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Comparing Treatment Modalities for End-Stage Renal Disease: A Meta-Analysis

May 2018 Vol 11, No 3 - Clinical, Original Research
Gilbert L. Queeley, PhD, and Ellen S. Campbell, PhD
Dr Queeley is Research Associate, and Dr Campbell is Associate Professor, Division of Economic Social and Administrative Pharmacy, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee.
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BACKGROUND: End-stage renal disease (ESRD) imposes significant economic and social burdens on patients and healthcare systems. In the United States alone, more than 600,000 Americans have ESRD, with an estimated annual cost of treatment of more than $30 billion. Peritoneal dialysis and hemodialysis are competing renal replacement therapies in ESRD; however, data comparing quality-of-life outcomes between these 2 modalities are limited.

OBJECTIVES: To compare the effectiveness of peritoneal dialysis with the more common treatment modality of hemodialysis on the health-related quality of life (HRQoL) of patients with ESRD in the general, physical, and psychological domains; and to determine whether the time of publication and the origin of each study influenced its findings regarding the effectiveness of the 2 modalities.

METHODS: This meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to collect the data. PubMed, MEDLINE, and PsycINFO were the primary databases searched. Only articles published in English were included in this meta-analysis. The measure of effect size was Cohen’s standardized mean difference. A random-effects model was used to test the hypothesis of equality in the mean HRQoL.

RESULTS: A total of 15 studies with a combined sample size of 4318 patients met the study criteria and were included in the analysis. The pooled effect sizes based on the random-effects model were 0.24 (95% confidence interval [CI], –0.17-0.66) in the general domain; 0.10 (95% CI, –0.09-0.29) in the physical­functioning domain; and 0.29 (95% CI, –0.13-0.71) in the psychological-functioning domain. None of the summary effect sizes was statistically significant. Subgroup analyses favored peritoneal dialysis regarding the time and country of publication.

CONCLUSION: The majority of the studies included in this analysis favored peritoneal dialysis over hemodialysis in all 3 domains. However, the pooled effect sizes were not significant, resulting in the inability to conclude that peritoneal dialysis is the more effective of these 2 treatment modalities.

Key Words: end-stage renal disease, health-related quality of life, hemodialysis, peritoneal dialysis, random-effects model, subgroup analysis

Am Health Drug Benefits.

Manuscript received May 23, 2017
Accepted in final form January 17, 2018

Disclosures are at end of text

As far as we know, Hippocrates was the first to formally recognize nutrition as an absolute therapeutic necessity. He is credited with memorable, and still remarkably relevant, quotes such as, “Let food be thy medicine and medicine be thy food,” and “Leave your drugs in the chemist’s pot if you can heal the patient with food.”

More than 2 millenia later, the goal of healthcare—getting the right therapy to the right patient at the right time—hasn’t changed all that much; however, our collective approach to incorporating new technologies in the treatment armamentarium must evolve. The following anecdote is a real-world example of what is happening in “niche” technology development across our industry.

An Age-Old Health Issue

I’ll begin with the very basic premise that adequate nutrition is vital to physiologic functioning and psychological well-being. For patients with a broad range of medical conditions, inadequate nutrition and/or ineffective nutritional support further compromise their health status and increase the cost of their care.

The term “malnutrition” may call to mind images of children and adults living in underdeveloped and developing countries. It may come as a surprise to many Americans, but physicians regularly diagnose and treat patients with malnutrition in intensive care units (ICUs) and in skilled nursing facilities across the United States. For the most medically advanced country in the world, this is unacceptable, even on a relatively small scale.

Target Populations

A variety of conditions are associated with digestive deficiency or malabsorption, such as patients who rely on tube feeding for nutrition, patients in ICUs, and infants in neonatal ICUs.

