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Hospitalization in Daily Home Hemodialysis and Matched Thrice-Weekly In-Center Hemodialysis Patients
Original Investigation Hospitalization in Daily Home Hemodialysis and Matched Thrice-Weekly In-Center Hemodialysis Patients Eric D. Weinhandl, MS,1 Kimberly M. Nieman, MS,1 David T. Gilbertson, PhD,1 and Allan J. Collins, MD1,2 Background: Cardiovascular disease is a common cause of hospitalization in dialysis patients. Daily hemodialysis improves some parameters of cardiovascular function, but whether it associates with lower hospitalization risk is unclear. Study Design: Observational cohort study using US Renal Data System data. Setting & Participants: Medicare-enrolled daily (5 or 6 sessions weekly) home hemodialysis (HHD) patients initiating NxStage System One use from January 1, 2006, through December 31, 2009, and contemporary thriceweekly in-center hemodialysis patients, matched 5 to 1. Predictor: Daily HHD or thrice-weekly in-center hemodialysis. Outcomes & Measurements: All-cause and cause-specific hospital admissions, hospital readmissions, and hospital days assessed from Medicare Part A claims. Results: For 3,480 daily HHD and 17,400 thrice-weekly in-center hemodialysis patients in intention-to-treat analysis, the HR of all-cause admission for daily HHD versus in-center hemodialysis was 1.01 (95% CI, 0.981.03). Cause-specific admission HRs were 0.89 (95% CI, 0.86-0.93) for cardiovascular disease, 1.18 (95% CI, 1.13-1.23) for infection, 1.01 (95% CI, 0.93-1.09) for vascular access dysfunction, and 1.02 (95% CI, 0.991.06) for other morbidity. Regarding cardiovascular disease, first admission and readmission HRs for daily HHD versus in-center hemodialysis were 0.91 and 0.87, respectively. Regarding infection, first admission and readmission HRs were 1.35 and 1.03, respectively. Protective associations of daily HHD with heart failure and hypertensive disease were most pronounced, as were adverse associations of daily HHD with bacteremia/sepsis, cardiac infection, osteomyelitis, and vascular access infection. Limitations: Results may be confounded by unmeasured factors, including vascular access type; information about dialysis frequency, duration, and dose was lacking; causes of admission may be misclassified; results may not apply to patients without Medicare coverage. Conclusions: All-cause hospitalization risk was similar in daily HHD and thrice-weekly in-center hemodialysis patients. However, risk of cardiovascular-related admission was lower with daily HHD, and risk of infection-related admission was higher. More attention should be afforded to infection in HHD patients. Am J Kidney Dis. 65(1):98-108. ª 2014 by the National Kidney Foundation, Inc. INDEX WORDS: Hemodialysis; home hemodialysis (HHD); daily HHD; hospitalization; hospital admission; cardiovascular disease; infection; end-stage renal disease (ESRD).
Editorial, p. 6
I
n the United States, 5,535 patients were treated with home hemodialysis (HHD) at the end of 2011, the largest year-end count since 1985.1 Most HHD patients are prescribed either 5 or 6 dialysis sessions per week.2 Daily hemodialysis improves some parameters of cardiovascular function. In the FHN (Frequent Hemodialysis Network) trial, a 12-month From the 1Chronic Disease Research Group, Minneapolis Medical Research Foundation; and 2Department of Medicine, University of Minnesota, Minneapolis, MN. Received February 3, 2014. Accepted in revised form June 9, 2014. Originally published online July 29, 2014. Address correspondence to Eric D. Weinhandl, MS, Chronic Disease Research Group, Minneapolis Medical Research Foundation, 914 S 8th St, Ste S4.100, Minneapolis, MN 55404. E-mail: [email protected] 2014 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2014.06.015 98
regimen of 6 versus 3 in-center hemodialysis sessions per week significantly decreased left ventricular mass and systolic blood pressure.3 In an earlier review, daily hemodialysis was associated with decreased systolic or mean arterial blood pressure in 10 of 11 studies.4 Although cardiovascular disease (CVD) is a leading cause of hospitalization in dialysis patients, limited data about hospitalization risk with daily hemodialysis have been published. In the FHN trial, hemodialysis frequency did not alter the risk of the composite end point of death or first hospitalization unrelated to vascular access.3 In an observational study of daily HHD (n 5 43) versus thrice-weekly in-center hemodialysis, admission rates were similar in the treatment groups.5 Because inpatient care imposes a substantial burden on hemodialysis patients and their payers, larger studies of hospitalization risk with daily hemodialysis are needed. We assessed hospitalization risk among Medicare beneficiaries treated with daily HHD versus thriceweekly in-center hemodialysis. Daily HHD patients initiated use of the NxStage System One (NxStage Am J Kidney Dis. 2015;65(1):98-108
Daily Home Hemodialysis and Hospitalization
Medical Inc) from 2006 through 2009. Matched incenter hemodialysis patients were identified from the US Renal Data System (USRDS) database. Our primary aim was to compare the hazard of all-cause admission in daily HHD versus thrice-weekly incenter hemodialysis. Secondary aims were to compare the hazards of first admission, readmission, and causespecific admission and rates of hospital admissions and days.
