Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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NSAID's including Diclofenac?
- Nathan P. Gottehrer (6 July 2003)
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Overall safety profile of nimesulide
- Bernard G Bannwarth (15 July 2003)
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LIVER INJURY ASSOCIATED WITH NIMESULIDE: IS IT A TRULY NEGLIGIBLE EVENT?
- Ezio Degli Esposti, Stefano Liverani, executive director, Local Health Authority of Ravenna; Alessandro Capone, Clicon S.r.l., Health, Economics, and Outcomes Research Ravenna; Pierluigi Russo, Department of Human Physiol. and Pharmacol. University of Rome La Sapienza (16 July 2003)
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How small risk ratios may have strong public health impact. The case of nimesulide
- Alfonso Carvajal, Miguel Angel Maciá; Javier García del Pozo; Francisco de Abajo; Dolores Montero; Fernando de Andrés (25 July 2003)
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Authors reply
- Giuseppe Traversa, Clara Bianchi, Roberto Da Cas, Iosief Abraha, Francesca Menniti-Ippolito, Mauro Venegoni (15 August 2003)
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Nathan P. Gottehrer, internal medicine health services fund
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Dear Sir I can not retrieve which NSAID's was implicated in the study. I would like to how many out of all prescription were Diclofenac. This drug was involved in many case of hepatitis, in large number of publication. Competing interests: None declared |
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Bernard G Bannwarth, Professor of therapeutics University Victor Segalen, 33076 Bordeaux, France
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Sir, In a retrospective cohort and nested case-control study, Traversa et al(1) compared the incidence of acute hepatotoxicity associated with nimesulide and certain other non-steroidal anti-inflammatory drugs (NSAIDs). They concluded that the risk of liver injury in patients taking nimesulide was small, albeit slightly higher than for other NSAIDs. In fact, the risk of all hepatopathies among current users of nimesulide was comparable to that for other NSAIDs (rate ratio 1.3, 95% confidence interval 0.7 to 2.3). However, this rate ratio was 1.9 (1.1 to 3.8) when only more severe diagnoses of liver injury were included in the analysis(1). In other words, the severity of acute hepatic injury rather than its frequency appeared to be increased in patients receiving nimesulide in comparison with those receiving other NSAIDs. Based on spontaneous reports to the Spanish Pharmacovigilance System (2) and the World Health Organization (3), nimesulide was also found to induce a high proportion of severe hepatic adverse reactions compared with other NSAIDs. This may explain why nimesulide was removed from the market in some countries. Since no fulminant hepatitis was observed in their study, the authors speculated that some of the spontaneously reported cases of fulminant hepatitis attributed to NSAIDs were linked to concomitant conditions that would lead to exclusions in epidemiological studies (1). In some cases, however, a causal relationship between the occurrence of fulminant hepatitis and nimesulide use was very likely (3,4). Finally, the authors underlined the need to evaluate the overall risk profile of NSAIDs, particularly the risk of serious gastrointestinal complications (1). In this respect, nimesulide does not offer any advantage over conventional NSAIDs such as diclofenac, ibuprofen or naproxen (5). In summary, nimesulide should not be considered as an NSAID of first choice. 1 Traversa G,Bianchi C,Da Cas R,Abraha I,Minneti-Ippolito F,Venegoni M. Cohort study of hepatotoxicity associated with nimesulide and other non -steroidal anti-inflammatory drugs. BMJ 2003;327:18-22. 2 Macia MA,Carvajal A,Garcia del Pozo J,Vera E,del Pino A. Hepatotoxicity associated with nimesulide: data from the Spanish Pharmacovigilance System. Clin Pharmacol Ther 2002; 72:596-7. 3 Merlani G,Fox M,Oehen HP,Cathomas G,Renner EL,Fattinger K, et al. Fatal hepatotoxicity to nimesulide. Eur J Clin Pharmacol 2001;57:321-6. 4 Dumortier J,Borel I,Delafosse B,Vial T,Scoazec JY, Boillot O. Transplantation hépatique pour hépatite subfulminante après prise de nimésulide. Gastroenterol Clin Biol 2002;26:415-6. 5 Garcia Rodriguez LA,Cattaruzzi C,Troncon MG,Agostinis L. Risk of hospitalization for upper gastrointestinal tract bleeding associated with ketorolac, other nonsteroidal anti-inflammatory drugs, calcium antagonists, and other antihypertensive drugs. Arch Intern Med 1998;158:33 -9. Competing interests: None declared |
