Evidence of Harm 1 EVIDENCE OF HARM – Presentation: Nashville, TN November 11, 2006 David Kirby.
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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.
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.
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 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.