METHODS Protection of Human Participants Daily HHD patient data were obtained through a data licensing agreement between NxStage Medical Inc and the Chronic Disease Research Group. Data were linked to the USRDS database by USRDS staff under data use agreements with the National Institute of Diabetes and Digestive and Kidney Diseases; the agreements stipulated confidentiality rules and security regulations. Study approval was obtained from the Hennepin County Medical Center Human Subjects Research Committee (Minneapolis, MN).
Study Cohort Daily HHD patients were identified from a registry of NxStage System One users maintained by NxStage Medical Inc. Each registry record included first and last names, date of birth, race, sex, beginning and ending dates of System One use, and the prescribed number of dialysis runs per week. Beginning dates ranged from January 1, 2006, through December 31, 2009, and ending dates (when observed) occurred as late as December 31, 2010. Almost all records (97.3%) were linked to patients in the USRDS database. We stratified patients by year of daily HHD initiation: 2006-2007 (era 1) or 2008-2009 (era 2). We retained 3,480 patients with 5 or 6 prescribed dialysis sessions per week and Medicare as primary payer on and during the 3 months preceding the date of daily HHD initiation (Fig 1). For each era, the source cohort of thrice-weekly in-center hemodialysis patients comprised those who were treated and had Medicare primary payer coverage for one or more days during the era (era 1, n 5 403,210; era 2, n 5 414,916). For each such patient, we constructed one record from each date (including off-dialysis dates) during the era when the patient was treated with in-center hemodialysis and had Medicare primary payer coverage on and during the 3 months preceding that date (era 1, n 5 114,343,334; era 2, n 5 126,538,807). We hereafter refer to each such patient-day as an in-center hemodialysis candidate record.
Data Elements For each daily HHD patient, we identified age, race, sex, primary cause of end-stage renal disease (ESRD), ESRD duration, ESRD Network, dual enrollment in Medicare and Medicaid, comorbid conditions, body mass index, recent catheter insertion, cumulative hospital days, kidney transplant wait-list registration, dialysis provider affiliation, and cumulative doses of epoetin alfa, darbepoetin alfa, intravenous iron, and intravenous vitamin D sterols. Age, ESRD duration, ESRD Network, dual enrollment, wait-list registration, and provider affiliation were defined at daily HHD initiation (index date). Body mass index was ascertained from the final outpatient dialysis claim during the 3 months preceding the index date, or in lieu of claims with body mass index data, from the ESRD Medical Evidence Report (Centers for Medicare & Medicaid Services [CMS] form CMS-2728). Catheter insertions, hospital days, and intravenous drug doses were ascertained from all claims, inpatient claims, and outpatient dialysis claims, respectively, during the 3 months preceding the index date. Am J Kidney Dis. 2015;65(1):98-108
Figure 1. Sample size, daily home hemodialysis (DHHD) patients in the study cohort, with iterative application of inclusion criteria. Era 1, 2006-2007; era 2, 2008-2009. Abbreviation: USRDS, US Renal Data System.
Comorbid conditions were defined from the Medical Evidence Report and all claims during the 6 months preceding the index date; we required one or more Medicare Part A or 2 or more Part B claims with relevant diagnosis codes to define conditions.6 For each in-center hemodialysis candidate record, we identified all aforementioned factors analogously. Regarding follow-up data, we ascertained dates of death, kidney transplantation, cessation of in-center hemodialysis therapy, and loss of Medicare primary payer coverage from USRDS data. Hospitalization dates were ascertained from inpatient claims. Using principal diagnosis and procedure codes on claims, we categorized each hospitalization into 1 of 4 causes: CVD, infection, vascular access dysfunction unrelated to infection, or other cause. CVD was divided into 7, and infection into 8, mutually exclusive types. Codes defining admission causes and types are listed in Table S1 (provided as online supplementary material).