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Ezio Degli Esposti, deputy head of department Clinical Effectiveness Unit, Local Health Authority of Ravenna, Via De Gasperi 8-48100 Ravenna Italy, Stefano Liverani, executive director, Local Health Authority of Ravenna; Alessandro Capone, Clicon S.r.l., Health, Economics, and Outcomes Research Ravenna; Pierluigi Russo, Department of Human Physiol. and Pharmacol. University of Rome La Sapienza
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Editor - The article by Traversa et al. provided an interesting
estimation of the risk of acute hepatotoxicity associated with nimesulide in
comparison with other non-steroidal anti-inflammatory drugs (NSAIDs).1
Overall, the risk for all hepatopathies in patients exposed to nimesulide was
small and not significantly higher than that of other NSAIDs, with the
exception relating to more severe liver injuries. We are currently performing a similar cohort study on the entire
population listed in the Local Health Unit (LHU) of Ravenna by cross-linking
information stored in different databases on a patient-by-patient basis. The
analysis of all prescriptions for nimesulide or other NSAIDs registered in the
pharmaceutical database in the period between January 1st 1997 and
August 31th 2002 (with an observation period of 5.7 years) generated
three different cohorts: patients exposed to nimesulide (n=45,884), those
exposed to other NSAIDs (n=113,316), and the control group of those never
exposed to any NSAID (n=239,513). In each patient of each cohort, on the basis
of the personal health number, from the nosocomial database have been retrieved
all hospital admissions for liver injury through the following ICD-9 codes:
570, 573.3, 573.8, 573.9. A total number of 587 patients hospitalised for liver
injury has been classified as eligible for analyses. The frequency of
hospitalisation in each cohort is reported in table 1.
*z-test A significantly higher frequency of liver injury has been observed among
patients exposed to nimesulide either compared to that of patients treated with
NSAIDs or that of population who never received any NSAID. Interestingly, no
significantly difference was found between patients exposed to other NSAIDs and
population never exposed. Based on the registered frequencies, two
epidemiological measures of impact relating to nimesulide were calculated: the
population attributable risk (PAR) and the attributable risk percentage (ARP).2
The PAR, that considers the proportion of cases of liver injury in the entire
population which can be attributed to the exposure to nimesulide, corresponded
to 4%. Furthermore the ARP, that considers in the exposed group the proportion
of cases which can be attributed to the exposure itself accounted for 19.5%. Contrary to the study by Traversa et al.,1 the chosen
approach to cross-link different databases on a patient-by-patient basis gave
the advantage to measure the actual epidemiological impact concerning liver
injuries attributable to an exposure to nimesulide. Data we evaluated provide
an indication suggesting that liver injury might be not an infrequent
experience and raise some important questions about the real risk of
hepatotoxicity associated with an exposure to nimesulide. This adverse event
surely deserves more attention, also considering the mean cost of 3,5 thousand
euros per patient per event, incurred by the LHU of Ravenna, which was
calculated on a fixed value (the DRG’s tariff) including large part of
hospitalisation expenses exclusively. References1 – Traversa G, Bianchi C, Da Cas R, Abraha I, Menniti-Ippolito F,
Venegoni M. Cohort study of hepatotoxicity associated with nimesulide and other
non-steroidal anti-inflammatory drugs. BMJ
2003;327:18-22 2 – Szklo M, Nieto FJ. Epidemiology: beyond the basics. Gaithersburg,
Maryland: AN Aspen Publication, 2000 Competing interests: None declared |
