Chronic kidney disease (CKD) is widely prevalent noncommunicable disease that is responsible for increasing morbidity in India [1]. Diabetes and hypertension have been reported to be the most common risk factors for CKD [2]. In view of this, it is fair to anticipate a parallelism between the number of diabetics and hypertensive and the number of CKD patients.

CKD patients present with several other co-morbidities such as hypertension, diabetes mellitus, coronary artery disease and infection [2,3]. The presence of these comorbidities has a twofold impact – first, it increases the cost of treatment and secondly, it poses a challenge for the treatment of CKD patients. Because of the multiple medications, CKD patients are at higher risk of developing drug-related problems. They need complex therapeutic regimen requiring frequent monitoring. Inappropriate use of drugs in these patients can lead to adverse drug reaction, increased hospital stay and increased cost of treatment.

Drug utilization changes with time period, physician, disease conditions and population, which makes it is important to study the drug utilization continuously over a period of time [4]. Drug utilization studies in CKD patients help to understand and build evidence for the drug use. CKD patients need to take medicines lifelong, which makes it is very important to study the prescribing trend on a regular basis. There is very limited evidence from India on the prescribing trends

There is very limited evidence from India on the prescribing trends in CKD patients [5,6]. This study offers such evidence from a public teaching Indian hospital.

Study design, setting and patient population

This cross-sectional study was carried out at the renal clinic of medicine OPD at Government Medical College and Hospital, Chandigarh.

Patients of either sex, age 18 years or more, diagnosed by the clinician to have chronic kidney disease and currently on drug treatment were included in study. Patients with cognitive impairment and those unable to complete the interview were excluded. The patients were included in this study after obtaining a written informed consent for participation. The patients with age 60 years or more were considered as elderly [7].

Data collection and interpretation

A predesigned case record form was used for data collection. The case record form did not contain the name of the patient, in order to protect the patient’s identity at all points of time. Patient information regarding demographics, socioeconomic, lifestyle (smoking, alcohol consumption) and medication was collected from patients OPD card and through patient interview. Biochemical parameters were captured from the latest laboratory investigation reports documented in the clinical records. Socioeconomic status was assessed by using the modified Kuppuswamy’s scale [8], which takes into account the educational qualification, occupation of the family head and monthly family income of the participant.

Anthropometric measurements including weight and height were taken from the patient OPD card. Serum creatinine, urea, calcium, potassium and phosphate levels were recorded from biochemical tests performed. Hemoglobin level was collected from the hemogram. Clinical systolic blood pressure (SBP) and diastolic blood pressure (DBP) levels, serum lipids, blood glucose and glycated hemoglobin (HbA_1c) was also recorded.

Data collected in the case record form was utilized to study the prescribing trends in patients of CKD. Drugs were classified into different groups based on Anatomic Therapeutic Chemical (ATC) classification. Data on utilization of different classes as well as individual drugs were subjected to descriptive analysis.

Sample size

According to the sample size calculation (with estimation error of 5% and a 95% confidence level), 384 patients were required.

Ethical consideration

This study was approved by the Research and Human Ethics Committee of Government Medical College and Hospital, sector 32, Chandigarh. Further, the study was conducted in accordance with ICMR rules and guidelines applicable for such studies [9].

Statistical analysis

Mean with standard deviation or median with interquartile range (IQR) were used to represent the continuous data. Percentage was used for representing the discrete variables. Student’s t-test (unpaired) was used to evaluate the difference between mean of Independent categorical variable and dependent continuous variable. A p-value of 0.05 was considered statistically significant. All analyses were done with IBM SPSS Statistics package ver 20.0 (SPSS Inc., Chicago, IL, USA).

Definitions of outcome parameters used in the study

CKD is defined as abnormalities of kidney structure or function (Albuminuria, urine sediment abnormalities, electrolyte and other abnormalities due to tubular disorders, abnormalities detected by histology, structural abnormalities detected by imaging, history of kidney transplantation, GFR<60 ml/min/1.73m²), present for over 3 months, with implications for health and CKD is classified based on cause, GFR category, and albuminuria category (CGA). The patients were classified into five stages on basis of GFR categories [10].

Further, the patients were classified on the basis of BMI as ‘underweight’ (<18.50kg/m²), ‘normal’ (<18.50-24.99 kg/m²), ‘overweight’ (≥ 25.00 kg/m²), ‘pre-obese’ (25.00-29.99 kg/m²) and ‘obese’ (≥ 30 kg/m²) [11]. Haemoglobin concentration less than 13 g/ dl in males and less than 12 g/dl in females were considered as anemic in age group more than 15 years [12]. Coronary artery disease was identified through the patient’s medical record for angina or myocardial infarction. Patients with fasting blood glucose ≥ 7.0 mmol/l (126 mg/ dl) or post-prandial over ≥ 11.1 mmol/l (200 mg/dl) or patients with HbA_1c ≥ 6.5%/48 mmol/mol or random plasma glucose ≥ 11.1 mmol/l (200 mg/dl) were considered as diabetic [13,14]. The participants were considered to be hypertensive if the patient was on antihypertensive medication (as documented in clinic records) or SBP ≥ 140 mmHg or DBP ≥ 90 mmHg [15]. Patients on hypolipidemic drug or patients with defined dyslipidaemia according to American association of clinical endocrinologist guideline for management of dyslipidemia and prevention of atherosclerosis were considered as dyslipidemic [16]. Cockcroft Gault equation (with SI units) was used for calculating the glomerular filtration rate (GFR) [17].

