASIN YOMA

Acknowledgement

PATSIYAKUN KANITNOI

Adviser

ANAN UDOMBHORNPRABHA

THEERASIN YOMA

Thank You For Attention

THEERASIN YOMA

THEERASIN YOMA