As a result of a lack of adequate pancreatic digestive enzymes, patients with exocrine pancreatic insufficiency have clinical symptoms related to malabsorption of fat. Exocrine pancreatic insufficiency is associated with diseases and conditions that affect the pancreas, including hereditary conditions (eg, cystic fibrosis) or acquired conditions (eg, chronic pancreatitis). For many of these patients, enteral nutrition is necessary to avoid malnourishment.1 Particularly in patients with cystic fibrosis, good nutritional status has been associated with improved clinical outcomes.2

Limited Therapeutic Options

None of the current US Food and Drug Administration (FDA)-approved pancreatic enzyme replacement therapies (PERTs) are indicated for use in patients who receive enteral nutrition for several reasons. PERT capsules are intended for oral use; when crushed and added to enteral nutrition feedings, they have been shown to clog the tubes. In addition, the capsules are not indicated for overnight enteral nutrition, because their activity peaks at 30 minutes and wanes thereafter. Most impor­tant, even when administered in large doses, PERT capsules do not resolve the issue of incomplete hydrolysis of fats from enteral nutrition. Many patients with exocrine pancreatic insufficiency who use PERT capsules continue to struggle nutritionally and have clinical symptoms related to fat malabsorption.

Innovative Solution

A new hybrid technology was developed to address the treatment gap for the population of patients with conditions associated with digestive deficiency and malabsorption, in particular for patients who rely on tube feeding for nutrition, patients with acute pancreatitis and/or pancreatic cancer, children with cystic fibrosis, patients in ICUs, and infants in neonatal ICUs.

Immobilized lipase (Relizorb) is a novel in-line digestive cartridge designed specifically for hydrolyzing fats in enteral formulas.3 Administered without the risk for clogging feeding tubes, this technology has been shown to break down more than 90% of fats in enteral nutrition formulas throughout feedings.3

This hybrid technology was cleared by the FDA in December 2015 after a lengthy approval process. There is growing real-world clinical evidence of tolerability and improved fatty acid absorption, including weight gain and increased patient adherence to oral nutrition in patients with cystic fibrosis.4 Specifically, cystic fibrosis centers that use this technology to treat patients with cystic fibrosis who are receiving enteral nutrition have documented weight gain and increased basal metabolic rate. The patients included in short- and long-term studies of the technology at these centers represent roughly 2% of the approximately 3600 patients with cystic fibrosis who are being fed via a feeding tube.5-8

The Value Question

I’ve heard it said that technology generates value only if the health benefit outweighs the cost. Herein lies the next hurdle—getting a firm grasp on costs. In the example of this new treatment, the direct costs associated with enteral nutrition can range from $80 to $200 daily, considering the cost of the formula, tube-feeding supplies, and oral pancreatic enzymes (ie, PERT). Despite its significant expense, patients with cystic fibrosis who receive enteral nutrition achieve only 60% of normal fat levels, even after years of treatment.4 As in patients with other conditions related to exocrine pancreatic insufficiency, hospitalization becomes necessary when malabsorption results in malnutrition. The in-hospital costs of enteral nutrition include the time spent by medical professionals crushing and adding PERTs to feeding bags and addressing unresolved symptoms in patients.

Clearly, the potential benefits of innovative therapies for their target populations are substantial, and can be life-changing for some people. But how do we weigh cost versus health benefits when the target population is extremely rare? In the United States, for example, only approximately 11% of patients with cystic fibrosis (approximately 3300 individuals) required supplemental enteral nutrition in 2014.9 Similar to many innovative treatments, this new technology does not fit the typical payer reimbursement model.

Payer Implications

Payers consistently reimburse providers for standard therapies, even those that often fail to achieve the intended goal, such as traditional enteral nutrition regimens. In this case, the use of a new technology may optimize enteral nutrition, enable patients to achieve nutritional goals, reduce or eliminate the need for PERT during tube feeding, and ultimately reduce the avoidable costs associated with frequent hospitalizations and increased length of stay.

My takeaway message is that targeted innovative therapy is the new reality, one that has unimaginable promise for subpopulations of patients who struggle with relatively rare conditions. All stakeholders must accept responsibility for cutting through the politics to clear the pathway and get the right therapies or new technologies to the right people at the earliest opportunity.