Matching Algorithm We used propensity score matching.7 We fit a logistic regression model of daily HHD initiation in the pooled set of daily HHD patients and in-center hemodialysis candidate records for each era to address the possibility of differential confounding between eras. Predictors included main effects for characteristics listed in Table 1, ESRD Network, and number of days between the first day of the era and date of either daily HHD initiation or in-center hemodialysis patient-day. All continuous factors were parameterized as quadratic polynomials. From the fitted model, we calculated the logit of the estimated probability of daily HHD initiation in each daily HHD patient and in-center hemodialysis candidate record. We ordered daily HHD patients by index date and arbitrarily within index date and applied a greedy matching algorithm in the specified order. For each daily HHD patient with propensity score logit equal to s, we identified the index date, ESRD duration (,1 or $1 year), hospitalization history (0 or .0 day), and dialysis provider affiliation (DaVita or other). We retained in-center hemodialysis candidate records on the day of the index date and with the same values of each aforementioned factor; we required exact matching for these factors because we hypothesized that each strongly predicted either daily HHD initiation or hospitalization risk. From this subset, we selected the 5 candidate records with 99
Weinhandl et al Table 1. Characteristics of Daily HHD and Matched Thrice-Weekly In-Center HD Patients Pooled Eras Characteristic
Era 1, 2006-2007
In-Center HD
No. in sample
3,480
17,400
1,396
6,980
Ageb (y)
53.4
53.6
52.5
52.5
0.0%
Race Black Nonblack
26.8% 73.2%
27.0% 73.0%
27.8% 72.2%
27.5% 72.5%
0.6% 0.6%
Sex Female Male
34.7% 65.3%
34.4% 65.6%
36.2% 63.8%
36.5% 63.5%
29.5% 21.4% 27.0%
30.5% 21.6% 26.2%
26.7% 20.8% 29.1%
22.1%
21.6%
23.4%
b
ESRD duration (y) Dual Medicare/Medicaid enrollmentc Comorbid conditionsc Cardiovascular conditions Cardiac disease, NOS Cerebrovascular disease Congestive heart failure Hypertension Ischemic heart disease Peripheral arterial disease Pulmonary heart disease Noncardiovascular conditions Cancer Chronic pulmonary disease Coagulopathy Dementia or psychosis Diabetes Fluid or electrolyte disorders Hemiplegia HIV or AIDS Iron deficiency anemia Liver disease Malnutrition Body mass indexb (kg/m2) Catheter insertiond Hospitalizationd Any hospitalization Cumulative hospitalized days Kidney transplant wait-list registrationb Affiliation of dialysis providerb DaVita Dialysis Clinic Inc Fresenius Medical Care Small dialysis organization Independent dialysis provider Hospital-based dialysis provider Unknown affiliation
In-Center HD
ASDa
Daily HHD
Primary cause of ESRD Diabetes Hypertension Glomerulonephritis or cystic kidney disease Other or unknown cause
Daily HHD
Era 2, 2008-2009 ASDa
Daily HHD
In-Center HD
2,084
10,420
54.0
54.3
1.6%
26.2% 73.8%
26.7% 73.3%
1.3% 1.3%
0.6% 0.6%
33.7% 66.3%
33.1% 66.9%
1.3% 1.3%
27.6% 20.2% 28.8%
2.1% 1.3% 0.6%
31.4% 21.7% 25.7%
32.5% 22.5% 24.5%
2.2% 1.9% 2.7%
23.3%
0.3%
21.2%
20.5%
1.6%
5.8
5.4
6.5
6.2
