Adherence to long-term use of renin-angiotensin II-aldosterone system inhibitors in children with chronic kidney disease

Childhood chronic kidney disease (CKD) increases the risk of renal replacement therapy, cardiovascular disease, and premature death in the pediatric population. Randomized controlled trials have shown that renin-angiotensin II-aldosterone system inhibitors (RASIs), including angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB), may control blood pressure [1], reduce proteinuria [2, 3], and slow CKD progression to end-stage renal disease (ESRD) in the pediatric population [4]. However, the effect of recommendations for the use of and adherence to RASI therapy in routine pediatric care settings remain unclear.

Medication adherence refers to the degree to which patients take their medications as prescribed (e.g., once daily), as well as whether they continue to take a prescribed medication [5]. Non-adherence is a growing concern to professionals, healthcare systems, and other stakeholders (e.g., payers) because of mounting evidence showing that 33 to 80% of youth are reportedly non-adherent to their prescribed chronic medicines [6‐8], resulting in poorer outcomes and higher costs of care in children and adolescents with chronic illness [9]. Assessment of pediatric patient medication adherence and use of interventions to improve adherence are limited in routine practice. Although the reasons for non-adherence vary, identifying patients by their adherence to a specific medication can facilitate effective intervention for the patients most likely to benefit [10].

Medication adherence in children and adolescents has been examined for childhood CKD, but limited in a short term (recent 7 days) time frame [11, 12]. Medication therapy is complex and a major burden for pediatric patients and their parents. Moreover, pediatric patients with progressive CKD require multiple classes of medications to delay progression (e.g., corticosteroids, immunosuppressive agents) and prevent and/or treat comorbid conditions (e.g., anti-hypertensives, phosphate binders, and lipid and iron medications). Considering that medication burden may be associated with poor adherence, as in adults [13], it is critical to understand patient-related factors and disease conditions related to long-term RASI use in order to improve adherence in children and adolescents with CKD who require multiple therapies. The aim of this study was to investigate adherence to ACEI/ARB/aliskiren initiation and concomitant medication use in children and adolescents with CKD. In addition, patient demographic and clinical factors associated with adherence to ACEI/ARB were identified.

The study used a population-based claims database to investigate prescription patterns and adherence to RASI for childhood CKD. The findings revealed that overall adherence to chronic RASI therapy was low and was highly correlated with the presence of CKD-related comorbid conditions among children and adolescents with CKD. Adherence to RASI therapy can be partially explained by clinical factors, such as advanced aggressive comorbidities, time since CKD diagnosis, and patient age and gender. However, the time to adherence with chronic therapy was not fully supported by guidelines, suggesting that more research on childhood CKD is needed to increase medication adherence.

The rate of ACEI/ARB use in our study was consistent with previous registry and claims database studies on childhood CKD [4] or childhood hypertension [20]. Age at the start of chronic RASI therapy in the present study (14.39 ± 4.86 years old) was similar to other pediatric reports (range: 11–17 years old) in Western countries [1, 11, 21]. Children with RASI more frequently had proteinuria and hypertension and related complications [11].

However, our finding of a low rate of adherence to chronic RASI treatment in children with CKD concurs with few studies. ACEIs and ARBs have been shown to decrease systemic and glomerular pressure and reduce proteinuria more effectively than other antihypertensive medications [1]. In patients with mild or transient proteinuria, no treatment or a short-course of treatment may be necessary. Dynamic strategies of antihypertensive therapy involving switching, combination, or monotherapy may be used in the group of patients with uncontrolled or resistant hypertension. This may explain the higher rate of RASI use at baseline, but adherence to chronic therapy was low after CKD diagnosis in our study cohort.

Adherence to RASI therapy might be influenced by adverse drug reactions and tolerability concerns (e.g., skin rashes, angioedema, hyperkalemia), which may lead to treatment interruption. For example, patients treated with ACEIs or ARBs should be monitored for hypotension, early decrease in glomerular filtration rate, and hyperkalemia [22]. Although the KDIGO guidelines state that these common side effects usually can be managed without discontinuation of the agent [22], they may lead to non-adherence in actual practice. Thus, a low rate of chronic RASI use should be considered justification for referral to multiple pediatric specialists in a real-world setting. A review study suggests that physician specialty and familiarity with antihypertensive regimens play a significant role in the management of hypertension [23]. Other factors were associated with medication adherence. For example, RASI adherence was associated with the presence of anemia and proteinuria. This is consistent with previous reports [11, 21] and clinical experience; more progressive CKD and/or symptomatic medical conditions may enforce patient adherence to chronic medication therapy.