These results were based on the data from 408 patients included for study purpose. Of all, 217 were male (84 were elderly) and 191 were female (67 were elderly).The mean age of the patients was 53.8(6.4) years. The mean age of the female patients was found higher than the male patients; however, the difference was statistically insignificant (Unpaired Student’s t-test; p=0.54). Mean hemoglobin, HbA_1c and serum creatinine was 9.5 (1.5), 7.7 (1.5) and 4.3 (0.9).

Of all, 37% were found to be elderly. On the basis of Kuppuswamy scale of socioeconomic status, the largest number of the patients belonged to lower middle class (40%).

This was followed by upper lower (27%), upper middle (22%), upper (6%) and lower socioeconomic categories (4%). Eighty-one percent of the patients paid out of pocket for treatment.

Of all the patients, 42% belonged to CKD stage 5 followed by stage 3, 4, 1 and 2 (22, 21, 8 and 7%, respectively). Over half of the patients (55%) were found to have hypertension as a comorbidity followed by anemia (46%), diabetes (40%), hyperlipidemia (36%), coronary artery disease (10%) and hypothyroidism (7%). Only 18% of the patients were found to be on hemodialysis.

Patients were classified on the basis of BMI. The median (IQR) BMI was 22.7 (19.8-25.7) Kg/m². Of all, 47% of the patients belonged to normal weight category followed by patients in overweight and underweight category (17% and 36%, respectively). Further, in overweight category, the pre-obese and obese patients were to the tune of 27% and 9%, respectively (Table 1).

Table 1: Baseline characteristics of CKD patients.

On the basis of this ATC classification, cardiovascular system (33.9%) class of drugs was the most commonly prescribed followed by drugs for alimentary tract and metabolism (15.8%) and drugs for treatment of musculoskeletal system (14.5%), blood and blood forming agents (14.1%) (Table 2).

Table 2: Drug classification according to ATC classification system.

A total of 2,681 drugs were prescribed in 408 prescriptions. The mean number of drugs was found to be 6.57 (2.3). Mean number of diagnosis was 3.6 (0.3). Median (IQR) duration of diabetes, CKD and hypertension was 12 (5-16), 3 (1-6), and 6 (2-9) years, respectively. All the drugs were prescribed with brand name only. Of total number of drugs prescribed, Eighty-one percent were prescribed from within the NLEM-2011. Only 11% of the medicines were prescribed as injections (Table 3).

Table 3: Prescriptions analysis in CKD patients.

Antihypertensive agents were the most commonly prescribed class of drugs constituting 28.8% of the total number of drugs prescribed; this was followed by hematopoietic drugs (15.2%), phosphate binders (14.5%) and vitamins and minerals (13.3%) in that rank order. Among the antihypertensive agents, the prescribing of the diuretics was followed by the calcium channel blockers, beta blockers, alpha blockers, ACE inhibitors and ARB (Table 4).

Table 4: Therapeutic class wise distribution of drug use.

Five most commonly prescribed drugs were calcium carbonate, vitamin D, iron, torsemide and amlodipine. Out of total, 176 patients were prescribed with more than six medications. The percentage of medication prescribed was found higher when the treatment was funded by the employer on compare to patients paying out of pocket (23% vs. 16%; Table 5).

Table 5: Pattern of poly-pharmacy among CKD patients.

This discussion is based on the data from 408 patients included in the study. The mean age of the patients in present study was 53.8 (6.4) years. The mean age was found similar to the results of Devi et al. and Al-Ramahi et al. ( 55.1 years and 55.6 years, respectively) [5,18]. This is higher than reported by Bajait et. al. (51 years) [19]. The mean age is on slightly higher side as in most of the cases CKD is caused by chronic illness like hypertension and diabetes.

The number of male patients was higher than the number of female patients in the study. This finding is in concurrence with the results of Bajait et. al. and Devi et al.[5].

In this study, maximum number of the patients (42%) had the end stage renal disease. These findings were similar to that of the results of Bajait et al. (42%) [19]. However, in the results of Devi et al. and Al-Ramahi et al. the ESRD patients were as high as 90% of the patients [5,18]. The reason for this difference lies in the inclusion and exclusion criteria of the study. In these studies only the patients of CKD stages III-V were recruited; however, in our study, the patients from all stage of CKD were included.