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Alfonso Carvajal, Professor of Pharmacology Institute of Pharmacoepidemiology; University of Valladolid; 47005 Valladolid (Spain), Miguel Angel Maciá; Javier García del Pozo; Francisco de Abajo; Dolores Montero; Fernando de Andrés
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Dear Editor, We are writing in response to the article by Traversa et al. assessing the hepatic damage associated with nimesulide and other non- steroidal anti-inflammatory drugs (NSAIDs) recently published in your journal (1); the article presents a study in which the risks were estimated in a retrospective cohort of users of such drugs in the region of Umbria (Italy). The main stated conclusion of this study is that the risk of liver injury in patients taking nimesulide and other NSAIDs is small. This may be so but the results also confirm that the risk is higher for nimesulide. We have recently published some estimates with data from the Spanish Pharmacovigilance System reaching a conclusion that clearly differs from that of these authors (2) and would like to specifically comment on some aspects of the study as well as discuss how small risk ratios may have strong public health impact: 1. It is at least arguable that with a rate ratio of 1.9 (95% CI, 1.1 -3.8) for the more severe hepatic injuries –when compared to the rest of NSAIDs– nimesulide is still regarded as having a small risk. Furthermore, since the drug is in widespread used in Italy, the population attributable risk could account for a considerable number of cases that could be avoided: 25 millions of prescriptions of nimesulide were issued in 2001, corresponding to 18 DDDs per 1000 inhabitants per day (3). With the rate figures from this study (more severe liver injury: nimesulide, 29.0 per 100 000 person-years; other non-steroidal non-antiinflammatory drugs, 15.6 per 100 000 person-years) and the above figures of consumption, around 140 cases of severe liver injury could be expected to appear in excess with nimesulide in one year in Italy. 2. Based on the numbers of packets per prescription, it is assumed that the characteristics of users of the different non-steroidal anti- inflammatory drugs were similar. If, rather than the number of packets, the number of DDDs per person had been taken –a more reliable approach–, the conclusion would have been different since the mean number of DDDs per user of nimesulide and NSAIDs were in fact 50.9 and 73.2, respectively. This does mean that these drugs are being used in a different manner, nimesulide being used for shorter periods or, unlikely, in smaller doses. Also, the number of prescriptions per user was different: nimesulide accounted for 2.9 and NSAIDs for 4.1 (not 2.2 as presented in table 1; also the number of prescriptions per user when considering “any NSAID” is not 2.4 as stated but 4.9). 3. An acute pattern of use of nimesulide when compared to the other NSAIDs has been consistently observed in Italy. It was described for the first time by the same authors with information coming from the same database although in the period 1993-1994 (4); then it was concluded that nimesulide was “used mainly in the symptomatic treatment of milder conditions (e.g., fever and upper respiratory infections) and the duration of use is shorter”. Recently, with data from the same database and for the period June 2000-July 2001, a similar pattern was found: most of the patients received nimesulide for shorter periods or in small amounts: 92.7% of nimesulide versus 54.1% of other NSAIDs users had less than 15 DDDs (3). 4. Time of exposure is an important feature for some types of hepatotoxicity to appear. A substantial proportion of nimesulide-induced hepatotoxicity occurred after relatively long time of exposure. In Spain, 5 out of the 11 most severe cases of hepatotoxicity related to nimesulide appeared following more than 1 month of treatment; the average duration until occurrence in a series of 13 published cases of severe hepatotoxicity was 62 days (5). As the use in Spain for nimesulide was mostly as an anti-inflammatory for chronic conditions and longer periods, hepatotoxicity was more likely to appear. Noteworthy, the study by Traversa et al (1) based on a particular pattern of use, may have missed the most severe cases appearing after longer treatment periods. In conclusión, the epidemiological study by Traversa et al (1) have shown