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Patients with chronic kidney disease (CKD) require multiple medications. There is no information on prescription patterns or the use of evidence-based therapies for management of CKD from low-middle-income countries. Using baseline data from the Indian CKD (ICKD) cohort, we describe the drug prescription practices in patients with mild to moderate CKD.
MethodsThe ICKD study is a prospective, observational cohort study of mild to moderate kidney disease across 11 tertiary care centers in India. We analyzed all the prescriptions captured at enrollment in the ICKD study. Drugs were categorized into 11 different groups. We provide descriptive data on prescription details and evaluate the appropriateness of medication use.
ResultsComplete prescription data were available in 3966 out of 4056 (97.8%) subjects enrolled in the ICKD database. Most patients had stage 3 CKD, 24.9% had diabetic kidney disease, 87% had hypertension, and 25.5% had moderate to severe proteinuria. Renin-angiotensin-aldosterone system blockers were prescribed in less than half (47.9%) and in 58.8% of patients with proteinuric CKD. Metformin was prescribed in 25.7% of diabetic subjects with CKD. Only 40.4% of patients were taking statins; 31.1% and 2.8% subjects with anemia were receiving iron and erythropoiesis-stimulating agents, respectively.
ConclusionThis study highlights the missed opportunities for improving outcomes through appropriate prescriptions of drugs in patients with CKD. There is need for dissemination of evidence-based guidelines and institution of sustainable implementation practices for improving the overall health of patients with CKD.
KeywordsChronic kidney disease (CKD) is an important global public health problem.1GBD Chronic Kidney Disease CollaborationThere are no large data sets on the prescription pattern of the medications in patients with CKD from the developing world. We describe prescription patterns at enrollment in patients with mild to moderate CKD included in the large ICKD cohort study.
MethodsThe ICKD study is a longitudinal study of subjects with mild to moderate CKD recruited at 11 centers across India. All centers except 2 are public sector hospitals. The study design has been previously published.19Kumar V. Yadav A.K. Gang S. et al.Indian Chronic Kidney Disease Study: design and methods. Briefly, the study recruits adult subjects between 18 and 70 years of age who have mild to moderate CKD and who are attending outpatient nephrology clinics at participating centers. Both incident and prevalent patients are eligible for enrollment. Patients undergoing dialysis, organ transplant recipients, those with malignancy, on immunosuppressive drug therapy, or with poor functional status are excluded. Subjects are being followed-up annually, and prescription as well as outcome data are being collected.Demographic details, diagnosis, comorbidities, clinical features, laboratory findings, and treatment details are recorded and stored anonymously in a secure database. The study has approval from the institutional review boards at all centers, and all participants provide written informed consent.
We included subjects with complete prescription data at recruitment in this analysis. Patients were categorized into different stages of CKD stages 1 to 4 as per estimated glomerular filtration rate (eGFR) used in Kidney Disease: Improving Global Outcomes (KDIGO) staging. eGFR was calculated using creatinine-based CKD Epidemiology Collaboration (CKD-EPICr) equation.20Levey A.S. Stevens L.A. Schmid C.H. et al.A new equation to estimate glomerular filtration rate. Educational status, employment status, living in rural or urban residence, hazardous occupational exposure, and alternative medication use (defined as use of indigenous, ayurvedic, or other unregulated medications) were captured. Directed questions to ascertain occupational exposure, the use of alternative drugs, and the use of nonsteroidal anti-inflammatory drugs after diagnosis of CKD were incorporated in the study questionnaire. Data regarding the use of alternative drugs in relation to onset of kidney disease were also recorded.The diagnosis of CKD and comorbidities were made after a review of history and medical records. Diabetes, hypertension, and cardiovascular disease were defined as per prevailing standards for diagnosis. Anemia was diagnosed and classified as per World Health Organization criteria.21World Health Organization websiteData were collected from the most recent prescription slip and verbal inquiry and then classified into 11 different categories used for the management of CKD or its complications: antihypertensives, antidiabetics, phosphate binders, iron supplementation, erythropoiesis-stimulating agent (ESA) therapy, lipid-lowering therapy, antiplatelet drugs, uric acid–lowering drugs, vitamin D analogues, sodium bicarbonate, and multivitamins. The antihypertensives were further categorized as drugs that block angiotensin system, that is, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), calcium channel blockers, beta blockers, central sympatholytics, and diuretics. The antidiabetics insulin or oral hypoglycemic agents, such as sulfonylureas, metformin, or dipeptidyl-peptidase 4 inhibitors, were also noted. Phosphate binders were divided into calcium or non–calcium-based phosphate binders. The use of phosphate binder in patients with or without hyperphosphatemia was also analyzed. The distribution of proportions of these categories of medicines as per CKD stages 1 to 4 was analyzed.
