Patterns of ADRs and Risk Factors Involved: Study In Cardiology Unit Of An Indian Tertiary Care Center
S Kaur, V Kapoor, R Mahajan, M Lal, S Gupta
adverse drug reaction monitoring, cardiology, incidence, risk factors
S Kaur, V Kapoor, R Mahajan, M Lal, S Gupta. Patterns of ADRs and Risk Factors Involved: Study In Cardiology Unit Of An Indian Tertiary Care Center. The Internet Journal of Pharmacology. 2009 Volume 8 Number 1.
Medical science has progressed a lot in recent years, but this development has led to a new group of diseases called the iatrogenic diseases. While most patients derive far more benefit than harm, a proportion of them experience adverse drug reactions (ADRs) from the use of the medicines at recommended doses and frequencies.
Epidemiological research performed in the United States shows the occurrence of ADRs in 10-20% of all hospitalized patients. It is estimated that ADRs are responsible for 3.2-6.5% of hospital admissions. 
Cardiovascular diseases (CVDs) remain a leading cause of morbidity and mortality world wide. Over 30% of all the deaths every year are attributed to CVDs.  Cardiovascular medications have been cited as one of the most common classes of drugs associated with medication errors and adverse drug reactions, which need to be monitored from time to time.  The adverse drug event (ADE) prevention study group reported that odds ratio (OR) of severe ADEs with cardiovascular medication was 2.4 times that of other medications. 
However sufficient data pertaining to ADRs in Indian population has still not been generated. India rates below 1% in pharmacovigilance as against the world rate of 5%. This is due to ignorance of the subject and also lack of training.  India is the fourth largest producer of pharmaceuticals in the world. It is also emerging as a clinical trials hub. Many new drugs are being introduced in the country, so there is an immense need to improve the pharmacovigilance system to protect the Indian population from potential harm that may be caused by some of the new drugs. 
There is no such pharmacovigilance system working presently in our set-up and moreover, there is paucity of data regarding ADR monitoring especially in relation to drugs used for the management of various cardiovascular conditions in India as a whole. Accordingly, the present study was designed to monitor the incidence of ADRs and the risk factors involved in indoor cardiology patients.
Materials and Methods
It was a prospective, observational study, spread over a period of one year. Study was commenced after getting approval from Institutional Ethical Committee (IEC). Indoor patients admitted in cardiology ICU were registered in the study, according to certain inclusion and exclusion criteria, after taking informed written consent.
Adult patients of both sexes admitted in the cardiology department receiving various drugs.
Both new and already admitted patients at the time of commencement of study.
Patients with age less than 18 years.
Cases of therapeutic failures; intentional or accidental poisoning; with a history of drug abuse and that of non-compliance.
Pregnant and lactating females.
Patients not perceiving the questionnaire.
A total of 966 patients were registered. Two methods, spontaneous reporting and intensive monitoring were employed to assess the ADR profile in the patients.
For spontaneous monitoring, treating physicians were provided with reporting cards on which they recorded suspected ADRs. After the initial notification of the suspected ADR by the physician, additional detail was collected by review of the patient case records and interviews. 
In the second method i.e. intensive monitoring which is based upon systematic evaluation of link between the adverse event and drugs involved; patients admitted to cardiology unit were followed-up until discharged. Out of these patients, cases of suspected ADRs were enrolled separately. For the information which was not recorded in the medical case sheets, direct patient interviews were conducted using a structural questionnaire.  The information was transferred to the performa which was adopted from the one used by Indian Council of Medical Research (ICMR),  after modifying it according to the study requirements.
Statistical analysis was performed by using Microsoft Excel and SPSS 10.0.1 for windows. Univariate analysis was carried out using Chi Square test and Z test for proportions. Odds Ratio (OR) with 95% confidence interval (CI) was calculated for assessing risk of each variable with the outcome i.e. occurrence of ADR. Multi-variate analysis was performed to assess the independent risk of variables found significant on univariate analysis by performing a stepwise logistic regression analysis. A p value of <0.05 was considered significant unless specified otherwise.
The age of patients enrolled in the study varied from 25 to 95 years, with a mean age of 61±13.47 years. Out of 966 patients enrolled, 354 (36.3%) patients were aged above 65 years. A total of 672 (69.5%) males and 294 (30.5%) females were included in the study. Characteristics of the patients enrolled in the study are shown in Table 1.
Incidence of ADRs
A total of 208 ADRs were reported from 188 patients. Thus the incidence rate of ADRs was 21.5%, while incidence of patients affected due to ADR was 19.5%. Out of these 188 patients, 62 patients were admitted because of ADRs and 126 developed ADRs during their stay in the hospital. Thus the incidence of hospitalization due to ADRs was 6.4%, while the incidence of ADRs in hospitalized patients was 13%. On an average there were 1.10 ADRs per patient.
