Improving Outcomes in Chronic Kidney Disease: Optimizing Management of Cardiovascular Diseases

Chronic kidney disease (CKD) is characterized by kidney damage (with or without proteinuria) and decreased renal function, as determined by glomerular filtration rate (GFR), which progressively decreases over time. CKD is described in stages, with stage representing the least amount of kidney damage with well-preserved kidney function, and stage 5 indicating a high degree of kidney damage with poor renal function. Recent evidence indicates that the prevalence of CKD is increasing in the United States.¹ Coresh and colleagues evaluated the National Health and Nutrition Examination Surveys data and were able to demonstrate that the prevalence of albuminuria and decreased GFR increased from 1988 to 1994 and 1999 to 2004.¹ Furthermore, the prevalence of CKD (stages 1 to 4) was 10% (95% confidence interval [CI], 9.2%-10.9%) in 1988 to 1994 and increased to 13.1% (95% CI, 12%-14.1%) in 1999 to 2004. Mean serum creatinine level was also higher in the second cohort.¹ Although serum creatinine is an indicator of reduced kidney function, it is not a sensitive measure, since GFR (which directly impacts serum creatinine) is dependent on other factors, such as age, sex, body weight/body mass, and race. Because routine measurement of GFR is impractical (due to complexity, expense, and time), clinicians routinely estimate GFR to stage CKD. Consequently, the Modification of Diet in Renal Disease equations (MDRD Study equations), which incorporate serum creatinine, urea nitrogen, and albumin levels, age, sex, and race to estimate GFR, are most commonly used to stage CKD.² It is important to note that many cardiovascular (CV) trials excluded patients with known CKD, usually by establishing a serum creatinine level cutoff. As such, information on CV disease (CVD) in CKD has been inferred from these trials, usually by post hoc analyses of data in patients enrolled in the trials with GFR estimates.

End-stage renal disease (ESRD) is loosely defined by signs and symptoms of kidney failure—a GFR less than 15 mL/min/1.73 m² and the requirement for renal replacement therapy (usually dialysis).³ CVD has long been recognized as the leading cause of death in patients with ESRD, occurring in more than 50% of patients.^4-6 CVD is also the leading cause of hospitalization among such patients.^4-6

As shown in

Table 1

, compared with a population without CKD, there is a graded inverse relationship between CKD and CVD; the lower the degree of kidney function, the higher the risk of CVD.⁶ Moreover, hospitalization rates and mortality increase as GFR decreases (

Figure

). These relationships were noted to be approximate and were affected by patient age. Several disease factors and comorbidities contribute to CVD in CKD. Among contributing factors are increased urinary albumin excretion, which is associated with an increased risk of CVD events in the general population⁷ and in those with hypertension,^8,9 diabetes,_^9-11 and established atherosclerotic disease.¹² Other factors that can contribute to CVD in CKD are hypertension, diabetes, dyslipidemia, smoking, and established CVD (cardiorenal syndrome).^13-23

Managing Hypertension and Dyslipidemia in Patients With CKD

Because hypertension and dyslipidemia play a significant role in CKD, several guidelines have set goals for the management of these risk factors. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) includes a blood pressure (BP) target of less than 130/80 mm Hg in patients with CKD.¹³ The National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (KDOQI) group published guideline recommendations for hypertension in the CKD population, which also targeted a BP goal of less than 130/80 mm Hg.¹⁷ In 2007, the American Heart Association (AHA) developed a scientific statement on treating hypertension; it designated the CKD population as a high coronary artery disease (CAD) risk group and recommended a BP goal of less than 130/80 mm Hg.²⁴ Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) are preferred antihypertensive agents in patients with CKD per the KDOQI and JNC 7 guidelines.^13,17 The AHA recommends these agents as first-line options, but categorizes CKD in the high-risk population and does not give specific recommendations for drug therapy in these patients.²⁴

