due pesi, o nessun peso, per valutare i contributi

Lettere all’Editore
Medicina hard e medicina soft:
due pesi, o nessun peso, per valutare i contributi
(Ann Ital Med Int 2003; 18: 117-118)
but it works well even in this setting7 and may have several advantages over more complex scoring systems. It is particularly appealing because it does not necessitate specific
training, minimizes the interference of confounding factors
and besides, the scores of probability can be easily and quickly determined even at the bedside.
We used the Naranjo scale to test the probability of a
causal role of ticlopidine and propafenone for the cases of
severe hepatitis reported by Varvello et al. and by La
Brocca in the same issue of the Annali8,9. The Naranjo
score was 4 in both cases described by Varvello et al. This
only indicates a likelihood that the adverse reaction involving the liver was indeed caused by ticlopidine. This confirms that other confounders, such as the chronic hepatitis C virus infection or concurrent treatment with other
drugs, were as important or even more important than the
use of ticlopidine to explain the liver dysfunction experienced by those patients. In contrast, we obtained a score
of 8 for the patient reported by La Brocca, which indicates
a high probability for propafenone-induced hepatotoxicity with no other factor confounding the attribution of
causality to this drug.
Scoring systems for drug-induced hepatotoxicity
To the Editor. We agree with Podda and Benetti1 that the
use of objective scores on validated scales may provide an
important tool for the diagnosis of drug-induced hepatotoxicity. However, we remain cautious and critical of the
conclusions of their editorial as the important question of
what scale should be referred to as the gold standard for use
in clinical practice has not been answered. The authors
emphasize the advantages of scoring systems, such as those
developed by the Council for International Organizations
for Medical Sciences2,3 and by Maria and Victorino4,5,
with the specific aim of attributing a probability score
when there is the suspect of an adverse drug reaction involving the liver. We believe that the importance and the practical utility of the adverse drug reaction probability scale
developed by Naranjo et al.6 in the early 80’s has been
neglected (Table I). In our Unit, we routinely rely on the
scores of the Naranjo scale when an adverse drug reaction
needs to be ruled out or confirmed. This, as soon as possible in the early steps of the process of clinical decision-making. This scoring system was not specifically designed to
be used in suspected cases of drug-induced hepatotoxicity
TABLE I. Naranjo adverse drug reaction probability scale.
Question
Yes
No
Do not know
Are there previous conclusive reports on this reaction?
Did the adverse event appear after the suspected drug was administered?
Did the adverse reaction improve when the drug was discontinued, or a specific antagonist was administered?
Did the adverse reaction reappear when the drug was readministered?
Are there alternative causes (other than the drug) that could themselves have caused the reaction?
Did the reaction reappear when a placebo was given?
Was the drug detected in the blood (or other fluids) in concentrations known to be toxic?
Was the reaction more severe when the dose was increased, or less severe when the dose was decreased?
Did the patient have a similar reaction to the same or similar drug in any previous exposure?
Was the adverse event confirmed by any objective evidence?
+1
+2
+1
+2
-1
-1
+1
+1
+1
+1
0
-1
0
-1
+2
+1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Scores > 9 indicate a high-probability that the adverse reaction was drug-induced; scores 5-8 indicate a probable relationship; scores 1-4 a possible relationship and scores ≤ 1 a doubtful relationship. See reference 6 for details.
117
Ann Ital Med Int Vol 18, N 2 Aprile-Giugno 2003
Our experience suggests that by carefully applying the
Naranjo scale to appropriate cases, the management of
patients with suspected adverse drug reactions, including
those involving the liver, may be highly improved.
proach offered by such scoring systems is the only ground
to assess the degree of probability of drug-induced liver
injury, as in drug development and post-marketing surveillance.
Our choice of the CIOMS scale2,3, which was specifically devised by an international expert panel to address
the issue of drug hepatotoxicity, is based on the available
literature. This method was compared with another specifically developed and validated clinical scale in a large
group of patients with suspected drug-induced liver disease4,5. Although we acknowledge the authors’ satisfaction with the Naranjo’s method on the basis of their clinical experience, there is no evidence that similar procedures were applied to the development of this scale.