Disclosure Statement
The general concepts and questions addressed in this editorial come across my desk with growing frequency. The issues are complex and a resolution will require multistakeholder input. To that end, we are working with the developers of this new technology to convene a national advisory panel.

Dr Queeley is Research Associate, and Dr Campbell is Associate Professor, Division of Economic Social and Administrative Pharmacy, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee.

1. Schwarzenberg SJ, Hempstead SE, McDonald CM, et al. Enteral tube feeding for individuals with cystic fibrosis: Cystic Fibrosis Foundation evidence-­informed guidelines. J Cyst Fibros. 2016;15:724-735.
2. Shoff SM, Tluczek A, Laxova A, et al. Nutritional status is associated with health-related quality of life in children with cystic fibrosis aged 9-19 years. J Cyst Fibros. 2013;12:746-753.
3. Relizorb (immobilized lipase) cartridge [product instructions]. Newton, MA: Alcresta Therapeutics; January 2018.
4. Freedman S, Orenstein D, Black P, et al. Increased fat absorption from enteral formula through an in-line digestive cartridge in patients with cystic fibrosis. J Pediatr Gastroenterol Nutr. 2017;65:97-101.
5. Stevens JC, Wyatt C, Brown P, et al. Long-term use of Relizorb by children and adults with CF receiving enteral feeding increases ω-3 fatty acid levels and improves nutritional parameters. Abstract presented at the 2017 North American Cystic Fibrosis Conference. Indianapolis, IN: November 2-4, 2017. Abstract 606.
6. Iwanicki C, Bouma S, Nasr S. Use of immobilized lipase cartridge with overnight enteral feeds improves symptoms and results in weight gain in children with cystic fibrosis. Abstract presented at the 2017 North American Cystic Fibrosis Conference. Indianapolis, IN: November 2-4, 2017. Abstract 612.
7. Minor M, Nemastil CK, Gemma S, et al. Digestive enzyme cartridge (Relizorb) during continuous enteral feeds among individuals with cystic fibrosis. Abstract presented at the 2017 North American Cystic Fibrosis Conference. Indianapolis, IN: November 2-4, 2017. Abstract 628.
8. Hendrix S, Flume P, Michel S, et al. Use of an in-line digestive enzyme cartridge in pediatric patients. Abstract presented at the 2017 North American Cystic Fibrosis Conference. Indianapolis, IN: November 2-4, 2017. Abstract 634.
9. Cystic Fibrosis Foundation. Patient Registry: 2014 Annual Data Report. Accessed April 27, 2018.

Stakeholder Perspective
Dialysis Procedures and Health-Related Quality of Life: The Challenge of Creating Evidence-Based Healthcare in End-Stage Renal Disease
Michael F. Murphy, MD, PhD
Chief Medical and Scientific Officer, Worldwide Clinical Trials

Evidence-based healthcare integrates research evidence derived from many sources with clinical expertise and patient values. Ascending through a pyramid of reports and sequentially more comprehensive and sophisticated studies,1 meta-analyses combine data from independent studies that address comparable questions with similar methodology. The quantitative estimates of treatment effects expressed as relative risk, odds ratio, or risk difference examine moderating variables on patient outcomes that extend the original impact of primary research potentially influencing the practice of medicine.2 Queeley and Campbell illustrate the process in end-stage renal disease related to health-related quality-of-life (HRQoL) assessments and the differential effects of peritoneal dialysis versus hemodialysis.3

RESEARCHERS: HRQoL has assumed increasing importance for the evaluation of treatment effectiveness given the improved survival of patients with chronic kidney disease (CKD). As a multidimensional construct, HRQoL incorporates physical health, psychological well-being, and social dimension scores, which progressively worsen as CKD progresses.4 The frequency of assessments has little to no impact on HRQoL,5 although observational research and randomized controlled trials (RCTs) suggest that feedback with intervention yield improvements in care.6 The International Society of Nephrology and the Kidney Disease: Improving Global Outcomes recommend periodic assessments of HRQoL as a standard of care for patient-­centered delivery, emphasizing nonpharmacologic interventions as a first-line intervention.7

