1047 J Epidemiol Community Health: first published as 10.1136/jech.2003.013409 on 16 November 2004. Downloaded from RESEARCH REPORT Lipid lowering drugs prescription and the risk of peripheral neuropathy: an exploratory case-control study using automated databases Giovanni Corrao, Antonella Zambon, Lorenza Bertu`, Edoardo Botteri, Olivia Leoni, Paolo Contiero ............................................................................................................................... J Epidemiol Community Health 2004;58:1047–1051. doi: 10.1136/jech.2003.013409 Study objective: Although lipid lowering drugs are effective in preventing morbidity and mortality from cardiovascular events, the extent of their adverse effects is not clear. This study explored the association between prescription of lipid lowering drugs and the risk of peripheral neuropathy. Design: A population based case-control study was carried out by linkage of several automated databases. Setting: Resident population of a northern Italian Province aged 40 years or more. Participants: Cases were patients discharged for peripheral neuropathy in 1998–1999. For each case up See end of article for authors’ affiliations to 20 controls were randomly selected among those eligible. Altogether 2040 case patients and 36 041 ....................... controls were included in the study. Exposure ascertainment: Prescription drug database was used to assess exposure to lipid lowering drugs Correspondence to: Professor G Corrao, at any time in the one year period preceding the index date. Dipartimento di Statistica, Analysis: Conditional logistic regression model for matched data was used to estimate the risk of Universita`degli Studi di peripheral neuropathy associated with exposure to statins, fibrates, and other lipid lowering drugs. Milano-Bicocca, Via Main results: Weak but significant effects of lipid lowering drugs as a whole (matched odds ratio: 1.27; Bicocca degli Arcimboldi, 8, Edificio U7, 20126 95% confidence intervals: 1.05 to 1.55), statins (1.19; 1.00 to 1.40), and fibrates (1.49; 1.03 to 2.17) Milano, Italy; giovanni. were observed. Significant linear trends towards increased risk at increased exposure to both statins and [email protected] fibrates were observed. copyright. Accepted for publication Conclusions: The use of both statins and fibrates was associated with the risk of peripheral neuropathy. 22 March 2004 The primary purpose of this exploratory study is signal generation. This requires further investigations to ....................... evaluate the causal role of lipid lowering drugs on the onset of peripheral neuropathy. re-market trials of new drugs have well recognised limits Lombardia Region, between Milan and the Italian-Swiss both in sample’s size and in patients’ selection.1 Some border, with a resident population aged more than 40 years of Padversedrugeffectsmaythereforebecameapparentonly 820 575 inhabitants according to the 2001 Italian population after the introduction in the market, as the general use census (target population). This population has been covered expands both the number and the diversity of patients receiv- since 1997 by an automated system of databases on the use of ing the drug.2 Post-market non-experimental studies on drugs’ healthy services including: (a) archive of residents who risk assessment have commonly used computerised adminis- receive health assistance from the National Health System trative health databases, in a context where urgent concerns (practically all the resident population), reporting demo- http://jech.bmj.com/ are related to drug safety and adverse conditions under study graphic and administrative data; (b) hospital discharge are rare.3 database reporting the hospitalisations that occurred in the The preventive effect of cholesterol lowering treatment public and private hospitals of the Lombardia Region; (c) with statins on the risk of coronary heart disease, stroke, and mortality database reporting death certificates of residents in total mortality is well reported.45 However, the recent the area, and (d) prescription drug database reporting withdrawal of cerivastatin from the world’s market after information about the prescriptions of drugs reimbursable deaths from rhabdomyolysis has focused the attention on the from the National Health System. risk of adverse events associated with statins. Several reports The privacy of patient records is ensured as no recognition on September 25, 2021 by guest. Protected suggest that statins may cause peripheral neuropathy.6–11 key is present. However, a unique individual identification However, either study designs are inadequate (case reports code (regional healthy code) is consistently reported for all or case series) or sample sizes of formally