4.8%
5.4
4.9
7.1%
29.0%
29.0%
26.4%
26.6%
0.5%
30.7%
30.5%
0.4%
31.7% 8.9% 34.8% 40.4% 29.3% 24.2% 2.0%
32.2% 9.2% 35.7% 41.0% 29.8% 24.2% 1.9%
29.2% 9.0% 31.9% 37.2% 25.9% 22.8% 1.3%
29.0% 9.3% 33.1% 37.6% 26.3% 22.9% 1.1%
0.4% 1.3% 2.3% 0.9% 0.9% 0.3% 1.6%
33.3% 8.9% 36.8% 42.5% 31.6% 25.2% 2.4%
34.4% 9.0% 37.5% 43.3% 32.3% 25.0% 2.5%
2.3% 0.8% 1.4% 1.5% 1.4% 0.5% 0.3%
10.3% 11.6% 6.4% 2.4% 46.1% 43.3% 0.9% 1.4% 83.5% 4.1% 7.4%
10.4% 11.6% 6.5% 2.3% 47.4% 43.4% 0.9% 1.4% 83.3% 4.3% 7.2%
9.7% 10.3% 6.7% 2.2% 41.7% 41.8% 0.9% 1.9% 81.9% 4.4% 8.5%
10.0% 10.5% 6.8% 2.1% 42.7% 41.5% 0.8% 2.0% 81.8% 4.5% 8.2%
1.1% 0.5% 0.4% 0.9% 2.0% 0.6% 0.5% 0.8% 0.3% 0.4% 1.1%
10.8% 12.5% 6.2% 2.5% 49.0% 44.3% 0.9% 1.1% 84.6% 3.9% 6.6%
10.7% 12.4% 6.3% 2.5% 50.6% 44.5% 1.0% 1.0% 84.2% 4.2% 6.5%
0.4% 0.3% 0.3% 0.2% 3.3% 0.3% 0.7% 0.3% 1.2% 1.1% 0.2%
28.5
28.6
27.9
27.9
1.2%
29.0
29.0
0.2%
8.4%
8.9%
6.7%
7.2%
1.7%
9.6%
10.1%
1.9%
25.1% 10.0
25.1% 10.5
22.8% 9.5
22.8% 9.5
0.0% 0.3%
26.7% 10.5
26.7% 11.2
0.0% 5.2%
34.6%
32.9%
37.0%
35.9%
2.4%
33.0%
30.9%
4.6%
44.8% 1.8% 4.0% 12.9% 23.9% 11.9% 0.7%
44.8% 1.9% 3.4% 13.0% 24.3% 12.0% 0.5%
38.3% 2.6% 3.9% 10.6% 28.5% 15.3% 0.9%
38.3% 2.7% 3.3% 11.0% 28.9% 15.3% 0.6%
0.0% 0.7% 3.5% 1.1% 0.9% 0.2% 3.5%
49.2% 1.3% 4.0% 14.4% 20.8% 9.6% 0.6%
49.2% 1.4% 3.5% 14.4% 21.3% 9.8% 0.5%
0.0% 0.5% 2.7% 0.2% 1.1% 0.7% 1.4%
(Continued)
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Am J Kidney Dis. 2015;65(1):98-108
Daily Home Hemodialysis and Hospitalization Table 1 (Cont’d). Characteristics of Daily HHD and Matched Thrice-Weekly In-Center HD Patients Pooled Eras
Era 1, 2006-2007
Era 2, 2008-2009
Daily HHD
In-Center HD
Daily HHD
In-Center HD
ASDa
Daily HHD
In-Center HD
ASDa
80.3% 218,618
79.7% 220,732
78.6% 233,420
78.0% 235,317
1.4% 1.8%
81.5% 208,702
81.0% 210,963
1.3% 1.1%
Darbepoetin alfa exposured Any exposure Cumulative dose (mg)
13.5% 560
13.1% 544
14.7% 697
14.2% 700
1.4% 4.7%
12.7% 468
12.5% 440
0.8% 4.5%
IV iron exposured Any exposure Cumulative dose (mg)
71.3% 775
71.0% 786
66.7% 743
65.1% 743
3.3% 0.0%
74.3% 796
74.9% 814
1.2% 2.9%
IV vitamin D sterol exposured Any exposure Cumulative dosee (mg)
63.5% 141
63.4% 139
62.1% 146
62.1% 147
0.1% 1.1%
64.4% 138
64.3% 134
0.2% 4.2%
Characteristic
Epoetin alfa exposured Any exposure Cumulative dose (IU)
Note: Unless otherwise indicated, values are given as means. Abbreviations: ASD, absolute standardized difference; ESRD, end-stage renal disease; HD, hemodialysis; HHD, home hemodialysis; HIV, human immunodeficiency virus; IV, intravenous; NOS, not otherwise specified. a Difference between daily HHD and matched in-center HD patients, in percentage of 1 standard deviation. b On index date. c During the 6 months preceding the index date. d During the 3 months preceding the index date. e In paricalcitol-equivalent units, with dose conversion ratios of 4.62 for calcitriol and 1.49 for doxercalciferol.
the smallest absolute differences between s and the logit of their respective propensity scores. After a patient was selected, other candidate records derived from that patient were removed from further matching consideration.