Research methodology for meta-analyses provides a framework for data extraction and analyses, with residual areas of uncertainty and debate. Methodologic rigor is enhanced by multiple independent raters selecting relevant publications using eligibility criteria in a transparent study selection process. Differences in baseline risk, concomitant therapy, and outcome definition across studies represent challenges in data aggregation and analyses, and exploring the impact of heterogeneity across studies is challenging. Formal examination of heterogeneity determines if differences across studies can be expected by chance. Identification of confounding variables that could modify trial results is essential, and sensitivity analysis evaluates study groups based on methodological or clinical characteristics likely to influence outcomes.

Conforming to PRISMA guidelines,8 Queeley and Campbell systematically address all eligibility criteria, including publication date, access to original data for effect-size analyses, use of recognized and sanctioned HRQoL measures, and duration of hemodialysis and peritoneal dialysis. They included small and larger studies without restriction, provided other eligibility criteria were satisfied. A random-effects model was used to test for homogeneity because of the variability in the extracted studies; an alternative approach using fixed-effects modeling assumes homogeneity of the intervention effect, leading to differences in point estimates and confidence intervals between these procedures.9 Standardized Cohen effect sizes were calculated with exploration of moderator variables (eg, more recent vs older articles, country of origin). The impact of standards of care and healthcare system by the country of origin were not assessed; 13 of the 15 studies were conducted outside of the United States. The most dominant quality of life (QOL) measures Queeley and Campbell noted was the Kidney Disease QOL Short Form 36 (SF-36) survey (used cross-sectionally), the World Health Organization Quality of Life Survey 100, and their variants, with 4318 patients considered. The 3 major HRQoL domains were separately presented with the 2 methods of dialysis.

When contrasting peritoneal dialysis with hemodialysis, a majority of studies suggested that peritoneal dialysis had a more favorable impact across all 3 domains of HRQoL. However, summary effect sizes from the meta­analysis indicated significant variation based on time of publication and study location (non-US studies were recent and favored peritoneal dialysis; US studies were older, larger, and nominally favored hemodialysis). Aggregate results, therefore, did not permit conclusions regarding peritoneal dialysis versus hemodialysis impact on HRQoL.

PAYERS: Health plans inform formulary placement, coverage, and reimbursement by using clinical evidence, including systematic reviews and meta-analysis. RCTs and observational studies also contribute to the decision process, acknowledging differences in implications that could be drawn from conclusions. For example, RCTs may exaggerate benefit for individual patients given the design features of an RCT, whereas implications from meta-analyses can differ based on the method used to extract and analyze the data.10 Translating analyses into policy is particularly difficult when heterogeneity across studies precludes practical clinical interpretation on a patient level.

Nephrology guidelines infrequently reference meta­analyses; when nephrologists are asked about the perceived role of meta-analyses in evidence-based medicine and their influence on patient care, the majority accept meta-analyses, acknowledge their contribution to guidelines, and indicate that they can influence patient care, although meta-analyses are not ranked higher in importance than RCTs.11

Extrapolation from non-US studies into the US healthcare system is a limitation of the present analysis, given the dominance of non-US information and the impact of publication date on the results.3 Country- or region-specific moderators are ubiquitous in interventional and observational studies, and these are often impactful, unless they are anticipated in design and/or incorporated into analysis. Although not addressed in the present meta-analysis,3 studies also have inconsistently demonstrated cost-effective differences contrasting continuous ambulatory peritoneal dialysis, hemo­dialysis, and automated peritoneal dialysis,12 which are possibly attributable to varying standards of care by country.13 Additional independent studies in different delivery settings permitting meta-analyses that sample a larger portfolio of studies are required to determine whether cost-effective dialysis procedures also provide the greatest HRQoL enhancements.