Statistical AnalysisThe statistical analysis was descriptive. Data were analyzed using Stata statistical software (version 14; Stata Corp LP, College Station, TX). Both descriptive and analytical statistics were performed showing sociodemographic, clinical, and biochemical characteristics of participants. The continuous variables were expressed as mean ± SD and median (25th, 75th percentile), and the categorical values were expressed in number and percentage in parenthesis. Distribution of various drugs across the CKD stages or in other subcategories are descriptive and presented as number (percentage).
ResultsOf 4056 patients recruited in the ICKD database, complete prescription data at baseline were available in 3966 (97.8%) patients, who constitute the study population for this paper. Table 1 shows the clinical characteristics and causes of CKD in the cohort. The mean age of the cohort participants was 50.3 ± 11.8 years, and 67.2% were male. A majority were either uneducated (26.9%) or had only school-level education (34%). A total of 64.7% patients had a rural background, and 50.4% had a history of hazardous occupational exposure. The median annual income was $1680 USD (interquartile range $1008–$4200 USD), and 32.1% had access to some form of medical insurance. Patients spent 11.7% (4.7%–26.0%) of their total annual household income on medical care. In 57%, the cost of care was >10% of their nonfood expenditure.Table 1Baseline characteristics of participants in the Indian Chronic Kidney Disease study
BMI, body mass index; CAKUT, congenital anomalies of the kidney and urinary tract; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; uACR, urine albumin to creatinine ratio; USD, U.S. dollar.
Data shown as mean ± SD, median (25th–75th percentile), and n (%).
The study cohort included 100 (2.5%) patients in stage 1; 309 (7.8%) in stage 2; 3131 (79%) in stage 3, and 426 (10.7%) in stage 4 CKD. The most commonly identified causes of CKD were diabetic kidney disease (24.9%) and chronic interstitial nephritis (23.2%), whereas the cause of CKD could not be determined in approximately 788 (19.4%) participants. Hypertension was the most common associated comorbidity, reported by 87% of participants. This was followed by anemia (64.7%), diabetes (37.5%), and other cardiovascular morbidities (21.8%). The medication burden with the number of different drug classes is shown in Figure 1. The median (25th–75th percentile) number of prescribed drugs was 5 (3–6) in the study cohort. More than half of patients were taking >5 different drug classes. A total of 924 (22.7%) patients admitted using alternative therapies. Five hundred twenty-two (56.5%) patients had used these drugs within 4 weeks before their diagnosis of kidney disease, and 252 (27.3%) patients had used these drugs for the treatment of kidney disease. Some patients (15.7%) admitted to using nonsteroidal anti-inflammatory drugs even after their diagnosis of CKD. A detailed description of prescription pattern is shown in Table 2.Figure 1Frequency of use of different classes of drugs in the study cohort.
Table 2Distribution of classes of drugs prescribed in different stages of CKD
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CKD, chronic kidney disease.