Among antihypertensive therapies, ACEIs have been studied the most for their ability to improve CV outcomes in the CKD population. ARB therapy has been evaluated, but the data are not as encouraging as those observed with ACEI therapy. There are reasons to use ACEI or ARB therapy beyond preventing CV events (ie, delaying progression of nephropathy), and these need to be considered when determining optimal therapy in patients with CKD.^13,17,24 The Eighth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8) is highly anticipated and is scheduled for publication in 2012.²⁵

The NKF KDOQI group published guidelines for the management of dyslipidemia in CKD in 2003 (

Table 2

).²⁶ The primary target of dyslipidemia in patients with CKD is low-density lipoprotein cholesterol (LDL-C) level. The guidelines recommend an LDL-C target of less than 100 mg/dL in patients with CKD (all stages), unless their triglycerides are above 500 mg/dL.²⁶ It is important to note that since the publishing of the guidelines, newer therapies and evidence have emerged, which necessitates an update in recommendations.

The recent Study of Heart and Renal Protection (SHARP) demonstrated that benefits (ie, long-term reduction in risk of heart attack, stroke, and operations to open blocked arteries) in the CKD population extend to a lower LDLC level than US guidelines currently recommend. SHARP achieved a mean LDL-C level of 75 mg/dL at 4.4 years.²⁷ This low LDL-C level helps support a lower LDL-C goal of less than 100 mg/dL, as recommended by the Third Report of The National Cholesterol Education Program

(NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) and NKF KDOQI guidelines.^26,28 Recently, the European Society of Cardiology and the European Atherosclerosis Society published updated guidelines on the management of dyslipidemia.²⁹ In these updated guidelines, patients with CKD are considered at very high risk of CVD and an LDL-C goal of less than 70 mg/dL is recommended.²⁹ The new Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel IV) guidelines are scheduled to be published in 2012, and are highly anticipated with the recent study findings from SHARP and the potential for a more aggressive LDL-C target in the CKD population.³⁰

Costs Associated With CKD

Patients with CKD comprise 6.8% of the US Medicare population, but consume over 14% of overall Medicare expenditures.³¹ The overall Medicare cost per person per year for CKD was $19,752 in 2008. Costs in the subsets of patients with CKD and diabetes were $21,740 for Caucasians, $25,352 for African Americans, and $28,809 and $35,009 in the respective cohorts among those with heart failure. In patients 65 years or older, average annual costs were determined to be $20,784 for all patients, $11,760 for those with a creatinine clearance of 60 mL/min or better, and $68,808 for those with ESRD, indicating that the costs increase as kidney function declines.³² The review also determined that death was an important cost to consider in patients with CKD, and estimated that the individual cost of death was $37,611.³²

Chronic conditions (eg, obesity, hypertension, myocardial infarction [MI], angina, diabetes, dyslipidemia, anemia, and hyperuricemia) are associated with an increase in cost of care in patients with CKD.³³ CVD is the leading cause of hospitalization in patients with CKD.³¹ In addition to the long-term costs associated with CKD and incident CVD, costs of dialysis initiation and maintenance are significant.³⁴ To examine the importance of comprehensive care in patients at risk for requiring dialysis, one study randomized patients to care by a nephrologist (n = 69) or a CKD care program (which included a nephrologist, trained nurses, and a dietitian with specific goals for patient education) (n = 71).³⁴ The comprehensive program was associated with lower total medical costs at dialysis initiation ($942 vs $2674; P <.001) due to early preparation for vascular access and lack of hospitalization at dialysis initiation.³⁴ Providing specialized comprehensive care to patients with CKD is important because inappropriate care can lead to unnecessary costs. In managed care populations, unneeded or inappropriate care is delivered as much as 30% of the time, resulting in unnecessary costs. If resources were added to improve the frequency of appropriate care to more than the current value of about 50%, it would be possible to improve outcomes and reduce overall costs.³⁵ Because care of the CKD population may often be inappropriate, and the costs of managing CKD are high, early recognition of CKD is likely to significantly reduce the cost of care to patients and the healthcare system.

