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CRITICAL APPRAISAL

EBM HARM I
KELOMPOK A13
SPECIAL SENSES SYSTEM
2012

Tinnitus Onset Rates from


Chemotherapeutic Agents and
Ototoxic Antibiotics : Results of A
Large Prospective Study
Marilyn F. Dille, Dawn Konrad-Martin, Frederick
Gollun, Wendy J. Helt, Jane S. Gordon, Kelly M.
Reavist, Gene W. Bratt, Stephen A. Fausti

ABSTRACT
Background
To report on the incidence and relative risk of tinnitus
onset from a variety of drug therapies known to be
ototoxic.

Methods
A prospective observational study design was used to
evaluate occurrence of significant otologic changes in
488 veterans (962 ears) receiving chemotherapeutic
agents (cisplatin, carboplatin), ototoxic antibiotics
(primarily aminoglycoside), or non-ototoxic drugs
(control medications). Subjects were tested prior to,
during, and following their treatment. Planned
comparisons using logistic regression, analysis of
variance (ANOVA), and x2 statistics were made among
groups by the type of medication taken, age, presence
of pre-existing hearing loss, days on drug and

ABSTRACT
Results
Baseline tinnitus rates were high (nearly 47%)
relative to the general population of a similar age.
Subjects with exposure to ototoxic medications had
significantly increased risk for developing tinnitus.
Those on chemotherapeutic agents were found to
have the greatest risk. Cisplatin elevated the risk by
5.53 times, while carboplatin increased the risk by
3.75 over non-ototoxic control medications. Ototoxic
antibiotics resulted in borderline risk for new
tinnitus. There is no proofs that subject factors, or
treatment factors contributed to rates of tinnitus
onset during treatment.

ABSTRACT
Interpretation
This large prospective study confirms that new
tinnitus during treatment is associated with
chemotherapy and with certain ototoxic antibiotic
treatments. Cisplatin and carboplatin were found to
be the most potent ototoxic agents causing tinnitus
at much greater numbers than the other drugs
studied. Implications for counseling and
audiological resource allocation are discussed.

EBM HARM WORKSHEET


Validity Importance Applicability

EBM Harm Worksheet - Validity

ARE THE RESULTS OF THIS


HARM STUDY VALID ?

Was there clearly defined


groups of patients, similar in all
important ways other than
exposure to the treatment or
other cause?

Yes.

Were treatments/exposures
and clinical outcomes
measured in the same ways in
both groups ? (Was the
assessment of outcomes either
objective or blinded to
exposure ?
No.

Was follow-up of patients


sufficiently long and complete?

Short and Complete


There are tinnitus
questionnaires

DO THE RESULTS SATISFY SOME


DIAGNOSTIC TESTS FOR CAUSATION?

Is it clear that the exposure


preceded the onset of the
outcome ?

Yes.

DO THE RESULTS SATISFY SOME


DIAGNOSTIC TESTS FOR CAUSATION?

Is there a dose-response
gradient ?

No.

DO THE RESULTS SATISFY SOME


DIAGNOSTIC TESTS FOR CAUSATION?

Is there positive evidence from


a dechallenge-rechallenge
study ?

No.

DO THE RESULTS SATISFY SOME


DIAGNOSTIC TESTS FOR CAUSATION?

Is the association consistent


from study to study?

No

DO THE RESULTS SATISFY SOME


DIAGNOSTIC TESTS FOR CAUSATION?

Does the association make


biological sense?

No.

EBM Harm Worksheet - Importance

ARE THE VALID RESULTS


OF THIS HARM STUDY
IMPORTANT ?

Adverse Outcome
CISPLATIN

Exposed to
The
Treatment

Totals

Present
(Case)

Absent
(Control)

Yes
(Cohort)

38

60

98

No
(Cohort)

53

57

42

113

155

Adverse Outcome
CARBOPLATIN

Exposed to
The
Treatment

Totals

Present
(Case)

Absent
(Control)

Yes
(Cohort)

10

28

38

No
(Cohort)

53

57

14

81

95

Adverse Outcome
OTOTOXIC ANTIBIOTICS

Exposed to
The
Treatment

Totals

Present
(Case)

Absent
(Control)

Yes
(Cohort)

13

54

67

No
(Cohort)

53

57

17

107

124

What is the magnitude of the


association between the
exposure and outcome ?
CISPLATIN : RR = 6,0167 ; NNH
= 3 orang
CARBOPLATIN : RR = 3,75 ;
NNH = 5 orang
OTOTOXIC ANTIBIOTICS : RR =
2,77 ; NNH = 8 orang

How precise is the estimate of


the treatment effect ?

95% CI, RR dari :


CISPLATIN = 2.080 14.681
CARBOPLATIN = 1.268 11.092
OTOTOXIC ANTIBIOTICS = 0.955
8.009

EBM HARM WORKSHEET - APPLICABILITY

SHOULD THESE VALID, POTENTIALLY


IMPORTANT RESULTS CHANGE THE
TREATMENT OF YOUR PATIENT?

Do these results apply to our


patients ?
Yes.
Is our patient so different from
those in the study that its
results cannot apply ?
No.

What are our patients risks of


the adverse event ?

Increased / Decreased Risk of


Tinnitus

What are our patients


preferences concerns and
expectations from this
treatment ?

The risk of having tinnitus


wont be increased.

What alternative treatments are


available ?

Decreased the dosage of


cisplatin/carboplatin (as the
first line therapy of cancer) or
replaced the drug with another
drugs.

THANK YOU!