Eur J Clin Pharmacol (2003) 59: 71–76 DOI 10.1007/s00228-003-0586-2 PHARMACOEPIDEMIOLOGY AND PRESCRIPTION M. Isabel Lucena Æ Rau´l J. Andrade Æ Gianni Tognoni Ramo´n Hidalgo Æ Felipe Sanchez de la Cuesta Æ the Spanish Collaborative Study Group on Therapeutic Management in Liver Diseases Drug use for non-hepatic associated conditions in patients with liver cirrhosis Received: 1 November 2002 / Accepted: 3 February 2003 / Published online: 9 April 2003 Ó Springer-Verlag 2003 Abstract Aims: To study the prescribing patterns of Keywords Pharmacoepidemiology Æ Drug use Æ Liver practising physicians for the most frequent non-hepatic cirrhosis associated conditions in patients with liver cirrhosis. Methods: A multi-centre prospective observational study carried out in 25 Spanish hospitals. Inpatients admitted to gastrointestinal and liver units with a diagnosis of liver cirrhosis were included in five centrally Introduction assigned index days, between February and June 1999. Information was collected about pharmacological treat- Cirrhosis of the liver is one of the most common ments used on admission and recommended at discharge. chronic diseases that can alter drug disposition and Results: Five hundred and sixty-eight in-patients with a effect [1, 2, 3]. The heterogeneity of the effects of liver diagnosis of liver cirrhosis (44% alcoholic cirrhosis) and disease on different routes of drug metabolism, the an average number of 2.5 co-morbid conditions were variability in the rates of these pathways and the ab- studied: diabetes mellitus (30%), infectious disorders sence of a routinely measurable test of metabolic (24%), cardiovascular disease (20%) and active alco- function of the liver make it difficult to accomplish a holism (15%)—the most common associated conditions. simple rule to individualise drug treatment in cirrhotic Chlormethiazole, amoxicillin–clavulanic acid, paraceta- patients [1, 4]. This is of further concern because mol, gliblenclamide, lorazepam, captopril and tiapride underlying liver dysfunction is one of the most com- were the drugs used most prevalently. The average pre- mon factors that increase the risk of adverse effects in scribed daily dose was <1 defined daily dose per day for medical practice [5]. Unfortunately, scarce or occa- most medication classes hepatically handled except for sionally conflicting data are available on whether the calcium channel blockers. presence of liver disease should influence drug choice Conclusions: The present study expands current knowl- and dosage adjustments for common associated con- edge of prescribing patterns for associated conditions in ditions [6, 7]. Nevertheless, there is general agreement patients with underlying liver cirrhosis. Drug dosing was regarding the hazards to which cirrhotic patients are affected in general by the influence of age and hepatic exposed when taking some drugs, such as non-steroid disease on the disposition of drugs, but knowledge on anti-inflammatory drugs (NSAIDs), or the appropri- drug selection needs further attention. ateness to perform a dosage modification for others (i.e. calcium channel blockers). However, the diverse influence of liver function on drug disposition may M.I. Lucena (&) Æ R.J. Andrade Æ F. Sanchez de la Cuesta lead health-care professionals to inappropriate drug Clinical Pharmacology Service and Liver Unit, selection, to inappropriate dosing of medicines or to Hospital Universitario, School of Medicine, University of Ma´laga, 29071 Ma´laga, Spain some degree of therapeutic nihilism, particularly if E-mail: [email protected] there is only a recommendation that the drug should Tel.: +34-952-131572 be used ‘‘with caution’’. Fax: +34-952-131568 The present study was aimed to assess the G. Tognoni prescribing patterns of practising physicians for the Istituto di Ricerche Pharmacologiche Mario Negri, Milan, Italy most frequently associated conditions (excluding dis- R. Hidalgo orders of the gastrointestinal tract) in hospitalised pa- Centro de Ca´lculo, University of Ma´laga, 29071 Ma´laga, Spain tients with underlying liver cirrhosis. 