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Can Spontaneous Adverse Event Reporting Systems Really Be Used to Compare Rates of Adverse Events Between Drugs?

2007; Lippincott Williams & Wilkins; Volume: 104; Issue: 2 Linguagem: Inglês

10.1213/01.ane.0000253671.90500.0b

1526-7598

Paul‐Michel Mertès, Anne Berit Guttormsen, T. Harboe, S. G. O. Johansson, Erik Florvaag, B. Husum, Lene H. Garvey, Morgens Kroigaard, Lars Gramstad, Kristin Thorseng Kvande, P. Tréchot, J. M. Malinovsky,

Pharmacovigilance and Adverse Drug Reactions

To the Editor: Bhaneker et al. (1) use the system of spontaneous reporting of adverse drug events in the United States (US) to state that the two neuromuscular blocking drugs (NMBDs), vecuronium and rocuronium, have the same potential to cause anaphylaxis. Part of the incentive to do the study was the concern raised by the frequent incidence of anaphylactic reactions to NMBDs in France (1 in 6500 anesthetics) (2) and in Norway (1 in 5200 anesthetics) (3). The authors challenged this view based on two different arguments. The first argument concerned the reliability of skin tests. However, results questioning the diagnostic value of skin tests have been derived from studies of healthy subjects and not selected patients with a history of anaphylaxis in connection with surgery and anesthesia. This is of critical importance when considering the performance of diagnostic tests. Indeed, the positive predictive value depends not only on its sensitivity and specificity, but also on the prevalence of the disease in the study population (4). In Europe, investigations are performed in highly selected patients presenting an immediate hypersensitive reaction within minutes of a drug injection, associated with increased serum tryptase levels confirming mast cell activation (5). The second argument referred to the incidence of reactions to NMBDs in Denmark which is very low (6). However, the results from Denmark were achieved by skin testing in the same manner as in France and Norway, and a tendency of false-positive NMBD skin tests can thus not be used to explain the difference between the two countries. In all surveys of anaphylaxis to NMBDs, succinylcholine was considered the major culprit (2,7–9). In some reports involving rocuronium, the frequency of allergic reactions has been assumed to reflect its market share (10), while other studies indicate succinylcholine and rocuronium to be prominent inducers of anaphylaxis (9,11,12). Regrettably, Bhananker et al. did not provide additional information concerning the remaining depolarizing and nondepolarizing NMBDs currently in use in the US, especially since they suggest possible differences in the use of NMBDs for tracheal intubation or intraoperative muscle relaxation maintenance between the US and other countries. In 2000, after receiving frequent reports of anaphylaxis during general anesthesia with rocuronium, the Norwegian Medicines Agency recommended that rocuronium should not be used routinely, but rather only with a positive indication. At that time, approximately 150,000 patients had received rocuronium over a period of 2.5 yr during which 29 reports of anaphylaxis in patients treated with rocuronium were received. Only four cases of anaphylaxis were reported in patients receiving other intermediate-acting NMBDs (approximately 130,000 patients exposed to vecuronium, atracurium, or cisatracurium) during the same period. In 2003 a Norwegian expert review reached the opinion that there was insufficient evidence to prove a higher probability of anaphylaxis with rocuronium than with other NMBDs. A prospective monitoring plan to assess whether there was a true increased incidence was proposed, but could not be achieved because of the low market share of rocuronium in Norway. The surveillance and analysis of adverse drug reactions represent a statistical challenge, because these reactions are rare, random, and mostly independent from the successive exposure of patients to a low-risk intervention. Because of possible biases and under-reporting, spontaneous reporting systems are considered inappropriate for the assessment of adverse drug reaction rates, or differences in incidence rates (13). In France, members from the governmental spontaneous adverse events reporting system stated that only 8% of the allergic reactions to an anesthetic drug, identified by the French allergo-anesthesia network (GERAP), were reported to their spontaneous reporting system (14). Another weakness of self-reporting is that responsible anesthesiologists seem to have little understanding of which of several drugs simultaneously administered during induction of anesthesia is actually causing the anaphylactic reaction (15). Because of these concerns, we believe it is inappropriate to use the Food and Drug Administration Adverse Event Reporting System to compare the anaphylactic potential of different NMBDs, and even more so to make comparisons among countries. We do not know the present incidence of anaphylactic reactions during anesthesia in the US, but there are differences among countries. These differences have offered insights into the mechanisms of sensitization to NMBDs (16). We promote the creation of specialized diagnostic centers and international networks to investigate hypersensitivity reactions in a standardized manner, thereby increasing our knowledge of their mechanisms and epidemiology. Paul M. Mertes, MD, PhD Service d’Anesthésie-Réanimation Chirurgicale Hôpital Central, CHU de Nancy Nancy, France [email protected] Anne B. Guttormsen, MD, PhD, DEAA, EDIC Torkel Harboe, MD Department of Anesthesia and Intensive Care Haukeland University Hospital Bergen, Norway S. Gunnar O. Johansson, MD, PhD Department of Medicine Clinical Immunology and Allergy Unit Karolinska University Hospital Stockholm, Sweden Erik Florvaag, MD, PhD Department of Occupational Medicine Laboratory of Clinical Biochemistry and Section for Clinical Allergology Haukeland University Hospital Bergen, Norway Bent Husum, MD Lene H. Garvey, MD Morgens Kroigaard, MD Department 4231 Danish Anaesthesia Allergy Centre Rigshospitalet, Denmark Lars Gramstad, DMSc Kristin T. Kvande, MSc Pharm Norwegian Medicines Agency Oslo, Norway Philippe Trechot, MD, PhD Centre de Pharmacovigilance de Nancy Hôpital Central CHU de Nancy Nancy, France Jean M. Malinovsky, MD, PhD Département d’Anesthésie–Réanimation CHU Reims Hopital Maison Blanche Reims, France