As far as the 2 cases reported by Varvello et al.6 in this
Journal are concerned, we agree that the relationship
between liver injury and ticlopidine administration may
only be classified as possible. However, we re-emphasize that suspicion of an adverse drug reaction is better
than proof in the clinical setting. Ticlopidine can be withdrawn with minor harm or easily replaced with a similar
agent, but its sustained administration may potentially
lead to severely progressive liver damage.
Giuseppe Famularo, Giulio Cesare Nicotra
Dipartimento di Medicina Interna
Ospedale San Camillo di Roma
References
1. Podda M, Benetti A. Drug-induced hepatotoxicity. Ann Ital Med
Int 2002; 17: 213-4.
2. Benichou C. Criteria of drug-induced liver disorders. Report of
an International Consensus Meeting. J Hepatol 1990; 11: 272-6.
3. Danan G, Benichou C. Causality assessment of adverse reactions to drugs. -I A novel method based on the conclusions of international consensus meetings: application to drug-induced liver
injuries. J Clin Epidemiol 1993; 46: 1323-30.
4. Maria VA, Victorino RM. Development and validation of a clinical scale for the diagnosis of drug-induced hepatitis. Hepatology
1997; 26: 664-9.
5. Aithal PG, Day CP. The natural history of histologically proved
drug induced liver disease. Gut 1999; 44: 731-5.
6. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther
1981; 30: 239-45.
7. Famularo G, Bizzarri C, Federico M, Martiradonna C, Polchi S,
Nicotra GC. Eosinophilic hepatitis associated with cefonicid
therapy. Ann Pharmacother 2001; 35: 1669-71.
Mauro Podda, Alberto Benetti
Clinica Medica
Dipartimento di Medicina, Chirurgia e Odontoiatria
Università degli Studi, Polo San Paolo di Milano
8. Varvello L, Arnò C, Coggiola M, Ramassotto E, Pascale C.
Colestasi da ticlopidina: descrizione di due casi clinici. Ann Ital
Med Int 2002; 17: 252-5.
9. La Brocca A. Tossicità epatica da propafenone: descrizione di un
caso. Ann Ital Med Int 2002; 17: 261-4.
References
01. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating
the probability of adverse drug reactions. Clin Pharmacol Ther
1981; 30: 239-45.
Response. The letter by Famularo and Nicotra underscores the usefulness of objective methods to assess the
probability of drug hepatotoxicity.
The authors argue for the use of a method developed by
Naranjo et al.1 about two decades ago, on the basis of the
experience with their patients.
In our editorial, we contrasted the choices made in clinical practice, which need to be conservative for the safety of our patients, with those based on the application
of probability score systems. Probability scales should be
the reference to check the soundness of our judgments, but
are not the only determinants of our clinical decisions. On
the other hand, in the research setting the standardized ap-
02. Danan G, Benichou C. Causality assessment of adverse reactions
to drugs - I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver
injuries. J Clin Epidemiol 1993; 46: 1323-30.
03. Benichou C. Criteria of drug-induced liver disorders. Report of
an international consensus meeting. J Hepatol 1990; 11: 272-6.
04. Maria VA, Victorino RM. Development and validation of a clinical scale for the diagnosis of drug-induced hepatitis. Hepatology
1997; 26: 664-9.
05. Lucena MI, Camargo R, Andrade RJ, Perez-Sanchez CJ, Sanchez
De la Cuesta F. Comparison of two clinical scales for causality assessment in hepatotoxicity. Hepatology 2001; 33: 123-30.
06. Varvello L, Arnò C, Coggiola M, Ramassotto E, Pascale C.
Colestasi da ticlopidina: descrizione di due casi clinici. Ann Ital
Med Int 2002; 17: 252-5.
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