Treatment of CVD in CKD

Despite a lack of formal risk-factor intervention studies in patients with CKD, much has been learned from studying the relationship of treatment and outcomes based on CKD markers, such as GFR and albuminuria. In patients with hypertension associated with CKD, albuminuria management should be considered an integral study of 8206 patients with left ventricular hypertrophy that lasted approximately 5 years, use of losartan to lower blood pressure and albuminuria reduced the composite end point of CV mortality, stroke, and MI (independent of BP reduction).³⁶ Evidence suggests that the goal BP in patients with CKD should be less than 130/80 mm Hg, unless proteinuria exceeds 1g/L (when BP should be <125/75 mm Hg).³⁷ A study assessed trandolapril for BP reduction in the absence of documented albuminuria and determined that it did not improve survival in the overall cohort with relatively normal GFR.³⁸ In a subgroup analysis of patients with a GFR less than 60 mL/min/1.73 m², however, reduction of BP with trandolapril decreased CV and all-cause mortality (P = .02).³⁸ Finally, in a formal, 7-year economic analysis conducted with benazepril for reduction of BP in patients with CKD, the cost-effectiveness ratio (CER) per qualityadjusted life-year (QALY) demonstrated reduced costs ($10,000-$13,000) over the course of the study due to improvement in outcomes.³⁹ These results suggest that ACEI therapy in advanced CKD (GFR <60 mL/min) may improve CV outcomes and result in cost savings.³⁹ Thus, ACEIs and ARBs may be useful to help decrease the incidence of CVD-related outcomes in patients with CKD, especially in those with lower GFRs.

It should be noted, however, that despite nearly universal awareness of hypertension, adequate control of BP in accordance with current consensus standards remains highly suboptimal.⁴⁰ A recent study used multivariable statistics to determine community-based factors associated with awareness of hypertension, treatment patterns, and control rates. The study evaluated patients with GFRs of 20 to 70 mL/min/1.73 m² and found that ACEIs and ARBs were associated with enhanced BP control. Older patients, African Americans, and those with higher urinary albumin excretion rates were less likely to achieve BP control.⁴⁰ The lack of BP control in patients with CKD, or lack of ACEI and ARB therapy, may be due to concerns among clinicians about GFR reductions and risk of acute renal failure associated with ARBs and ACEIs.⁴¹ Because of the documented benefits of ACEIs and ARBs in hypertension, diabetic nephropathy, heart failure, and CAD, however, these agents should be used with caution rather than avoided in patients with CKD.

The impact of ACEIs and ARBs on reduction of GFR is also commonly used as a therapeutic tool for the management of proteinuria associated with diabetes. ACEIs and ARBs are the most studied agents in prevention of progression of CKD in diabetes, and they have been evaluated for their effects in CVD outcomes.^41-43 In 2 large diabetic nephropathy studies, losartan and irbesartan failed to improve CV outcomes or death rates, although progression to ESRD was reduced, suggesting a potential inadequate follow-up period to assess impact on CVD.^42,43 Clearly, patients with CKD and diabetes should be managed with a patient-specific, customized approach (rather than a specific agent) due to the frequent presence of concomitant hyperglycemia, dyslipidemia, and hypertension.⁴⁴

In an economic evaluation examining the cost-effectiveness of a multifactorial approach to reducing CVD in diabetes, patients were randomized to the Diabetes Care Protocol (DCP) or usual care.⁴⁵ The DCP consisted of a 1-hour consultation by a practice nurse and a computerized decision support software assessment that provided patient-specific advice (on targets for glycosylated hemoglobin, BP, body weight, cholesterol, and smoking cessation); the practice and patient received feedback every 3 months. The incremental CER was €38,243 (approximately $55,307) per QALY in the overall population. In patients with CVD, the CER was €14,814 ($21,424) per QALY, and the coronary heart disease costs were reduced by €587 ($849) (P <.05). In contrast, the CER per QALY for patients with diabetes and no CVD was €121,285 ($175,402). It should be noted that this study did not specifically evaluate patients with CKD, but it did demonstrate that patients with diabetes and CVD could be treated in a cost-effective and potentially cost-saving manner using a comprehensive intervention.⁴⁵