that nimesulide has an increased risk of acute liver injury, in particular for the most severe cases, as compared to other NSAIDs, confirming the signal raised by the spontaneous reporting systems of Spain and Finland. Probably, the way the drug is being used in Italy –in shorter periods of time– precludes to some extent the occurrence of a number of cases –also the publicity given to this particular association has refrained many doctors from using the drug in those prone to develop hepatic damage. Notwithstanding, widespread use could account for an excess of this type of reactions. On the other hand, nimesulide does not appear to have any demonstrated advantage over the most widely used NSAIDs either in efficacy or safety. Regarding upper gastrointestinal complications, it has been shown by García-Rodríguez et al in a case- control study performed in Italy (nimesulide OR=4.4; 95% CI: 2.5-7.7; ibuprofen, OR=2.1; 0.6-7.1; diclofenac, OR=2.7, 1.5-4.8) (6). Bearing all this in mind, our opinion is that the comparative benefit-risk balance of nimesulide is very questionable and we would discourage its generalized use. Alfonso Carvajal
Miguel Angel Maciá
Javier García del Pozo*
* Spanish Medicines Agency, Madrid (Spain) References 1. Traversa G, Bianchi C, Da Cas R, Abraha I, Minneti-Ippolito F, Venegoni M. Cohort study of hepatotoxicity associated with nimesulide and other non -steroidal anti-inflammatory drugs. BMJ 2003;327:18-22. 2. Macia MA, Carvajal A, Garcia del Pozo J, Vera E, del Pino A. Hepatotoxicity associated with nimesulide: data from the Spanish Pharmacovigilance System. Clin Pharmacol Ther 2002; 72:596-7. 3.http://www.ministerosalute.it/medicinali/resources/documenti/note_informative/rapporto.PDF 4. Menniti-Ippolito F, Maggini M, Raschetti, Da Cas R, Traversa G, Walker AM. Ketorolac use in outpatients and gastrointestinal hospitalization: a comparison with other non-steroidal anti-inflammatory drugs in Italy. Eur J Clin Pharmacol 1998; 54: 393-7. 5. Merlani G, Fox M, Oehen HP, Cathomas G, Renner EL, Fattinger K, Schneemann M, Kullak-Ublick GA. Fatal hepatoxicity secondary to nimesulide Eur J Clin Pharmacol 2001; 57: 321-6. 6. García Rodríguez LA, Cattaruzz C, Troncon MG, Agostinis L. Risk of hospitalization for upper gastrointestinal tract bleeding associated with ketorolac, other nonsteroidal anti-inflammatory drugs, calcium antagonists, and other antihypertensive drugs. Arch Intern Med 1998;158: 33-39. Competing interests: None declared |
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Giuseppe Traversa, Senior epidemiologist Dept. of Epidemiology, Istituto Superiore di Sanità, Rome, Italy, Clara Bianchi, Roberto Da Cas, Iosief Abraha, Francesca Menniti-Ippolito, Mauro Venegoni
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In the conclusion of his letter, prof. Bannwarth affirms that “nimesulide should not be considered as an NSAID of first choice” and that, with regard to serious gastrointestinal complications, it “does not offer any advantage over conventional NSAIDs such as diclofenac, ibuprofen, or naproxen” (1). We entirely share the widely accepted view that ibuprofen, diclofenac, and naproxen, should be considered as first choice NSAIDs: these substances have been studied in a large number of efficacy trials, and represent the reference NSAIDs for the study of gastroduodenal toxicity, the main adverse reaction associated with NSAID use. When we planned our study, at the end of the summer 2002, the discussion did not concern the selection of first choice NSAIDs. We were facing the signal of a greater hepatotoxicity associated to nimesulide use, which had brought to suspending the marketing of the drug in Finland and later in Spain. Despite the fact that the signal was not confirmed in Italy, it was imperative to conduct further analyses since nimesulide was the most frequently prescribed NSAID in Italy. The overall conclusions of our study suggested that the increase in the risk of liver damage associated to NSAID use was low (rate ratio, RR, 1.4; 95% confidence intervals 0.9 to 2.1) (2). In comparison with other NSAIDs the increase associated to the use of nimesulide ranged from 1.3 (0.7 to 2.3) when all hepatopathies were included in the analysis, to 1.7 (0.9 to 3.3) when the analysis was restricted to liver injuries, to 1.9 (1.1 to 3.8) when applying a