Implementing Guideline-Recommended Therapy for Patients With CKD: Is Hope on the Horizon?

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AJPB® Translating Evidence-Based Research Into Value-Based Decisions®, March/April 2015, Volume 7, Issue 2

This commentary addresses the possible reasons for treatment gaps between recommended therapy for patients with CKD, and the realities of current practices, and examines new developments that may bridge the gap.

Chronic kidney disease (CKD) affects nearly 14% of the US population and is a leading cause of morbidity and mortality.1,2 CKD disproportionately affects older Americans its prevalence increases to 33% in patients older than 60 years and it generates billions of dollars in related healthcare costs. For example, CKD-related Medicare expenditures were estimated to total $45 billion in 2012.1 Increasing obesity and the development of diabetes in younger Americans has contributed to rapidly increasing rates of CKD in patients covered by private insurance.

Healthcare costs associated with the management and treatment of CKD are not as well surveyed in the privately insured population, but the most recent estimates from the United States Renal Data System (USRDS) indicate an annual cost of $16 billion in 2011.1 Other research has found that for private insurers, the per patient per year cost of services to treat CKD roughly doubles with each stage of the disease’s progression,3,4 due in part to the frequent occurrence of cardiovascular complications including heart failure, myocardial infarction, and stroke. In the case of heart failure, CKD has been associated with increased hospitalization for chronic heart failure and higher mortality, which increases with worsening kidney function.

Landmark clinical trials performed over the last 2 decades have demonstrated that inhibition of the renin-angiotensin-aldosterone system (RAAS) slows the progression of kidney disease.5-10 Members of the RAAS inhibitor class include angiotensin-converting-enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs), direct renin inhibitors, and mineralocorticoid receptor antagonists (MRAs). Clinical guidelines from the American Heart Association, American College of Cardiology, American Diabetes Association, and National Kidney Foundation recommend the use of RAAS inhibitors in patients with diabetic nephropathy, chronic kidney disease, and heart failure.11-13 In CKD and heart failure patients, RAAS inhibitors have been associated with reductions in hospitalizations and healthcare costs.8,14-16

To understand more about the financial impact of RAAS inhibitors in privately insured patients, we modeled the clinical outcomes and economic impact of RAAS inhibitor use based on a landmark clinical trial (RENAAL)9 for a specific ARB medication: losartan. Based on findings from the RENAAL trial wherein the absolute risk of CKD progression was reduced by 25% and the risk of ESRD progression was reduced by 29%, respectively, for patients receiving losartan versus placebo9 we estimated CKD progression, progression to end-stage renal disease (ESRD), mortality, and costs for up to 10 years among privately insured patients with advanced diabetic CKD. We found that among patients with advanced diabetic CKD similar to that of patients in the RENAAL trial, use of the studied RAAS inhibitor medication would save an estimated $3408 per patient in year 1 medical costs, reaching an annual savings of nearly $11,000 per patient in year 10. It would also delay progression to ESRD for 101 patients and could save 56 lives over 10 years over the modeled 1513-person cohort.17 Our investigation focused on the potential for improved outcomes in patients with advanced diabetic CKD.

It is also important to note that guideline-recommended RAAS inhibitor therapy may reduce other adverse outcomes in subjects with CKD. Indeed, 30% of all heart failure patients are reported to have concomitant chronic kidney disease.18 Combinations of ACE inhibitors, ARBs, and/or beta-blockers with MRAs have shown a reduction in cardiovascular events in subjects with early stages of CKD (eGFR >30 mL/min).19-21

Despite well-characterized clinical and economic benefits, some evidence suggests that a substantial percentage of the highest risk patients are not prescribed RAAS inhibitor medications, or are taking lower-than-recommended doses. USRDS survey data indicate that RAAS inhibitor therapy was prescribed for approximately 76% of patients with CKD, yet usage declined at more severe stages of the disease.22 Among patients with both CKD and heart failure, RAAS inhibitor use is even lower, at about 52% of patients.2,22

Not all patients can tolerate RAAS inhibitors. Monitoring of serum creatinine and serum potassium is recommended when RAAS inhibitor therapy is initiated.11 The risk of hyperkalemia (elevated serum potassium) is often cited by clinicians as a reason for RAAS inhibitor discontinuation or down-titration, although less is known about why some patients are never started on RAAS inhibitors.23 Although hyperkalemia has been variously defined as a serum potassium >5.0, >5.5, or >6.0 mEq/L, most clinicians generally diagnose mild hyperkalemia when the serum potassium laboratory value is >5.0 mEq/L. Hyperkalemia is an important electrolyte abnormality that has been associated with life-threatening electrophysiological disturbances and death, even though patients with severe hyperkalemia are often asymptomatic.

