Characteristics and risk factors of Cardiovascular Drugs induced Adverse Drug Reactions: Hospital based Active Surveillance Study.
Background: Adverse Drug Reactions (ADRs) is one of the major drug-related problems in hospitalized patients. Several studies report the incidence various from 10 – 50% of all hospital admissions due to ADRs and no recent data available on the safety of cardiovascular drug from India.
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Aim: This study aims 1). To estimate incidence and characteristics of ADRs due to cardiovascular drugs in patients admitted in cardiology unit of a tertiary care teaching hospital. 2) To identify the risk factors for ADRs in hospitalized patients treated with cardiovascular drugs.
Methods: A prospective active surveillance study was carried out in the cardiology department of a south Indian tertiary care teaching hospital for eight months. Population averaged Poisson regression [Generalized Estimating Equation (GEE)] models was used to estimate the adjusted relative risk associated with ADR.
Results: The overall incidence of cardiovascular drug induced ADRs was 31.8%. A total of 757 patients treated cardiovascular medications. Of which 241 patients (31.8%) including 122 (16.1%) females and 119 (15.7%) males reported at least one ADR. Aspirin produced the highest number of ADRs (150; 38.7%) followed by Heparin (45; 11.6%), Atorvastatin (24; 6.2%) and Ramipril (24; 6.2%). The causality assessment reveals that 85.3% of ADRs were probable in nature. GEE was used to estimate the adjusted relative risk of each covariate associated with ADRs. The predictors of ADRs identified were: female gender, age > 60 years, multiple drug therapy (p= 0.0231) and concurrent diseases like diabetes, drugs like Heparin (RR-2.90, 95% CI 2.22-3.8) and Enalapril (RR-1.95, 95% CI 1.34-2.83).
Conclusion: The incidence of cardiovascular ADRs was 31.8%. The most common drugs causing ADRs were the anti- platelet and anticoagulant class of drugs. Female gender, age > 60 years, multiple drug therapy, concurrent illness and certain drugs like heparin were identified as potential predictors for adverse reactions.
Keywords: adverse drug reactions, hospitalized patients, cardiovascular drugs, pharmacovigilance, Risk factors
- This study reports the risk factors for adverse reactions to cardiovascular drugs from an Indian clinical setting.
- The incidence of cardiovascular drugs induced ADRs was 31.8%, which is higher than many reported studies.
- Anti-platelet and anticoagulant drugs were commonly associated with ADRs in the study population.
Adverse Drug Reactions (ADRs) is one of the major drug-related problems in hospitalized patients. ADRs are one of the major drug-related problems, resulting in increased morbidity and mortality and healthcare costs.[1-3]The WHO defines an ADR as “a response to a drug that 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”.
The prevalence of cardiovascular diseases (CVDs) has increased in recent years and it has been estimated that CVDs are the most common cause of death. Reports on drug related problems including adverse drug reactions associated with cardiovascular pharmacotherapy are available.[6-10]Studies report that cardiovascular drugs may account for 10 to 50% of all hospital admissions due to ADRs.[11-13] There are reports of serious adverse drug events with cardiovascular drugs.Continuous monitoring of ADRs are important in patients treated with cardiovascular drugs since, these patients who need multiple drug therapies to treat their comorbid conditions and other related risks
Various methods are used to detect ADRs in hospitalized patients. Analyzing the adverse reaction data in relation to the presence of risk factors provide the link between the ADRs and the associated factors. Such analysis might help to identify patients who are at increased risk for the adverse reaction and therefore employing suitable monitoring and the preventive procedure is possible. Reports are available on the risk factors for adverse reactions.[18-20]
Studies have shown that the cardiovascular drugs are most common cause of ADRs.[6,21]A university hospital-based studies report 49 % ADRs are due to commonly used cardiovascular drugs (nitrates, digoxin, propranolol, heparin, warfarin, anti-hypertensive and anti-arrhythmic drugs) A number of studies are available on the adverse effects of cardiovascular drugs. In the Indian context data on adverse effects of the cardiovascular drugs is not available. Therefore, the current study was planned to evaluate ADRs due to cardiovascular drugs in hospitalized patients. This study aims 1). To estimate incidence and characteristics of ADRs due to cardiovascular drugs in patients admitted in cardiology unit of a tertiary care teaching hospital. 2) To identify the risk factors for ADRs in hospitalized patients treated with cardiovascular drugs.
Subjects and Methods:
A prospective active surveillance study was carried out in the department of cardiology of a tertiary care teaching hospital for eight months (Feb to Sep 2009). The study protocol was reviewed and approved by the institutional ethical committee. All patients admitted to the cardiovascular units were monitored and evaluated for cardiovascular drugs induced adverse reactions. Patients who were previously treated or newly prescribed with cardiovascular drugs were monitored and followed for detecting and recording of ADRs. Adverse drug reactions were identified by conducting a daily patient charts review, patient interview, and consultations with treating physicians. In the suspected cases, past medical/medication history of patients were collected. In addition to patient’s medication history, information on co-morbidities was also collected. We used the WHO criteria for defining ADRs. For every identified patient with ADR, two patients without ADRs were enrolled as matched controls.