further restriction to more serious forms of liver injury. Dr. Degli Esposti and colleagues presented some preliminary findings of a cohort study which is currently performed in Ravenna (Italy) (3). It is suggested that their data “raise some important questions about the real risk of hepatotoxicity associated with an exposure to nimesulide”. For the time being, from the table presented we can derive a relative risk of liver injury of 1.3 (for nimesulide in comparison with other NSAIDs), which coincides with the lowest estimate provided in our study. The publication of the study will allow to understand in more detail both methods and findings, and may provide a further contribution to the current discussion on NSAIDs hepatotoxicity. Most of the comments by prof. Carvajal and colleagues concern the interpretation of our findings (4). A main objection relates to a supposedly shorter duration of use of nimesulide in comparison with other NSAIDs. In Table 1 of our article was indicated that the number of packages per prescription was similar for nimesulide and for other NSAIDs (1.2 and 1.3 respectively). Prof. Carvajal et al. recalculated the number of DDDs and of prescriptions per user. We are sorry that, due to insufficient information reported in Table 1, we may have induced an incorrect calculation. To clarify the discrepancy (and to answer dr. Gottehrer’s question (5) regarding diclofenac) we provide some prescription details relevant to the three most prescribed NSAIDs (other than nimesulide), which represent 47.7% of the overall prescriptions. During the 5 year period, users of diclofenac (464,979 prescriptions and 6,487,494 DDDs), ketoprofen (249,030 prescriptions and 3,445,572 DDDs), and piroxicam (216,177 prescriptions and 4,801,941 DDDs) received a number of prescriptions per user (2.6, 2.0, and 2.1, respectively) and DDDs per user (36.0, 28.3, and 46.8, respectively) which were even lower than for nimesulide (6). In Table 1 of our article (2), the number of users referred to individuals who received one or more NSAIDs (if a user received different NSAIDs he/she contributed only once to the number of users), whereas in the calculation of prescriptions per user he/she contributed as many times as the number of different NSAIDs. As a consequence, a user of any NSAID received 4.9 prescriptions during the study period, though the average number of prescriptions per user of each single NSAID was 2.4 (2.2 for the category “other NSAIDs”; Table 1, reference 2). Similarly, no discrepancy is present in a pilot analysis we conducted on the use of nimesulide (7), where in one of the nine tables is indicated that 92.7% of incident users appear to have received prescriptions of nimesulide for up to 15 days (versus 54.1 for the other NSAIDs). This is not surprising when considering that basically all the packages available in Italy have the same duration, namely 15 days (Appendix ref. 7). Had we put the cut off at 14 days, we would have found that no user of nimesulide, and 48% for the other NSAISDs, had received prescriptions for up to two weeks. It is obviously a matter of speculation whether a greater hepatotoxicity would have been estimated, had the actual pattern of use of nimesulide been consistently longer than the one observed. We would also discard the possibility that “the publicity given to this particular association has refrained many doctors from using the drug [nimesulide] in those prone to develop hepatic damage” (4). On the one hand, our exclusion criteria should have already removed the population of patients at higher risk of liver damage. On the other hand, a crude indication of the concomitant clinical conditions which affected users of different NSAIDs can be derived from the proportion of concomitant prescriptions (on the same day of the NSAID prescription) of any other drug (different from NSAIDs and gastroprotective agents). During the 5 year period the prescriptions of other drugs associated to NSAIDs were greater for nimesulide (46.6% of the prescriptions) than for other NSAIDs (40.2% of the prescriptions) (6). Prof. Carvajal and colleagues express their doubts that the highest risk estimate we provided might be regarded as a small increase in the risk. We understand their concern. What we propose for the present and future discussions is to adopt a coherent view for