Advanced chronic kidney disease is the most common predisposing condition for hyperkalemia.24,25 Guideline-recommended RAAS inhibitor therapy may further impair potassium excretion in such subjects. The association between RAAS inhibitor use and hyperkalemia has been evaluated in a large number of controlled trials, including RENAAL,9 IDNT,10 NEPHRON-D,26 and ALTITUDE.27 RAAS inhibitors given as monotherapy or as dual therapy in these clinical trials were found to increase the risk for mild and moderate to severe hyperkalemia versus control groups.

A number of risk factors for hyperkalemia have been identified, including eGFR <45 mL/min, serum potassium >4.5 mEq/L before initiating therapy, the presence of diabetic kidney disease, and older age.28 However, identifying which patients will experience hyperkalemia, when, and how frequently has been challenging. Contributing to this challenge is the absence of clinical trials designed to identify recommended timing and frequency of potassium monitoring for patients at high risk of hyperkalemia. Moreover, treatments for hyperkalemia have largely addressed acute episodes of the condition despite evidence that many patients experience hyperkalemia on a recurring basis.29 Indeed, dietary restriction, evaluation of potassium supplements, and reduction or discontinuation of RAAS inhibitors are the only recommended longer-term management approaches for RAAS inhibitor—associated hyperkalemia addressed in clinical guidelines for patients with CKD.13 Thus, hyperkalemia poses a therapeutic challenge for many clinicians that involves balancing the risks of RAAS inhibitor–associated hyperkalemia with the adverse consequences of disease progression in CKD that can be mitigated through the use of the very same agents.

Two investigational agents that have e30,31merged patiromer and ZS-9 may help in addressing the aforementioned unmet clinical need for the treatment of hyperkalemia. In a recent New England Journal of Medicine editorial published in conjunction with 2 separate clinical studies reporting the effects of each of these drugs for the treatment of hyperkalemia, the editor described the promise of potential new hyperkalemia treatments.32

Patiromer, a non-absorbed, metal-free polymer, binds potassium in exchange for calcium, predominantly in the colon, where the concentration of potassium is the highest. In the 12-week OPAL-HK trial, which included a 4-week treatment phase and an 8-week placebo-controlled randomized withdrawal phase, 76% (95% CI, 70%-81%) of patients treated with patiromer (starting doses of 4.2 g or 8.4 g twice daily) achieved target serum potassium levels by week 4. In the withdrawal phase, hyperkalemia recurred in significantly fewer patients in the patiromer group compared with patients in the placebo group at the end of 8 weeks (15% vs 60%; P <.001).30 As a result of recurrent hyperkalemia, discontinuation of RAAS inhibitor therapy was required to control serum potassium levels adequately in 56% of the patients in the placebo group compared with 6% of patients in the patiromer group.

ZS-9 is a transition metal-based oral sorbent designed to bind potassium in exchange for sodium and hydrogen in the gastrointestinal tract. In its 2-phase trial, ZS-9 2.5 g, 5 g, or 10 g (but not 1.25 g) given 3 times daily was associated with significant decreases in serum potassium from baseline to 48 hours (P <.001). During the maintenance phase, higher doses of ZS-9 (5 g and 10 g once daily) maintained serum potassium levels between 4.5 and 4.7 mEq/L, compared with a level slightly above 5.0 mEq/L in the placebo group (P <.01); lower doses (1.25 g or 2.5 g once daily) did not differ from placebo.31 Changes in RAAS inhibitor therapy in ZS-9-treated and placebo-treated patients were not assessed.

In conclusion, RAAS inhibitor therapy offers well-established therapeutic benefits to patients with CKD, yet its full promise in managing CKD has yet to be realized. The next few years may offer an opportunity to see if emerging therapies for managing hyperkalemia will result in more patients receiving the protective benefits of RAAS inhibitor therapy.