well designed the databases to permit linkage among them. epidemiological studies are small, so that evidences on this 10 11 topic are still inconclusive. Moreover, the toxic effect of Cases and controls selection other lipid lowering drugs on peripheral nerves has never Hospital discharge and mortality databases were used to 12–15 been adequately investigated. identify case patients. Residents in the Province of Varese, The objective of this study was to explore a possible aged 40 years or more, hospitalised or dead in the years 1998– association between the use of lipid lowering drugs and the 1999 and for whom the diagnosis of peripheral neuropathy occurrence of peripheral neuropathy. (codes 350 to 359 according to the International Classification of Diseases, 9th revision) was the principal reason for admission or METHODS death, were identified from both sources. The date of the first Target population and data sources The study focused on all the residents in the Province of Abbreviations: DDD, defined daily dose; ATC, anatomical therapeutic Varese, an Italian industrialised area located in the chemical www.jech.com 1048 Corrao,Zambon,Bertu`, et al J Epidemiol Community Health: first published as 10.1136/jech.2003.013409 on 16 November 2004. Downloaded from episode of peripheral neuropathy was referred as the index the first peripheral neuropathy diagnosis, were retrieved from date. medical records. Up to 20 controls for each case patient were randomly selected from the archive of residents in the Province of Statistical analysis Varese after matching for index date, gender, age (¡ 5 The risk of peripheral neuropathy associated with lipid years), and the general practitioner. lowering drugs was estimated by fitting logistic regression Eligible patients reporting peripheral neuropathy as ‘‘sec- models,17 and expressed as odds ratios (OR) and correspond- ondary diagnosis’’ or as ‘‘other relevant condition’’ in ing 95% confidence intervals (CI). Models first evaluated the presence of another primary diagnosis in the period ranging separate effects of each lipid lowering drug without and with from 1997 to 1999 and those hospitalised for peripheral adjustment for the presence of all the above reported neuropathy during 1997 (if cases), or in the years 1997, 1998, concomitant conditions. Subsequently, with the aim to and 1999 (if controls), were excluded. evaluate the joint effect of lipid lowering drugs and concomitant conditions on the risk of peripheral neuropathy, Exposure to lipid lowering drugs logistic regression models were fitted including only the main Prescription drug database was used to identify cases and terms and also their interactions. Eventual departure of the controls to whom lipid lowering drugs were prescribed at any joint action from the multiplicative structure was tested by time in the one year period preceding the index date. All means the likelihood ratio test.18 drugs were coded according to the anatomical rherapeutic Dose-response effects were investigated by estimating OR chemical (ATC) classification of the World Health Organi- for increasing categories of DDD. Trends in OR were tested sation.16 To screen for specific associations, the entire class of according to the statistical significance of the regression lipid lowering drugs (ATC code: C10), statins (C10AA), coefficient of the exposure variables obtained by scoring the fibrates (C10AB), and bile acid binding resins (C10AC) as a corresponding categories. whole, and five statins (simvastatin, pravastatin, fluvastatin, As a matching procedure was used in the selection of atorvastatin, and cerivastatin) and three fibrates (bezafibrate, controls, the corresponding parameters were estimated by gemfibrozil, and fenofibrate) reimbursable from the National maximising the conditional likelihood function.17 For all the Health System in the considered years were investigated. models, CI were calculated from the variance-covariance Defined daily dose (DDD) unit, established as the typical matrix of the parameters. The corresponding calculations adult’s daily maintenance dose,16 was recorded for each were carried out using the PHREG procedure of the SAS prescribed drug (15 mg simvastatin, 20 mg pravastatin, package.19 40 mg fluvastatin, 10 mg atorvastatin, 0.2 mg cerivastatin, 600 mg bezafibrate, 1200 mg gemfibrozil, and 200 mg RESULTS fenofibrate). In this way, the number of DDD units Overall, 2040 case patients discharged with the diagnosis of cumulatively prescribed during the year preceding the index peripheral neuropathy (no patient was identified from copyright. date for each included subject was computed. mortality database) and 36 041 controls met the inclusion criteria and have been considered in subsequent analyses. Ascertainment