72 represented 38% (218), and cirrhosis of unknown cause Methods 18% (102). The mean age was 61 years (range 27– 92 years); 30% of the patients was younger than This study was part of a large-scale study carried out in Spain and aimed to describe the prescribing patterns of practising physicians 55 years, while 45% was 65 years or older. The younger for patients with liver cirrhosis and to determine the extent of patients were mainly classified in the diagnostic group of practice variability across participating centres, which represented alcoholic cirrhosis of the liver. Women were older than up to one-quarter of the national health system [8]. men. Of the female sample, 58% was older than A multi-centre prospective observational study was carried out 65 years, while the same age group made up 39% of the in 25 Spanish hospitals with a catchment population of 10.8 million inhabitants. A network was set up under the methodological and male patient population. operational co-ordination of a clinical pharmacology research unit. Ascites was the most prevalent major complication of The methodology followed was described previously [8]. Briefly, all cirrhosis in this population (49%), followed by portal– patients admitted to gastrointestinal and liver units with a diag- systemic encephalopathy (24%) and variceal bleeding nosis of liver cirrhosis on five centrally assigned index days, be- tween February and June 1999, were included. The research (22%). Of the patients, 82% was class B–C according to protocol was approved by the locally appointed ethics committee. Child–Pugh classification. Diabetes mellitus (125 patients), infectious disorders other than spontaneous bacterial peritonitis (110 pa- Data collection tients), active alcoholism (68 patients), chronic respira- tory diseases (49 patients), heart disease (47 patients), In each participating hospital, the physician in charge of the study hypertension (45 patients), pain disorders (37 patients) prospectively collected (with a standardised form) information on and non-liver cancer (16 patients) were the most com- all patients with a diagnosis of liver cirrhosis that were admitted in any of the assigned days. Information consisted of demographic monly associated conditions. One hundred and four variables, present medical condition and pharmacological treat- patients (17%) did not have any associated condition. ments prescribed for non-liver related co-morbid conditions on Fifty-seven patients (10%) died during hospitalisation. admission (refers to drugs that patients were already receiving at Multiple co-morbid conditions were prevalent, as indi- time of hospital admission) and at discharge from hospital. Infor- cated by an average number of 2.5±1.7 diagnoses. The mation was obtained by interviewing patients and from the clinical records. Patients were questioned to identify drugs used for other drugs used for the management of these conditions are medical problems not related to the liver that might not have been shown in Table 1. recorded in the medical record. In addition, family members were Prescribed oral hypoglycaemics accounted for 41% interviewed when patients were not able to collaborate. Medication of the total diabetes prescriptions (47 of 116) on ad- containers, which family members were asked to bring to the hospital, were inspected. A written medication plan was provided mission and 26% at discharge (26 of 99). The most by the patient when available. The name of each drug, daily dose, frequently prescribed sulfonamides at discharge were route and frequency of administration, and diagnosis motivating glibenclamide (69%) followed by gliclazide, glipizide the prescription were recorded. The diagnosis of liver cirrhosis was and chlorpropamide (8% each). usually made before admission to hospital and according to the standardised clinical, ultrasonographic, endoscopic and histologi- A total of 26 benzodiazepine agents were used at cal criteria. The severity of chronic liver disease was assessed using discharge, lorazepam being the most common (50%), the Child–Pugh classification, with score C representing the most followed by oxacepam, bromazepam, clorazepate and advanced disease. Forms were checked for completeness at the co- lormetazepam (8% each). On admission, the rank order ordinating centre before data entry. was lorazepam (34%), clorazepate (10%), diazepam and The prescribed daily dose (PDD) was recorded as a percentage of the defined daily dose (DDD) for the selected main medication oxazepam (7% each) and others (five compounds: lor- classes by dividing the PDD by the DDD [9]. The DDD of a metazepam, bromazepam, bentazepam, alprazolam and substance is established by the Nordic Council on Medicines and flunitrazepam; 3%). Hydroxyzine, a diphenylmethane the World Health Organization (WHO) Drug Utilization Research derivative, was used for the treatment of pruritus related Group and represents the recommended average daily dose of a drug, if used for its main indication in an average adult. Medicines to liver cirrhosis in five patients on admission but only in were classified according to the Anatomical Classification System three patients (3 of 14) at discharge. (ATC) recommended by WHO Europe. Those medications for Overall, 9 patients received drugs for insomnia and 19 which the liver has a great contribution to their metabolism and patients for the management of alcohol deprivation disposition were chosen. The data were analysed using the Statistical