Antihypertensive TherapiesOverall, 80.9% of patients in CKD cohort were taking antihypertensive medications. Of those with a diagnosis of hypertension, 92.5% were taking antihypertensive drugs, with a similar proportion between males and females. Subjects Supplementary Table S1. The most commonly prescribed antihypertensive agents were renin-angiotensin-aldosterone system (RAAS) blockers in 47.9% (ACEIs 22.5%, ARBs 25.4%), followed by calcium channel blockers (42.6%), diuretics (28.7%), beta-blockers (27.1%), alpha-blockers (10.7%), and central sympatholytic drugs (3%; Table 2). A total of 72% of patients with stage 1 CKD, 59% of patients with stage 2 CKD, 47% of patients with stage 3 CKD, and 30% of patients with stage 4 CKD were prescribed RAAS blockers. The use of the calcium channel blockers increased and the use of ACEIs/ARBs decreased with advancing CKD stages. The number of antihypertensive drugs prescribed were: 1 in 1221 (30.8%), 2 in 1134 (28.6%), 3 in 598 (15.1%), 4 in 211 (5.3), and ≥5 to 7 in 45 (1.1%) patients with CKD. Of the 1467 subjects with diabetes, 55.8% were taking ACEIs/ARBs. Of the 967 patients with proteinuric illnesses (albumin to creatinine ratio >300 mg/g), 58.8% were prescribed ACEIs/ARBs. Antidiabetic PrescriptionsOf 1467 participants with a diagnosis of diabetes (all type 2 disease), 959 (65.4%) were receiving ≥1 antidiabetic medicine: 27.7% were taking sulfonylureas, followed by insulin (26.4%), metformin (25.7%), dipeptidyl-peptidase 4 inhibitors (9.5%), and others (3.6%; Table 3). More than half (52.9%) of patients with stage 1 CKD, 30.1% of patients with stage 2 CKD, 26.2% of patients with stage 3 CKD, and 16.6% of patients with stage 4 CKD with diabetes were taking metformin (Table 3). Of 1310 and 157 patients with diabetes with GFR ≥30 ml/min/1.73m2 and 2, 351 (26.80%) and 26 (16.60%) were taking metformin, respectively. More than one third (34.5%) of patients with diabetes were not receiving any antidiabetic drugs. Among those with a diagnosis of diabetes, the use of antidiabetic drugs was similar across sex and age groups, defined by ≥60 orTable 3CKD stagewise distribution of antidiabetic drugs in subjects with diabetes
CKD, chronic kidney disease; DPP4, dipeptidyl-peptidase 4.
StatinsLipid-lowering therapy with a statin was prescribed to a total of 40.4% of patients. A majority (58.1%) of patients with diabetes were receiving a statin. Of those >50 years of age, only 47.4% (59.5% of patients with diabetes and 35.2% of patients without diabetes) were prescribed a statin drug.
Phosphate BindersOf 1455 (36.7%) patients who had been prescribed phosphate binders, a majority (1294; 89%) were given a calcium-based binder. The use of calcium-based phosphate binders was higher across all CKD stages (Table 2). The phosphate levels in subjects taking phosphate binder were 4.5 ± 1.4 mg/dl compared with 3.9 ± 1.2 mg/dl for those who were not taking a phosphate binder. Moreover, 52.1% of subjects with serum phosphate levels ≥4.5 mg/dl were not prescribed any phosphate binder. Anemia ManagementA total of 26.4% of patients were prescribed any iron compounds. Only 772 (31.1%) anemic subjects were taking iron supplements. Over 99% of the prescriptions were for oral iron agents. Only 112 (2.8%) had been prescribed an ESA. Of 181 patients with CKD with hemoglobin levels <9 g/dl, 14 (7.7%) were taking ESAs, with a majority (91; 2.3%) taking epoetin alfa.