Statistical Analysis We calculated mean summaries of measured factors in daily HHD and matched in-center hemodialysis patients by era. We assessed the match quality with absolute standardized differences; differences , 10% indicate sufficient similarity to obviate adjustment.8 We used both intention-to-treat and on-treatment approaches during follow-up. In the former, we followed up patients from the index date (daily HHD patients) or date of in-center hemodialysis (matched patients) to the earliest of death, kidney transplantation, loss of Medicare primary payer coverage, and December 31, 2009 (era 1) or December 31, 2010 (era 2). In the latter, we added the date exactly 2 months after cessation of daily HHD therapy (daily HHD patients) or in-center hemodialysis (matched patients) to the list of dates on which follow-up may end; the 2-month extension after a change in dialytic modality assigned late admissions to the first modality. To compare the risk of hospitalization between daily HHD and in-center hemodialysis patients, we used 3 analytical techniques. First, we calculated the cumulative incidence of first admission and readmission (given live discharge following admission due to the corresponding cause, as applicable). Regarding readmission, each discharge constituted an observation for follow-up; we imposed no upper bound on time between discharge and subsequent readmission. Death and kidney transplantation were classified as competing risks. We repeated analyses for all-cause and causespecific admission. Second, we used the Prentice-WilliamsPeterson conditional gap-time model to estimate relative hazards of all-cause, cause-specific, and type-specific admission for daily HHD versus in-center hemodialysis patients.9 Heuristically, the Prentice-Williams-Peterson model is a stratified Cox model in which each stratum groups follow-up time that is preceded by the same Am J Kidney Dis. 2015;65(1):98-108
number of discharges. Specifically, stratum 1 includes time from the beginning of follow-up to the first admission or the end of follow-up; stratum 2 includes time from the first discharge to the second admission or the end of follow-up; and so on. The structure of the model accounts for changes in admission hazard functions after each additional discharge; in the study cohort, admission hazard increased with each additional discharge. We estimated hazard ratios (HRs) under assumptions of homogeneous and heterogeneous associations for first admission and subsequent readmission. Third, we calculated absolute and relative rates of hospital admissions and days. We used Poisson regression to estimate relative rates and repeated analyses for all-cause and cause-specific admission. We fit Prentice-Williams-Peterson and Poisson models separately by era and used sandwich covariance estimation to account for intrapatient correlation among repeated observations. We calculated pooled HR and relative rate estimates by calculating mean values of era-specific estimates; standard errors of pooled estimates were calculated under an assumption of independence between era-specific estimates.
RESULTS Descriptive Analysis We identified 1,396 and 2,084 daily HHD patients in eras 1 and 2, respectively. Mean ages were 52.5 years in era 1 and 54.0 years in era 2, 72.2% and 73.8% of patients were of nonblack race, and 63.8% and 66.3% were men, respectively (Table 1). Mean ESRD duration at daily HHD initiation was 6.5 years in era 1 and 5.4 years in era 2. From era 1 to era 2, most comorbid condition metrics increased among daily HHD patients. Compared with in-center hemodialysis patients, daily HHD patients were younger, healthier, and less likely to be concurrently enrolled in 101
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Figure 2. Cumulative incidence estimates of first (A) all-cause, (B) cardiovascular-related, (C) infectionrelated, (D) vascular access dysfunction–related, and (E) other cause–related admission in intention-to-treat analysis. Abbreviations: DHHD, daily home hemodialysis; IHD, in-center hemodialysis.