PATIENTS: Across indications, the impetus for disease-specific patient-related outcomes is pronounced. Individualized HRQoL measures are attractive, because they permit patients to identify domains pertinent to their individual condition. These data increasingly are captured electronically and are integrated into electronic medical records. Modifying factors for individualized QOL, such as race and age, can suggest differences based on method of dialysis.14 Correlations between the more frequently used SF-36 and individualized HRQoL can be robust; however, for systematic reviews and meta-analyses, the use of standardized measures is preferred.

Acknowledging the adage that “researchers live at the mean, while clinicians live within standard deviations,” the importance of patient-specific measures looms large in the delivery of healthcare. For example, in CKD, patient differences in HRQoL between peritoneal dialysis and hemodialysis are noted at trend levels of statistical significance, with patients using peritoneal dialysis more likely to identify kidney health and disease as QOL factors. In addition, individual symptoms (eg, pruritus, depressive symptoms, sleep disorder, and sexual dysfunction) rather than domain scores also influence individualized patient care and tend to be underestimated by healthcare providers precluding early effective intervention.15 Although the preservation of residual renal function, correction of anemia, and physical therapy and rehabilitation are known to preserve HRQoL, identifying systematic differences between the methods of dialysis and subjective measures, such as HRQoL assessments, remains elusive.

Michael F. Murphy, MD, PhD Chief Medical and Scientific Officer, Worldwide Clinical Trials

1. Glover J, Izzo D, Odato K, Wang L. EBM Pyramid. Trustees of Dartmouth College and Yale University; 2008. Accessed May 10, 2018.
2. Berlin JA, Golub RM. Meta-analysis as evidence: building a better pyramid. JAMA. 2014;312:603-605.
3. Queeley GL, Campbell ES. Comparing treatment modalities for end-stage renal disease: a meta-analysis. Am Health Drug Benefits. 2018;11(3):118-127.
4. Joshi VD. Quality of life in end stage renal disease patients. World J Nephrol. 2014;3:308-316.
5. Chen SS, Al Mawed S, Unruh M. Health-related quality of life in end-stage renal disease patients: how often should we ask and what do we do with the answer? Blood Purif. 2016;41:218-224.
6. Weisbord SD, Mor MK, Green JA, et al. Comparison of symptom management strategies for pain, erectile dysfunction, and depression in patients receiving chronic hemodialysis: a cluster randomized effectiveness trial. Clin J Am Soc Nephrol. 2013;8:90-99.
7. Davison SN, Levin A, Moss AH, et al. Executive summary of the KDIGO Controversies Conference on Supportive Care in Chronic Kidney Disease: developing a roadmap to improving quality care. Kidney Int. 2015;88:447-459.
8. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62:e1-e34.
9. Villar J, Mackey ME, Carroli G, Donner A. Meta-analyses in systematic reviews of randomized controlled trials in perinatal medicine: comparison of fixed and random effects models. Stat Med. 2001;20:3635-3647.
10. Dechartres A, Altman DG, Trinquart L, et al. Association between analytic strategy and estimates of treatment outcomes in meta-analyses. JAMA. 2014;312:623-630.
11. Mohan S, Radhakrishnan J. Do meta-analyses in nephrology change the way we treat patients? Kidney Int. 2010;78:1080-1087.
12. Yang F, Lau T, Luo N. Cost-effectiveness of haemodialysis and peritoneal dialysis for patients with end-stage renal disease in Singapore. Nephrology (Carlton). 2016;21:669-677.
13. Stroetmann KA, Gruetzmacher P, Stroetmann VN. Improving quality of life for dialysis patients through telecare. J Telemed Telecare. 2000;6(suppl 1):S1:80-S1:83.
14. Abdel-Kader K, Myaskovsky L, Karpov I, et al. Individual quality of life in chronic kidney disease: influence of age and dialysis modality. Clin J Am Soc Nephrol. 2009;4:711-718.
15. Weisbord SD, Fried LF, Mor MK, et al. Renal provider recognition of symptoms in patients on maintenance hemodialysis. Clin J Am Soc Nephrol. 2007;2:960-967.

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