Patients and Methods: EMPADE study was single-centered, prospective, observational, cross-sectional, conducted at Respiratory Intensive Care Unit after acquiring an approval from the Medical Superintendent (Approval no: DCMS/PEH/740/2013), while ethics committee waiver was taken from the hospital’s ethics committee. A total of 1,044 prescriptions were analysed from October 2012 to April 2014. Individual patients who cooperated were interviewed and relevant information was recorded in case report form (CRF), which was designed in a manner to collect data related to medication utilization, ADEs, patient’s habits and family history. Verbal consent was taken from each patient before their enrollment. The patient population was divided into adults with 18-59 years and geriatrics who were 60 years of age or above.

Patients elder than 18 years of both genders suffering from COPD and willing to give consent were included, whereas pregnant women and pediatric patients were excluded from the study.

Data comprising patient demographics, co-morbidities, medications prescribed and daily progress of patient were collected from treatment charts/case sheets, laboratory reports and verbal information from patients during interviews. Data was compiled by classifying it in independent variables, evaluated by Chi-square test and calculated in percentages.

Analysis of 1,044 patients revealed that COPD was more prevalent in males (59.8%) than in females (40.2%) with a male to female ratio of 1.49 and mean age of 61.29 years. Demographic characteristics revealed that patients above 60 years were suffering more (58.6%) from COPD than adults (41.4%). Of all the patients, about 34.9% were current smokers, besides 11.9% who were smokers in their past life. Most of the patients (44.8%) in EMPADE study were prescribed 11-15 drugs in their prescriptions, while 17.6% and 37.5% were prescribed ≤10 and ≥16 drugs in their prescriptions, respectively. Despite the best efforts of the medical team, 12 patients unfortunately breathed their last during the course of study [Table/Fig-1]. Patients were found to be suffering from different co-morbidities as seen in [Table/Fig-2].

A total of 15,360 drugs were prescribed to 1,044 patients at an average of 14.71 drugs. Based on the usage, important drugs in this study were clubbed together in decreasing order from β₂-agonists to Leukotriene antagonists as seen in [Table/Fig-3]. These drugs constituted about 61.2% of all drugs utilized in the study while rest was used for minor ailments/co-morbidities.

Antibiotics were used in 56.32%, penicillins were the most commonly prescribed antibiotics (42.2%) accounting for nearly half of the whole antibiotics, followed by cephalosporins, fluoroquinolones and others. About 95.4% of total COPD patients were given the combination of LABA/SABA+ICS+LAMA/SAMA, whereas mono-therapy of LABA/SABA was used in just 20 patients and dual therapy of LABA/SABA+ICS in 28 patients.

Oral tablet/capsule (39.1%) were the most frequently prescribed dosage form followed by parenterals (35.4%), nebulization (12.4%), syrups (8.9%), inhalers (2.1%) and others (1.4%).

A high proportion of drugs were utilized for treating co-morbidities related to cardiovascular and endocrinological diseases, which are represented in [Table/Fig-4].

Among 1,044 patients involved in the study, 252 patients suffered ADEs, wherein 144 (57.1%) were males and 108 (42.9%) were females. A substantial number of ADEs (71.4%) were found in patients above 60 years of age compared to adults (28.6%) {Chi square (χ²) value of 9.355 (dF=3); p<0.025} as shown in [Table/Fig-5]. A total of 372 ADEs were experienced by 252 patients indicating that some patients may have experienced multiple ADEs. Overall, 164 patients experienced single ADE, 68 patients experienced two ADEs, 12 patients experienced three ADEs and 4 patients each experienced four and five ADEs. Among 252 ADE experienced patients, 24 (9.5%) patients were hospitalized because of an ADE.

Various organ systems were affected by the ADEs, as depicted in [Table/Fig-6]. Gastrointestinal tract was affected the most accounting 48.38% of all ADEs. The five most frequently observed ADEs were restlessness, abdominal pain, diarrhea, nausea and constipation. ADEs were classified according to Naranjo’s scale as: Definite-52, Probable-232, Possible-88 and Doubtful-0.

[Table/Fig-6]:

Distribution of adverse drug events into different systems

A total of 372 ADEs (2.42%) were observed from 15,360 drugs utilized in the study. Bronchodilators were responsible for 16.1% ADEs and theophylline was most commonly involved in causing ADEs with 168 (45.2%) events. Drug with highest suspected prevalence rate was levofloxacin, however it was administered to a small size of patients (24) as represented in [Table/Fig-7].

A high number of average drugs per prescription shows physicians’ tendency to prescribe more drugs to control acute exacerbations of COPD. β₂-agonist and corticosteroids were the preferred drugs in the present study, which was similar to observations from other studies [12]. However, extensive usage of mucolytics was a sharp contrast to previous studies [12,13]. Antibiotics usage was slightly higher than that of other studies [13], but the trend of using amoxicillin as a preferred agent was similar to the reviewed literature [14,15]. The study highlights that among all the antibiotics used, the preferred agents were penicillins especially the combination of amoxicillin-clavulanate. This combination is preferred in cases of complicated exacerbations (>4 exacerbations per year and FEV1 35%-50% of predicted). Second and Third generation cephalosporins and macrolides are preferred in uncomplicated exacerbations (<4 exacerbations per year FEV1 >50% of predicted).

It is widely acknowledged that LABA/SABA-ICS combination therapy is far better than LABA/SABA mono-therapy in controlling COPD; this combination not only reduces the risk of exacerbations but also improves QOL and airflow measures [16–19]. Anti-inflammatory activity of the combination may help in reducing the risks of re-hospitalization or death [20]. In the present study most of the patients were treated by the said combination as COPD exacerbations is the chief cause of patients to be admitted in ICU. During exacerbations, intensification of bronchodilator regimens is used commonly. Short acting beta 2 agonists were preferred owing to their rapid onset of action, while anti-cholinergics were added if symptoms persist after increased doses of beta 2 agonist.

Adding theophylline, leukotriene antagonists or antihistamines in routine treatment protocol seem to ameliorate respiratory symptoms [21], improve PFT, dyspnea score and QOL in stable COPD [22], accordingly these agents were utilized wherever necessary. Oral tablets/capsules were preferred dosage form; however, it is highly recommended that physicians prescribe inhalers more than tablets/capsules.

ADEs in patients above 60 years of age were higher than adults specifying that elderly are more prone to drug’s adverse effects. This observation was relatively similar to a previous study with ratio of ADEs in patients above 60 years to adults as 2.5 [7]. The five most frequently observed ADEs in our study were different from a past study [23]. Out of the total drugs, just 2.43% lead to ADEs, which was extremely less compared to a study conducted by N Tyagi et al, wherein the number was 31.5% [5]. Gallelli and Buajordet with their teams found that bronchodilators were responsible for 18.5% and 19.5% of all ADEs [7], whereas theophylline was found to be responsible for maximum ADEs, these reports were similar to our results [7,23].

The ongoing COPD management in Indian Hospitals is not sufficiently rational. Based on the lacunae in the current prescribing practice, there is a necessity to persuade physicians to follow GOLD guidelines while managing COPD patients. Unnecessary usage of antibiotics and high risk drugs such as theophylline led to a number of ADEs in the present study, therefore usage of these drugs should be restricted by physicians, unless patient’s condition demands. These situations not only endanger the quality of patients’ life but also increase the financial burden on patients. Authors of EMPADE study suggest physicians to prescribe least number of drugs considering the risk of drug-drug interactions resulting from multiple drugs usage. The present work may help improve the management of COPD by rectifying the loopholes postulated in this article.