The information pertaining to the suspected ADRs was collected and documented in a specially designed ADR computerized documentation database for further assessment. An ADR alert card was distributed to those patients who experienced severe adverse reactions to prevent further re-exposure of the suspected drug. All ADRs were reviewed and assessed by the research team. The documented ADRs were evaluated and characterized respect to patient demographics, nature of the reactions, drugs and organ system involved and outcome of the reactions. Using standard approach, the Causality, severity, preventability and the presences of predisposing factors of the reactions were assessed and reported.
Patient’s age and sex were considered for the analysis. ADRs were classified as either ‘Type A’ or ‘Type B’ according to the system introduced by Rawlins and Thompson. The suspected drugs were classified according to Anatomical Therapeutic Chemical (ATC) classification based on WHO-ATC Index 2009.Using WHO Adverse Reaction Terminology documented ADRs were further classified into various organ system classes. Management strategies employed for the ADRs were categorized as drug withdrawal, dose reduction, additional treatment for ADR and no change in a regimen without any additional treatment. Patient outcomes were reported as fatal, fully recovered, recovering and unknown.
The causality of suspected ADRs was assessed using Naranjo’s ADR probability scale and classified into certain, probable, possible and unlikely to be drug induced depending upon the level of association. The preventability of ADRs was analyzed and categorized into definitely preventable, probably preventable and not preventable using the modified criteria of Schumock and Thornton by Lau et al.Using the criterion developed by Hartwig et al., for severity assessment, we assessed the suspected ADRs and classified into mild, moderate and severe reactions. The onset of ADRs was assessed and classified into sub-acute, latent and acute groups.
Many patient-related factors predispose the occurrence of ADRs. The patient related factors like age, gender, multiple and inter-current disease states, and polypharmacy are considered as significant risk factor for developing ADR. Patient’s age was categorized into 6 groups (less than 20 years, 21-30 years, 31-40 years, 41-50 years, 51-60 years, more than 60 years). Polypharmacy was categorized as minor (2-3 drugs), moderate (4-5 drugs) or major (5 drugs) based on the classification by Veehof et al. Gender of the patient was also considered as a one of the predispose factor for the development of ADRs. Multiple disease state ( > 2 coded diseases) of the patient at the time of reaction also include in the analysis. The overall incidence of ADRs was calculated using the total number of in-patient episodes which resulted in ADRs in relation to the total number of in-patients followed during the study period.
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The length of hospital stay for each patient was collected from Hospital Patient Administrative System (HPAS) and used to compare the Length of Stay (LOS) between patients with and without ADRs. Additional hospital stay due to ADRs was assessed using the nature and clinical features of ADRs, discussion with treating medical staffs and assessment of patient’s medical records.
Descriptive statistics was used summarize the patient demographic and clinical characteristics like gender, diagnosis, a number of drug dispensed, the frequency of ADR, drugs involved, organ system involved and severity of ADRs. Mean with 95% confidence interval was used to summarize age and LOS. Chi-square test was used to find the association between age group, gender, the LOS with and without ADRs. Relative risk was used to measure the strength of association. The data were hierarchically arranged, to count the multiple ADR episodes which can occur with multiple admissions. Population averaged Poisson regression (GEE) was used to estimate the adjusted relative risk of each covariate associated with ADR.[32,33] Further compound symmetry was used to account for the within-subject correlation. All analysis was performed using SPSS for window 15 (SPSS Inc., South Asia, Bangalore). The significance level was set at P< 0.05.
A total of 757 patients (431 men and 326 women) using cardiovascular medications were intensively monitored. The mean age of the study population was 57.21 Â± 14.22 years (18 -92 years). The average length of hospital stay was 10.6 Â± 5.8 days. Overall, the incidence of ADRs was 31.84%. Two hundred and fourteen patients including 122 females and 119 males reported at least one ADR. Maximum of six ADRs were reported from one patient. Compared to males, females developed more of ADRs was observed more in females when (p 0.0001). The length of stay was increased due to ADR for a minimum of 3 days and a maximum of 28 days.
The frequency of different age groups in patients with and without ADRs is presented in table-1. The main diagnosis of the study population is listed in table-1. Age group of less than 20 years is excluded because of lower sample size. Age group of more than 60 years had more ADRs compared to other age groups. Cardiovascular risk factors of a patient with and without ADR are shown in table-2.
