Prevalence of Adverse Drug Reactions: a Self-Reported Random Digit Dialing Study in The

FACULTY OF MEDICINE – UNIVERSITY OF PORTO Department of Biostatistics and Medical Informatics Introdução à Medicina 2005/2006

Prevalence of adverse drug reactions: A self-reported random digit dialing study in the adult population of Porto

Júlia Barbosa, Ruben Barreto, Sara Cunha, [email protected] [email protected] [email protected] Sara Mota, Sara Nogueira, Sara Oliveira, [email protected] [email protected] [email protected] Sérgio Azevedo, Sílvia Monteiro, Sílvia Silva [email protected] [email protected] [email protected] Adviser: Dr. João Fonseca – jfonsecaed.up.pt , Dr Luis Azevedo – [email protected], Class: 21

Abstract

Introduction – Adverse reactions to medicines is the response to a drug, noxious and unintended, for prophylactics, of diagnosis or therapeutics effects, or for modification of the psychological function that happens in normal dosage. Multiple factors associated to these side effects as well as a lack of diagnosis methods to some specific drugs lead to difficult diagnosis.

Aims - To estimate the prevalence of adverse drug reactions in the adult population of Porto; to identify the most common symptoms; to identify the drugs more usually associated to the symptoms referred.

Methods - In order to obtain, in a certain moment, a sample from the population it was used a cross-sectional study. Relevant variables are related to the existence of reaction, its durability and symptoms. The participant selection obeyed to specific rules as in each Porto telephone households only one adult individual was inquired. Because all telephone numbers were selected at random we analysed a random sample of households with telephone in the Porto region.

1 FACULTY OF MEDICINE – UNIVERSITY OF PORTO Department of Biostatistics and Medical Informatics Introdução à Medicina 2005/2006

Results - Out of 200 phone calls, 103 individuals answered the questionnaire, so the rate of participation was 51,5%.

Participants ranging from 18 to 85 years (mean 50,6 ± 15,5 years) and the majority were female (52,5%).

The prevalence of self-reported adverse drug reactions was 26,8%.

The prevalence of self-reported drug allergy was 21,4% from which 51,5% have doctor confirmation. The most referred drug was penicillin (47,4%).

From 103 subjects 9,7% were submitted to tests in order to confirm the reaction. The most common were skin and blood tests (60,0% and 20,0%, respectively).

Discussion - After analysing our results we realized that the percentage of subjects who claimed to have adverse drug reactions was far superior (21,4%),.We believe that the differences were due to vies and the reduced sample.

Key-words: Drug allergy, drug hypersensitivity, self-reported drug allergy, adverse drug reactions.

Introduction

Adverse reactions to medicines is the response to a drug, noxious and unintended, for prophylactics, of diagnosis or therapeutics effects, or for modification of the psychological function that happens in normal dosage [1]. However, this is an inaccurate definition, so some authors [2] defined it as "an unpleasant reaction and significantly harmful, as a result of an intervention related with the use of medical products, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen or withdrawal of the product". There are two types of

2 FACULTY OF MEDICINE – UNIVERSITY OF PORTO Department of Biostatistics and Medical Informatics Introdução à Medicina 2005/2006 adverse drug reactions: drugs hypersensitivity and allergic reactions to drugs. When immunological mechanisms are involved, that reaction is classified as an allergic reaction to the medicine [3].

Drugs hypersensitivity is difficult to diagnose because there are many factors that can be associated with the emergence of the symptoms [4]. The identification of the responsible agent for the reaction is important. That identification [5], should be based “mainly on the observation of the clinical signs, their durability, eventually answering to anti-allergic treatments, and, more important, in answer to appropriate tests, like DPT (Drug Provocation Testing)”. Some epidemiologic studies approach the prevalence of adverse reactions to medicines, including hypersensitivity, mainly in inpatients, and in pharmacological surveillance programs. Has been recently reported [6], the goal-analysis of 33 prospective US studies conducted from 1966 to 1996. Those investigators showed that 15.1% of hospitalized patients suffer an opposes drug reaction (of which 6.7% plows severe), and that the incidence of drug-related hospital admissions screech from 3.1 to 6.2%.

A recent French survey [7], conducted over 14 days in a representative sample of both teaching and general hospitals, support these data; 3.2% patients had been admitted to hospital because of an adverse reaction. In another study [8], nurses and pharmacists of the Boston Collaborative Drug Surveillance Program, in USA, collected information about adverse drug reactions from 4037 patients hospitalized during a six month period. In a a total of 247 identified reactions (incidence of 6,1%), 41,7% were severe and 1,2% lead to death.

According to a different study [9], 0.009% of deaths in USA in 1995 were due to adverse drug reactions. According to the above author, using Medwath 1995 database, 6,3% of adverse drug reactions leaded to death.

In 10-20% of hospitalized Patients occur adverse drug reactions [10].

On the basis of the data presented by several authors [6, 7, 8, 11, 12], hypersensitivity drug reactions represent up to one-third of adverse drug reactions, which can affect 10-15% of hospitalized patients and are, in most cases, not reported.