safety assessment of all NSAIDs. It is well known that the main adverse events associated to NSAID use is represented by gastroduodenal lesions. Even limiting the analysis to the most severe ones (haemorrhages and perforations), which carry a distinct risk of death, it has been estimated that around 400 events per 100,000 persons per year are expected among NSAID users (assuming a relative risk of 4), with around 300 extra cases per 100,000 persons per year (8). Is there any reason to accept for severe gastroduodenal lesions, whose incidence among users of NSAIDs may even be 10 times higher than liver damages, differences in the relative risk far greater than the ones described in our study? To answer this question let us focus, as an example, on the study mentioned by prof. Carvajal and colleagues, which concerns the risk of gastrointestinal bleeding associated with different NSAIDs. We deem of interest to mention, in addition to the odds ratios already reported (for ibuprofen, diclofenac, and nimesulide), that a level of risk similar to nimesulide was observed for naproxen (OR 4.3; 1.6 to 11.2) and tenoxicam (OR 4.3; 1.9 to 9.7), whereas higher risks were relevant to piroxicam (OR 9.5; 6.5 to 13.8) and ketorolac (OR 24.7; 9.6 to 63.5) (9). Similar levels of variability have been observed in many other studies concerning gastroduodenal adverse events associated to NSAID use. In comparison with these wide ranges of estimates, we believe that the differences between nimesulide and other NSAIDs in the risk of hepatic events can be regarded as limited. It is also limited the difference among individual NSAIDs: in comparison with non use, we estimated a rate ratio of liver injury of 2.2 (1.3 to 3.9) among users of nimesulide and 1.5 (0.7 to 3.2) among users of diclofenac, the second most prescribed NSAIDs. We are aware of a risk: the use of highly gastrotoxic NSAIDs does not justify the prescription of substances whose safety profile may be considered poorer for other organs. Nonetheless, it would not be wise to support regulatory actions based on rarer adverse events combined with lower risk differences. Until an overall revision of NSAIDs as a class is carried out, though, other interventions are possible. The overall available evidence already provides a large amount of information to encourage a cautious use of NSAIDs, and to promote the prescription of safer NSAIDs in everyday practice. G. Traversa(1), C. Bianchi(1), R. Da Cas(1), I. Abraha(2), F. Menniti -Ippolito(1), and M. Venegoni(3) (1) Dept. of Epidemiology, Istituto Superiore di Sanità, Rome, Italy. (2) Regional Health Authority of the Umbria Region, Perugia, Italy. (3) Dept. of Internal Medicine, Fatebenefratelli Hospital, Milano, Italy. References 1. Bannwarth BG. Overall safety profile of nimesulide. BMJ 327:18-22, rapid response. 2. Traversa G, Bianchi C, Da Cas R, Abraha I, Menniti-Ippolito F, Venegoni M. Cohort study of hepatotoxicity associated with nimesulide and other non-steroidal anti-inflammatory drugs. BMJ 2003;327:18-22. 3. Degli Esposti E, Liverani S, Capone A, Russo P. Liver injury associated to nimesulide: is it a truly negligible event? BMJ 327:18-22, rapid response. 4. Carvajal A, Maciá MA, García del Pozo J, de Abajo F, Montero D, de Andrés-Trelles F. How small risk ratios may have strong public health impact. BMJ 327:18-22, rapid response. 5. Gottehrer NP. NSAIDs including diclofenac? BMJ 327:18-22, rapid response. 6. Traversa G, Bianchi C, Da Cas R, Abraha I, Menniti-Ippolito F, Venegoni M. Nimesulide-associated hepatotoxicity. Epidemiological study in the Umbria region. Report to the CPMP, May 2003. 7. Traversa G, Bianchi C, Da Cas R, Maggini M. Rapporto sull’uso della nimesulide in Italia. http://www.ministerosalute.it/medicinali/resources/documenti/note_informative/rapporto.pdf 8. Hernandez-Diaz S, García-Rodríguez LA. Epidemiologic assessment of the safety of conventional nonsteroidal anti-inflammatory drugs. Am J Med 2001; 110: 20S-27S. 9. García-Rodríguez LA, Cattaruzzi C, Troncon MG, Agostinis L. Risk of hospitalisation for upper gastrointestinal tract bleeding associated with ketorolac, other non-steroidal antinflammatory drugs, calcium antagonists, and other antihypertensive drugs. Arch Intern Med 1998;158:33 -39. Competing interests: None declared |
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