In the present study, hypertension was found to be the most commonly occurring co-morbidity (55% of the cases) followed by diabetes, anemia, coronary artery disease and hyperlipidemia. These findings were found similar to that of study by Bajait et al. where hypertension was found to be the most commonly occurring comorbidity reported in 55% of the patients followed by the occurrence of diabetes, anemia and coronary artery disease. However, in the study carried out by Al-Ramahi et al. hypertension was found to affect 84% of the CKD patients followed by anemia in 80% of the patients [18,19]. The most likely reason for the hypertension as most commonly occurring comorbidity is well explained by the fact that renin angiotensin system is affected in the patients of CKD which helps in controlling blood pressure.

Only 18% of the patients were found to be on hemodialysis. The main reason for this might be that patients in this study belonged to lower socioeconomic class and they could not afford the cost of hemodialysis. Only 25% of the patients were found to be on hemodialysis in study carried out by Bajait et al. However the study by Al-Ramahi et al. reported over 50% of the patients on hemodialysis [18,19].

Most of the patients in the present study belonged to lower middle socioeconomic class of status (40%). However, Tanvir et al. have reported maximum number of patients in lower socioeconomic class [20].

Body mass index is known to affect the outcomes in the patient of CKD. Overweight is a major problem in the patients of diabetic nephropathy. However underweight was found to associated with more mortality and morbidity in certain studies [21,22]. In present study 36% of the patients were found underweight.

According to ATC classification system drugs from the cardiovascular class was the most commonly utilized class of drugs (33.9%). This was found higher than the study carried out by Devi et al. and Bajait et al. which reported it to be 28% and 22%, respectively [5,19].

Alimentary tract and metabolism class of drugs, and blood forming agents was prescribed to a tune of 15.8% and 14.1%, respectively. However, according to the study by Bajait et al. the drugs from blood forming agents and alimentary tract and metabolism class of drugs were contribute 21% and 45% of the prescribed drugs, respectively.

The average number of drugs prescribed in the present study was 6.57, which is smaller than that reported by Devi et al., Bajait et al., and Al-Ramahi et al. (7.4, 9.4 and 9.3, respectively). This difference in average number of medicines can be due to different study population, comorbidities and difference in physician prescribing behaviour [5,18,19]. All the drugs in the present study were found to prescribed by brand name only like that of study carried out by Devi et al.[5]. Bajait et al., reported 12% of drugs prescribed by generic name [19]. Physician trust in the quality of branded medicine might be one of the reasons for this high number of drug prescribing by brand name in present study. The drug prescribing from the national list of essential medicine in present study was found much higher than the reported by the other studies carried out by Devi et al. and Bajait et al. in similar settings (81%, 53% and 42%) [5,19].

The cost and pain associated with parenteral drugs is likely to reduce adherence. However, there are certain medicines like insulin and erythropoietin that are available only as parenteral form. The number of drugs prescribed as parenteral was found 11% of the total number of medicines. The study carried out by Devi et al. reported the use of injections for 32% [5,19]. This difference might be due to smaller number of diabetic patients on insulin therapy in the present study.

Diuretics were the most commonly used cardiovascular agents in the present study followed by calcium channel blockers and Angiotensin II Receptor Blockers (ARB) (8.2%, 6.3% and 2.8%, respectively). Bajait et al. reported that diuretics, calcium channel blockers and beta blockers contribute to 10%, 6% and 1%, respectively of total drugs prescribed [5,19]. Sonawane et al. and Jessani et al., however, had shown beta blockers as the most commonly used antihypertensives [23,24]. In present study, 54% of the patients were prescribed with diuretics. The other studies by Yazdanshenas et al., St. Peter et al. and Devi et al. reported that 60% 59% and 50% of the patients, respectively were prescribed with diuretics [25,26]. The use of hypolipidemic agents in present study was found lower than that of the other study carried out by Al-Ramahi et al. (34% and 47%, respectively).

Phosphate binders are one of the most commonly prescribed medicines in CKD. In present study, 91% of the patients were prescribed with calcium based phosphate binders followed by non-calcium based phosphate binders (4%). While the study by Navaneethan et al. reported the use of calcium based phosphate binders and non-calcium based phosphate binders to a tune of 75% and 25% respectively [27]. Hematopoietic agents are required to correct the deficiency of blood in CKD patients. Iron was found to be the most commonly utilized agents. 13% of all drugs were given as iron; 15% of drugs were given as hematopoietic agent in the study carried out by Bajait et al. [19]. The use of vitamin D in present study was found to be higher than of the study by Bajait et al. (15% and11%, respectively).

Drugs from cardiovascular system were the most commonly utilized according to the ATC system of classification. All of the drugs were prescribed by brand name. A fair proportion of drugs were prescribed from the NLEM. Iron, calcium, vitamin D and torsemide were found to be most commonly utilized drugs in the present study.