Data showed preponderance of ADRs in female subjects as compared to males. Of all females enrolled, 27.9% suffered from one or the other form of ADR as compared to 15.8% males. This difference was found to be statistically significant (Z=4.37, p<0.05). Incidence of ADRs was found to be higher in patients aged more than 65years as compared to patients with age ≤65years (24.9% vs 16.3%). This difference was also found to be statistically significant (Z=2.52, p<0.05). (Table 2)
There was a certain correlation between number of other co-morbid conditions present in the patients and the incidence of ADR; it was 37.9% in patients with more than two co-morbid conditions as compared to 10.7% in patients with ≤2 co-morbid conditions, with a statistically significant difference (Z=5.11, p<0.05). Incidence of ADR was 23.5% in patients taking more than ten drugs as compared to 8.4% in patients taking ≤10 drugs. This difference was statistically significant (Z=5.27, p<0.05). (Table 2)
Univariate analysis identified age, sex, number of co-morbid conditions and number of drug being taken, as risk factors for ADRs. Risk was twice as high in females as compared to males (OR=2.07, CI= 1.47-2.91); 1.5 times as high in patients over 65years age (OR=1.5, CI=1.08-2.09); six times higher in patients with more than two co-morbid conditions as compared to patients with ≤2 co-morbid conditions (OR=6.16, CI=4.30-8.83) and five times higher in patients taking more than ten drugs as compared to patients taking ≤10 drugs (OR=5.21, CI=3.17-7.63). (Table 2)
A logistic regression analysis showed that female gender (adjusted OR=3.49) and elderly age group (adjusted OR=0.53) were significant independent predictors of ADRs after controlling for the effect of other variables. Co-morbidity was not shown to be a significant risk factor when other variables were adjusted. Number of drugs taken could not be assessed as a risk factor due to inability of patients to recall the exact number of drugs they were taking prior to admission in the hospital.
Drugs Involved and Commonly Reported ADRs
The various drugs which caused ADRs and the total number and type of ADR caused by them are shown in Table 3.
Out of 208 reported ADRs in Cardiology department, cardiovascular drugs were responsible for maximum number of ADRs (138), followed by anti-bacterial agents (40) and intravenous contrast media (14). Among cardiovascular drugs, highest frequency was seen with nitrates (37), followed by diuretics (24). Most common adverse reaction reported was hypersensitivity skin reaction (54), followed by headache (37) and bradycardia (27). (Table 3)
An adverse drug reaction (ADR) has been defined by World Health Organization (WHO) as “a response to a drug which is noxious and unintended and occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease or for modification of physiological function”.  Growing importance of ADR monitoring can be gauzed from the fact that Medical Council of India has recently recommended to establish Pharmacovigilance Committee in every teaching hospital. 
In the present study, out of 966 patients enrolled, 62 (6.4%) were admitted to the hospital due to an ADR while 126 (13%) patients developed ADRs during their stay in the hospital. In an earlier study, 1.2% hospital admissions were reported due to ADRs while 11.24% patients developed ADRs during hospital stay, in cardiology set-up.  A higher incidence of ADRs reported in present study may be due to the fact that in present study two different methodologies (spontaneous reporting and intensive monitoring) were employed to monitor ADRs. Moreover, in the present study, adverse effects of all the drugs prescribed in the cardiology department were studied in contrast to monitoring of adverse effects of only cardiovascular drugs in the earlier study.  Also the incidence of ADRs may vary from place to place and even within a country because of difference in prescribing patterns. 
Predisposing factors like age, gender, co-morbidity, number of drugs taken and length of stay in the hospital have been reported as significant risk factors for the development of ADRs. [14, 15] On multivariate analysis, the present study revealed that advanced age and female gender were the independent risk factors for development of ADRs.
Age is an important risk factor for ADRs; and incidence of ADRs increases steadily with age. This is due to pharmacodynamics and pharmacokinetics changes which, together with impairment of homeostatic mechanisms and the effect of co-existing disease, contribute to a significant increase in the incidence of ADRs. Another reason for increased incidence of ADRs in elderly is increased consumption of medicines.  Present study confirmed the fact that polypharmacy and co-morbidity played a significant role in causation of ADRs in elderly patients, as 93% of the elderly patients (aged >65 years) were suffering from more than two diseases and all of them were receiving more than ten drugs.
Although present study has some limitations like enrollment of only indoor patients, inability to assess outcome after de-challenge and re-challenge, inability to perform logistic regression on the number of drugs administered as a parameter (due to patient’s inability to recall exact numbers); nevertheless, this study would definitely give an insight into the pattern of ADRs in cardiology set-up in a tertiary care center and may help to increase awareness for further Pharmacovigilance studies.