Other TherapiesOnly 11.8% of the patients had a prescription of a vitamin D compound or its analogs. Calcitriol was prescribed to 4.6% patients and cholecalciferol to 7.5%. Overall, 42.9% of the patients had been prescribed sodium bicarbonate. A total of 21.7% were receiving any antiplatelet therapy, the majority (20.3%) taking aspirin. More than half (57.3%) of subjects with a history of cardiovascular disease (CVD) were receiving antiplatelet therapy. Overall, 15.1% subjects were receiving uric acid–lowering therapy—a majority (14.2%) were taking febuxostat (Table 2).DiscussionThis is the first and the largest study documenting pharmacologic prescription practices among patients with CKD in the developing world. Compared with Western cohorts with CKD, the ICKD population is relatively young and predominantly from rural regions.22Imai E. Matsuo S. Makino H. et al.Chronic Kidney Disease Japan Cohort study: baseline characteristics and factors associated with causative diseases and renal function., 23Kang E. Han M. Kim H. et al.Baseline general characteristics of the Korean chronic kidney disease: report from the KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD)., 24Lash J.P. Go A.S. Appel L.J. et al.Chronic Renal Insufficiency Cohort (CRIC) Study: baseline characteristics and associations with kidney function., 25Levin A. Rigatto C. Brendan B. et al.Cohort profile: Canadian study of prediction of death, dialysis and interim cardiovascular events (CanPREDDICT)., 26Yuan J. Zou X.R. Han S.P. et al.Prevalence and risk factors for cardiovascular disease among chronic kidney disease patients: results from the Chinese cohort study of chronic kidney disease (C-STRIDE). We provide insight into treatment preferences and identify gaps with regard to the use of evidence-based therapies for the management of kidney disease in the context of slowing progression and the development of cardiovascular complications in resource-limited settings. A notable finding is the suboptimal use of drugs that block the renin-angiotensin pathway and lipid-lowering agents. On the other hand, we identify the use of non–evidence-based therapies, such as uric acid lowering. These identify important knowledge gaps that need to be addressed through targeted education of nephrologists and general physicians as well as the implementation of incentives. Adoption of evidence-based approaches will not only improve patient outcomes but will also result in cost savings by preventing the development of kidney failure and/or complications that require expensive therapies. Compelling evidence to show that drugs that block renin-angiotensin-aldosterone pathway have a salutary effect on hard clinical outcomes in patients with CKD is available from large-scale, randomized clinical trials.3Xie X. Liu Y. Perkovic V. et al.Renin-angiotensin system inhibitors and kidney and cardiovascular outcomes in patients with CKD: a Bayesian network meta-analysis of randomized clinical trials. Less than half of the prescriptions in the ICKD cohort included ACEIs and/or ARBs. Even among patients with proteinuric illnesses, where the indication for their use is the strongest (class I recommendation by KDIGO Blood Pressure Guidelines), only 59% had been prescribed an ACEI/ARB.27Cheung A.K. Chang T.I. Cushman W.C. et al.Blood pressure in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Similarly, only 56% of those with diabetic kidney disease were taking these agents. We also noted a decline in the use of RAAS blockers with increasing CKD severity. Only 30% of patients with stage 4 CKD were taking these agents. In the Chronic Renal Insufficiency Study (CRIC) cohort, 70% were receiving RAAS blockers, with as much as 75% and 37% of those in stage 3 and stage 5 CKD, respectively.28Ku E. McCulloch C.E. Vittinghoff E. et al.Use of antihypertensive agents and association with risk of adverse outcomes in chronic kidney disease: focus on angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. In the German CKD study, about 83% received RAAS blockers.29Schneider M.P. Hilgers K.F. Schmid M. et al.Blood pressure control in chronic kidney disease: a cross-sectional analysis from the German Chronic Kidney Disease (GCKD) study. In addition to retarding CKD progression, RAAS blockers reduce the risk of heart failure and death regardless of disease severity. In a meta-analysis, the International Network of CKD cohorts documented wide variations in antihypertensive prescription patterns and blood pressure control internationally.30Alencar de Pinho N. Levin A. Fukagawa M. et al.Considerable international variation exists in blood pressure control and antihypertensive prescription patterns in chronic kidney disease. RAAS blocker use ranged from 54% to 91%. Calcium channel blockers were more frequently used in Asian cohorts. Whether this is related to drug preference, availability, or ease of monitoring is not known.Among patients with diabetes, sulfonylureas were the most frequently prescribed oral hypoglycemic agents. Only a minority of patients were taking metformin, even among those with an eGFR >30 ml/min/1.73m2. This differs from the dominant use of metformin (55%–91%) in the general diabetes population in India.31Muhas C. Salim C.M. Mufeeda T.P. et al.Prescription pattern of anti-diabetic drugs in a rural area of South Malabar region of Kerala, South India., 32Seshadri K.G. Venkataraman S. Manikandan C.D. et al.Antidiabetes drug prescription in Indian scenario—a cross-sectional analysis from a large, pan India database of the Apollo Sugar Clinics., 33Singla R. Bindra J. Singla A. et al.Drug prescription patterns and cost analysis of diabetes therapy in India: audit of an endocrine practice. Despite the recommendation by guidelines to use metformin in view of its multiple advantages, 2, with dose reduction advised at 45 ml/min/1.73 m2.34Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group
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