Some studies [10, 13, 14; 15] about the prevalence of adverse reactions to medicines, specifically hypersensitivity, esteem that 3-7% of the population presented adverse reactions to medicines. A Recent study [16], refer that the prevalence of adverse reactions to medicines was self-reported at 7,8% of the inquired UP individuals. Similar results, obtained by other study [17], verified that 7,7% of those students referred ADR. The allergic reactions to medicines have been having an increasing clinical and economical relevance, due to the morbidity and mortality caused by the reactions. In a marry-control study [11], 1580 patients who suffered opposes drug reactions that occurred during hospitalization were compared with 20 197 control individuals. The patients were hospitalized goes 1.91 days longer than were the control individuals, incurring additional costs of US$2262 per patient. Some authors [6], analyzed 33 prospective US studies from 1966 to 1996, and showed that 0.32% of hospitalized patients died from opposes drug reactions, resulting in an estimated 106 000 deaths goes the year 1994 – the fourth causes of death in the USA.

The purpose of this study was to estimate the prevalence of adverse drug reactions in the adult population of Porto, the most referred symptoms and medicines frequently associated.

Participants and Methods Study design

This is a cross-sectional survey of the general adult population of Grande Porto. We selected a random sample of participants. A questionnaire about the occurrence of adverse drug reactions in adults was applied through telephone interviews. Detailed information about the reaction and the clinical history of the participants were used to better characterize the different types of reactions.

Study population

The study population was every adult (18 years or above) in Grande Porto, with telephone in their house, and, for each phone call it were interviewed the adult with the nearest birthday.

Selection of participants

The selection of participants involves 2 phases: (1) the 1st step bases on the selection of the numbers. Starting from 2 lists, one of prefixes and another of suffixes randomly chosen, a prefix is combined with a suffix. If the number is not attributed or it is not a household, we pass for the following prefix of the list; if the number is attributed and if it is a household, we proceed for to 2nd step. (2) in the 2nd step, having identified a prefix that is a household, we use the same prefix with the following suffixes of the list until 5 valid numbers (with or without answering to the questionnaire) are achieved, including the first. When a suffix is not attributed, the following of the list is used; if it is attributed, but the call is not assisted, we try for 2 consecutive days considering it not a household (not valid) at the end of that period; when we have 5 numbers attributed with the same prefix, and at least 1 don't assist, the process is blocked, until assisting or being considered invalid. After the obtaining of 5 valid numbers with the same prefix, we pass for the following prefix.

At the end, we had forty prefixes, corresponding to two hundred valid numbers.

Data collection methods

We used a structured questionnaire given by the service of biostatistics and medical informatics of medical faculty of Porto University. This questionnaire was not validated; however, we applied it according with the suggestions given.

It’s composed by questions of closed response and questions of short and objective answers. It’s divided in six sections:

1. The first section consist of the interviewer presentation and confirmation of the interviewed availability to answer the questionnaire;

2. The second section consists in a brief presentation of the aims of the work, as well as, the identifications of the existence or not of adverse drug reactions history;

3. The third section is only to those who reported an adverse drug reaction history. It’s sub-divided according to the symptoms referred (cutaneous, respiratory, digestive and others), being each one made by a brief history of the reaction (starting of the symptoms, drugs related to the symptoms and its evolution);

4. In the fourth section we tried to obtain the medical conformation of the allergy to the specific drug, as well as the test made to confirm that diagnosis;

5. In the fifth section it is questioned the allergic background of the subject as well as another non-allergic pathologies;

6. In the sixth and last section of the questionnaire we made some questions about the subject such as the age, sex and residence.

Statistical analysis

The data processing and the evaluation of the results were made in a SPSS statistical package (version 13.0). Then, a descriptive analysis was done. Continuous variables were described as mean and standard deviation (SD) or median and percentiles as appropriate; categorical variables were described as absolute and relative frequencies (%). Prevalence was calculated as the proportion of the sample having certain characteristic and 95% confidence intervals for proportions were calculated using the approximate method of Wald. The prevalence of response was compared among groups using the Pearson 2 test. A level of significance of 5% (=5%) was used in all the hypothesis tests.

Results

General characteristics of the sample

Out of 200 phone calls, 103 individuals answered the questionnaire, so the rate of participation was 51,5%. Among the individuals that didn’t answered the questionnaire 28,9% were females so, the difference between sexes for a significance level of 0,05 was significant (p<0,001) and 14,4% were aged between 51 and 65 years old therefore the differences between age ranges were also significant (p<0,001) for the same confidence level. Participants ranging from 18 to 85 years (mean 50,6 ± 15,5 years) and the majority were female (52,5%). The prevalence of self-reported adverse drug reactions was 26,8%. (table 1). We can report with 95% of confidence that between the range of 18%-36% individuals show adverse drug reations The prevalence of self-reported drug allergy was 21,4% (table 2) and18,4% have doctor confirmation (table 3). We can report with 95% of confidence that between the range of 13%-29% individuals believe to be allergic to drugs, and we can report with 95% of confidence that between the range of 11%-26% individuals had doctors confirmation of allergic to drugs. The most referred medicines were penicillin (47,4%), antibiotics (10,5%) and others non-specified (26,3%) (graphic 1). The most common tests were skin and blood tests (60,0% and 20,0%, respectively). Rhinitis is the

7 FACULTY OF MEDICINE – UNIVERSITY OF PORTO Department of Biostatistics and Medical Informatics Introdução à Medicina 2005/2006 most frequent allergic disease (36,4%). 34,0% of the subjects had other non-medicine allergic reactions like dust, animals and food.