There is a paucity of research examining time to ACEI/ARB initiation and its impacts on treatment adherence and persistence in clinical practice. However, a cross-sectional study suggested that CKD duration had no effect on medication adherence, although only the prior 7 days of adherence were evaluated [11].

CKD and associated comorbidities impose a substantial pill burden on children and adolescents. It explains that a longer time since CKD diagnosis, which implies a more advanced stage of kidney disease, is more likely to be associated with adherence than a shorter duration of CKD in the present study. But, ACEI/ARB (18%) was one of the most frequently reported not being taken prescription (slightly lower than 23% for alkali treatments, 26% for phosphate binders and 25% growth hormone) in a childhood CKD cohort [11]. In that study, the number of medication classes was higher in children with advanced stage of CKD; however, neither a larger number of medicines used nor worsening estimated glomerular filtration rate (eGFR) was found to be independently associated with 7-day medication adherence in childhood CKD [11]. Not number of medication groups or types of CKD, but comorbidity is linked with RASI adherence were consistent with our findings. This effect could be explained by patient understanding of the importance of medication in association with progressive comorbidity and kidney function deterioration. Non-adherence to chronic medication was frequently reported among adolescents [11, 24] and males in other pediatric studies, similar to our study findings.

Growing evidence has shown that hypertension is undertreated in pediatric populations. For example, almost half of all children and adolescents with CKD had uncontrolled hypertension: 44.1% (n = 744) in multiple pediatric nephrology clinics in Taiwan [25], and 48.5% (n = 202) in a registered US pediatric cohort [26]. Children with hypertension not receiving RASI therapy have an increased prevalence of uncontrolled blood pressure [20, 26]. The delay to start of chronic RASI therapy may be a contributor to the high prevalence of cardiovascular disease and kidney function deterioration. Moreover, continuous users of RASI therapy had a superior renal protective effect, compared with non-users (37% lower) and short-term users (21% lower), with slowing of CKD progression in an observational registry trial [4].

Both updated European and US clinical guidelines emphasize the importance of diagnosis and management of hypertension in children with and without CKD, ACEI or ARB is recommended to treat CKD children with hypertension and proteinuria to reduce their risk of cardiovascular complications and CKD progression [27] There is a general paucity of both medication adherence and persistence evidence for children with CKD worldwide. This article represents the first step toward a better understanding of chronic medication adherence in a large childhood CKD cohort, comparable with other populations of pediatric patients with CKD in the literature. The implications for clinical practice given these findings are multiple: (1) reviewing patient’s medication history is the most useful way for clinicians to evaluate adherence; (2) adherence evaluation should occur at regular intervals in a practice setting, in order to identify possible medication-related problems (such as adverse drug reactions) that may interfere with adherence [28, 29], (3) effective interventions to improve adherence include educational interventions, providing specific information about CKD and its comorbidities, and prescribed treatment according to the adolescent’s cognitive abilities and health literacy, empowering adolescents to deal with adherence issues, and ensuring family support and motivational therapy [24]. The 80% threshold of PDC following the first 90 days RASI therapy may shed light on the optimal signal for the intervention of mediation nonadherence to discriminate poor outcome risk in childhood CKD.

This study was subject to certain limitations common to studies using claims data. First, laboratory results regarding proteinuria, hypertension, or disease severity (e.g., eGFR stage) are not available in the NHI dataset. This limitation was addressed by using the proxy of the number of medication classes at 3-month intervals. Second, medication adherence was determined by indirect measurement using pharmacy prescription filling data. Accurate medication adherence is difficult to examine, and is a challenge at both individual and population levels [30]. Pharmacy refill adherence for antihypertensive medication is superior to self-reporting to enable correlate with cardiovascular disease incidence in elderly populations [31]. Pharmacy refills are calculated using monthly data points over 3 months (i.e., as-treated effect) and are more reflective of adherence behavior over time, but may yield a more conservative, lower rate than other measures of adherence. Another limitation of this study is that the switching of RASIs to other categories of antihypertensive therapy and discontinuation due to adverse ACEI/ARB reactions were unclear, which limits the ability to draw conclusions about causes of non-adherence. Further research is needed to investigate patient and family member attitudes toward medication use for chronic illness, as well as barriers and challenges to adherence.

Adherence to chronic RASI therapy in children and adolescents with CKD was heavily influenced by age and comorbid conditions related to progressive kidney disease in the present study cohort. Further research on understanding of the role of demographics (i.e., adolescents and young adults, males), the CKD care delivery process, and socioeconomic determinants of prescribing is imperative for the design of effective intervention strategies to improve management of hypertension and related chronic complications in childhood and young adulthood.