harm 1

CRITICAL APPRAISALEBM HARM I

KELOMPOK A13SPECIAL 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 cumulative dose of drug.

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

ARE THE RESULTS OF THIS HARM STUDY VALID ?

EBM Harm Worksheet - Validity

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 CompleteThere 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.

ARE THE VALID RESULTS OF THIS HARM STUDY IMPORTANT ?

EBM Harm Worksheet - Importance

CISPLATIN

Adverse Outcome

Totals

Present (Case) Absent (Control)

Exposed to The Treatment

Yes (Cohort) 38 60 98

No (Cohort) 4 53 57

42 113 155

CARBOPLATIN

Adverse Outcome

Totals

Present (Case) Absent (Control)

Exposed to The Treatment

Yes (Cohort) 10 28 38

No (Cohort) 4 53 57

14 81 95

OTOTOXIC ANTIBIOTICS

Adverse Outcome

Totals

Present (Case) Absent (Control)

Exposed to The Treatment

Yes (Cohort) 13 54 67

No (Cohort) 4 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 – 11.092OTOTOXIC ANTIBIOTICS = 0.955 – 8.009

SHOULD THESE VALID, POTENTIALLY IMPORTANT RESULTS CHANGE THE TREATMENT OF YOUR PATIENT?

EBM HARM WORKSHEET - APPLICABILITY

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 patient’s risks of the adverse event ?

Increased / Decreased Risk of Tinnitus

What are our patient’s preferences concerns and expectations from this

treatment ?

The risk of having tinnitus won’t 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!