A Cochrane review evaluated the effects of statins in CKD patients who do not require dialysis.⁴⁶ The evaluation consisted of 25,017 patients from 26 studies, and demonstrated a statin-induced reduction in low-density lipoprotein (LDL) cholesterol (-42.38 mg/dL), total cholesterol (-41.48 mg/dL), all-cause death (19% reduction), CV death (20% reduction), and 24-hour urinary protein excretion (-0.73 g/24 hours), but no improvement in creatinine clearance. Statins appeared to be well tolerated, with associated adverse effects similar to those in controls. ⁴⁶ The therapeutic benefits observed in the Cochrane review are consistent with recent trials.⁴⁷ In the absence of well-designed cost-effectiveness studies, it may be inferred that statins, with their established benefits and tolerability, appear to be a worthwhile intervention for CKD patients with dyslipidemia or CVD.

To a similar extent, evidence of cost-effectiveness of interventions for CAD, MI, and heart failure in patients with CKD is lacking.^48-50 However, similar trends are noted— standard therapies are effective, but they are underutilized. ⁴⁹ For example, standard therapies for MI (eg, ACEIs, ARBs, beta-blockers, aspirin, statins) are underutilized in patients with CKD, despite current evidence supporting their use in the presence of CAD or heart failure.^48-50

Efforts to improve adherence are another important consideration in the treatment of CVD in CKD. In a 2007 survey of patients with Medicare Part D prescription drug plans, 23% to 31% of patients with ESRD reported costrelated nonadherence to prescription medication in the preceding 6 months. Patients with ESRD were 2.34-fold more likely than those without ESRD to report cost-related nonadherence.⁵¹ African Americans and patients with Medicare Part D Low-Income Subsidy assistance reported higher rates of cost-related nonadherence than other subgroups.⁵¹ Any treatment decisions should include assessment of the patient’s ability to pay, as well as the availability of well-tested, less costly generic options, especially when the regimen may be complicated and involve multiple medications.

In a study of a privately insured population, patients taking medications for hypertension, dyslipidemia, and diabetes between 2004 and 2008 were evaluated for adherence (days per year covered by a filled prescription).⁵² Adherence was defined as a medication possession ratio of 80% or more. Adherence was highest with medications for diabetes, followed by agents for hypertension and dyslipidemia. Interestingly, adherence was highest among patients taking the most medications (ie, those treated for all 3 conditions).⁵² Enhanced compliance when multiple conditions are managed supports the theory that recognition of disease improves delivery of treatment. This is especially important in patients with CKD because they tend to have multiple comorbidities and consequently require numerous medications. The suggestion that more medications result in better compliance is encouraging because once patients with CKD are identified, they can take an active role in their care by more adequately following therapeutic regimens.

Summary

Based on available evidence, CVD is prevalent in patients with CKD. Thus, managing patients with CKD and hypertension or dyslipidemia can result in better outcomes. Managing hypertension in CKD demonstrates CV benefits and a delay in progression of nephropathy. Similarly, better control of LDL-C levels is associated with long-term risk reduction in heart attack and stroke, as evidenced from SHARP. ACEIs, ARBs, and statins have the most robust data in CKD; outcomes will be influenced by choosing the most appropriate therapy for each patient and promoting adherence. Optimizing control of CVD also has economic implications, especially considering that CVD is the most common cause of hospitalization in patients with CKD. Improving the management of CKD and addressing CVD comorbidities can lead to improved clinical and economic outcomes.