Valid Frequency Valid Percent Yes 26 26,8 Table 1 – Self-report about adverse drug reactions

Believe that is allergic to drugs Valid Frequency Percent Yes 22 21,4 Table 2 - Self-report about adverse drug reaction

With doctor confirmation Valid Frequency Percent Yes 19 18,4 Table 3 - Doctor alergic drug reaction confirmation

Graphic 1 - Drugs confirmed by a doctor

Drugs with doctor's confirmation

Subjects penicilina with self- reported adverse desconhecido drugs

antibiótico

reactions s g u r D Claudicat Wo men were significantly cartia more likely to have self- C-gripe reported adverse drug reactions 0 2 4 6 8 10 (78,9%). Count

In spite of this difference the proportion of adverse drug reactions, to a 0,05 confidence level, is the same to male and female (p=0,642). We can report with 95% of confidence that between the range of 10%-29% female individuals show adverse drug reations. To the male sex the range is between 10-30%.

15% of the inquired individuals are aged between 18-35 years old; 21,5% between 35-50; 22% between 51-65; above 65 years old only 12%. The proportion between the adverse drug reactions of different age ranges is equal to a confidence level of 0,05 (p=0,927). Can be reported with 95% of confidence, to a confidence range between 1% and 33%, that people between 18-35 years old show adverse drug reactions; to a confidence range between 6%-34% the individuals aged between 36-50 have adverse drug reactions; to individuals with ages between 51-65 can be said, with 95% of confidence, with a confidence range between 5%-35%, that they show adverse drug reactions; we can also tell, with the same confidence percentage, with a confidence range between 3%-43% that individuals with more than 65 years old had adverse drug reactions.

Recalled clinical manifestations were separated into cutaneous, respiratory and digestive reactions. The most common manifestations were cutaneous and digestive symptoms (48% both) (table 4).

Cutaneous reactions were more frequent in people 40-50 years old. The most referred medicines related to this manifestation were penicillin (23,1%) and others non- specified (30,8%). In 92,3% of these subjects it was the first time they were in contact with the drug. 30,8% had doctor’s confirmation and 60,0% made tests. 15,4% had the same reaction without the drug.

Digestive reactions predominate in people 30-40 years old. The most referred medicines related to this manifestation were brufen (16,7%) and others non-specified (25,0%). In 75,0% of these subjects it was the first time they were in contact with the drug.

69,2% had doctor’s confirmation and 40,0% made tests. 33,3% had the same reaction without the drug.

Respiratory reactions prevalence in 11,5% of the individuals and were more common in people 18-35 years old. The most referred medicine related to this manifestation was penicillin (66,7%). In 100% of these subjects it was the first they were in contact with this drug. None of them had doctor’s confirmation, made tests or had the same reaction without the drug.

Other diseases like diabetes mellitus and hypertension were recorded in the subjects (8%) (table 4).

Type of reaction Valid Frequency Valid Percent Cutaneous reaction Yes 12 48 Respiratory reaction Yes 3 11,5 Digestive reaction Yes 12 48 Other reactions Yes 2 8 Table 4 - Most common symptoms referred.

Discussion

According to some authors [6, 10, 13, 14, 15] adverse drug reactions affect 3-7% of in-patients or patients that have been admitted in the hospital. Similar results have been obtained by Portuguese authors who studied adverse drug reactions in the population of Porto [16, 17]. However, after analyzing our results we realized that the percentage of subjects who claimed to have adverse drug reactions was far superior (26/103, 26,8%), as well as those who claimed to be allergic to drug (22/103, 21,4%) and that had doctor's confirmation (19/103, 18,4%).

In spite of having more responses from females (52,5%) and from the age range of 51-65 years old (22%) these differences do not have significant statistical value according to Pearson 2 tests (p=0,642).

We believe that the differences were due to bias of information as the information given by the subjects may be incomplete or even wrong. The differences between the methods used by us and the others studies, as well as the different populations studied could be other reason for the difference between results.

Once our sample is too small when compared whit the study population, we can not extrapolate this results to the general population.

If we had the chance to repeat this study, we would certainly interview a bigger sample, using a more specific questionnaire.

Acknowledgments

We thank to Dr Prof. Altamiro, Dr Luís Azevedo and Dr João Fonseca for their help to the work.

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