The most frequent system-organ class affected by ADRs was Platelet, bleeding & clotting disorders (188, 48.89%), followed by metabolic and nutritional disorders (53, 13.66%) and gastrointestinal system disorders (50, 12.89%) (Table-3). The most common strategy for management of ADRs was drug withdrawal (94.3%) and dose alteration (5.4%) (Table-4). The mean length of hospital stay was 13.3 and 6.5 days for patients with and without ADR respectively. The length of stay was found to be longer in patients with ADR.
Aspirin produced the highest number of reactions (150; 38.7%) followed by heparin (45; 11.6%), Atorvastatin (24; 6.2%) and Ramipril (24; 6.2%) (Table -3) with Platelet, bleeding & clotting disorders (188, 48.89%). The most frequently reported reaction was bleeding (186; 47.9%) followed by gastric ulcer (52, 13.4%) (Table-3). The causality assessment of ADRs revealed that 85.31% of ADRs were classified as probable, followed by 7.99% as definite and 6.7% as possible. 64.4 % patients recovered from the ADRs and 35.6 % were recovering at the time of discharge (Table-4).
The GEE analysis shows that the female, alcoholics, smokers and patients those taking more than 7 drugs had a higher risk for developing an ADR. (Table-2). Statistical analyses also revealed that patient taking Heparin (RR 2.90, 95% CI 2.22-3.80, Enalapril (RR 1.95, 95% CI 1.34-2.83), warfarin (RR 1.69, 95% CI 1.33-2.54) had a significantly increased probability of developing of ADRs (Table-5).
ADRs can significantly increase patients’ mortality or morbidity and consequently higher healthcare expenditure. The study findings reveal that developing an ADRs in hospitalized patients substantially contribute to patients’ morbidity, further increasing the disease burden and cost of managing ADRs. The incidence of ADRs (31.8%) found in this study was twice higher than a previously reported systematic review of international studies (15.1%). The present study showed that females experienced a higher incidence of ADRs (9.87%) when compared to males (7.23%) which are similar to the findings of previously published studies.[1,35-37]Several reasons have been put forth for this observed difference. Men and women have a different pharmacodynamic response to various drugs; which may consider as one of the factors for women to develop more number of ADRs. But in a study reported by Jose., on comparable Indian population male patients were found to have more ADRs than female population.
The incidence of ADRs was higher in the elderly patients (31.19%; age > 60 Years) compare to other age groups. (Ï‡2= 23.03, df-5, p 0.0001); this finding is similar to the results of Mohebbi et al. Studies have shown that the incidence of ADRs may increase with increasing age. Again, due to multiple comorbid conditions and receive multiple drug therapy the elderly patients tend to have a higher risk for developing an ADR. In addition, older individuals undergo changes in drug responsiveness and disposition. It appears that elderly patients need more attention to prevent the occurrence of ADRs.
In this study, the incidence of Aspirin-induced ADRs was 38.7% (n=150); which was the highest rate compared to other cardiovascular drugs in this study. However, High rates of ADRs with streptokinase have been reported previously.Studies reported a rate of amiodarone-induced ADRs as 16%, whereas in the current study it was too low at 0.5%. This might be due to the lower use of amiodarone in the current study subjects. In a study conducted by Wiffen et al., investigating ADRs induced by all groups of drugs, warfarin was among the top three drugs causing ADRs. In our study, the rate of ADRs attributed to warfarin was just 3.6%, whereas heparin-induced bleeding was the second highest ADR in this study population (45, 11.6%).
In this study, we found central nervous and gastrointestinal systems are the most frequently affected organ system classes by ADRs. These findings were similar to the findings of a study conducted in Iran.The incidence of preventable ADRs in this study (6.9%) is comparably lower than those detected in other studies.This might be probably due to intensive monitoring of CCU patients in our study. The rate of serious ADRs (22.2%) detected in this study tend to be higher than other studies.
Population averaged Poisson regression (GEE) model showed that factors like gender and age of more than 60 years, multiple drug therapy and the presence of co-morbidity were risk factors for experiencing ADRs. The average duration of drug usage was found to be longer in patients without ADR. It appears that most of the ADRs have been noted shortly after initiating cardiovascular drugs and the incidence of ADRs in this study population was not related to the duration of usage. Similar to findings of many other studies, increasing the number of drugs led to increased frequency of ADRs.
The finding of this study indicates that cardiovascular drugs cause serious and frequent adverse reactions. The incidence of cardiovascular ADRs was 31.84%. The most common drugs causing ADRs were the anti-platelet and anticoagulant class of drugs. Female gender, age more than 60 years and use of more than 7 drugs was found to be the risk factors for developing ADRs. The identified incidence was higher than many reported studies. The current study identified the common ADRs and their predictors. Patients with identified predictors for adverse drug reactions can be intensively monitored and necessary preventive measures can be initiated if signs of reactions are observed.
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