Medicaid (Table S2). In both eras, matching balanced all measured factors between daily HHD and in-center hemodialysis patients; standardized differences were uniformly ,10%. Cumulative Incidence of Admission and Readmission Figures 2 and 3 show cumulative incidences of first admission and readmission, respectively. With intention-to-treat follow-up, cumulative incidence of first admission for daily HHD versus in-center hemodialysis was 62.8% versus 58.3% after 1 year and 80.2% versus 74.9% after 2 years (Fig 2A). After 1 year, cumulative incidence of cause-specific admission was 24.1% versus 26.7% for CVD (Fig 2B), 29.5% versus 22.9% for infection (Fig 2C), 7.8% versus 7.2% for vascular access dysfunction (Fig 2D), and 36.1% versus 34.1% for other causes (Fig 2E). With intentionto-treat follow-up, cumulative incidence of readmission (after discharge) for daily HHD versus in-center hemodialysis was 81.8% versus 82.6% after 1 year and 90.2% versus 90.3% after 2 years (Fig 3A). After 1 year, cumulative incidence of cause-specific readmission was 47.1% versus 55.0% for CVD (Fig 3B), 53.5% versus 51.1% for infection (Fig 3C), 22.8% versus 31.5% for vascular access dysfunction (Fig 3D), and 60.8% versus 62.6% for other causes (Fig 3E). 102
Relative Hazards of Admission and Readmission Figure 4 shows relative hazards of admission, first admission, and readmission. With intention-to-treat follow-up, the pooled HR of admission for daily HHD versus in-center hemodialysis patients was 1.01 (95% confidence interval [CI], 0.98-1.03); for first admission and readmission, the corresponding HRs were 1.14 (95% CI, 1.09-1.19) and 0.96 (95% CI, 0.94-0.99), respectively. With on-treatment followup, results were similar. However, there was substantial variation by cause. With intention-to-treat follow-up, the pooled HR of CVD-related admission was 0.89 (95% CI, 0.86-0.93), and corresponding HRs for first admission and readmission were 0.91 and 0.87, respectively. In contrast, the pooled HR of infection-related admission was 1.18 (95% CI, 1.131.23), and corresponding HRs for first admission and readmission were 1.35 and 1.03, respectively. Pooled HRs for vascular access dysfunction–related and other cause–related admission were 1.01 (95% CI, 0.931.09) and 1.02 (95% CI, 0.99-1.06), respectively; for both, HRs of first admission were greater than 1, and HRs of readmission were less than 1. With on-treatment follow-up, results from cause-specific admission analyses were similar. For all comparisons in Fig 4, HRs in eras 1 and 2 did not differ significantly (P . 0.05). Am J Kidney Dis. 2015;65(1):98-108
Daily Home Hemodialysis and Hospitalization
Figure 3. Cumulative incidence estimates of (A) all-cause, (B) cardiovascular-related, (C) infectionrelated, (D) vascular access dysfunction–related, and (E) other cause–related readmission, given discharge following admission due to the corresponding cause, in intention-to-treat analysis. Abbreviations: DHHD, daily home hemodialysis; IHD, in-center hemodialysis.
Relative hazards of type-specific admission are shown in Table 2. With intention-to-treat follow-up, HRs of heart failure, fluid overload, and cardiomyopathy (0.69) and hypertensive disease (0.88) were significant (P , 0.05) among CVD-related types. Among infection-related types, HRs of bacteremia/ sepsis (1.35), cardiac infection (3.42), osteomyelitis (1.48), vascular access infection (1.39), and other infection (1.22) were significant. Absolute and Relative Rates of Hospitalization Absolute and relative rates of hospital admissions and days are shown in Table 3. With intention-to-treat follow-up, admission rates for daily HHD patients in eras 1 and 2 were 161.9 and 178.0 admits per 100 patient-years, respectively, and corresponding day rates were 985.1 and 1025.1 days per 100 patient-years. For daily HHD versus in-center hemodialysis, relative rates of admissions and days were 1.03 (95% CI, 0.99-1.08) and 1.04 (95% CI, 0.98-1.11), respectively. Corresponding relative rates of cause-specific admissions were 0.83 (95% CI, 0.78-0.88) for CVD, 1.32 (95% CI, 1.24-1.40) for infection, 1.01 (95% CI, 0.90-1.13) for vascular access dysfunction, and 1.02 (95% CI, 0.97-1.09) for other causes. Relative rates of causespecific days were concordant with relative rates Am J Kidney Dis. 2015;65(1):98-108
of admissions. Results with on-treatment follow-up were similar. Absolute and relative rates of typespecific hospital admissions and days are shown in Table S3. Competing Risks With intention-to-treat follow-up, kidney transplantation rates were 7.1 and 7.0 events per 100 patient-years in daily HHD and in-center hemodialysis patients, respectively. Corresponding death rates were 13.1 and 13.5 events per 100 patient-years. With on-treatment follow-up, death rates were 12.4 and 13.6 events per 100 patient-years in daily HHD and in-center hemodialysis patients, respectively. Corresponding dialytic modality change rates were 21.3 and 2.0 events per 100 patient-years. Most changes among daily HHD patients were conversions to incenter hemodialysis, and all changes among incenter hemodialysis patients were conversions to peritoneal dialysis therapy.
DISCUSSION In light of accumulating data indicating improved cardiovascular function with daily hemodialysis, a report of increased risk of infection-related death with daily HHD,2 and a trial finding of shortened time to 103
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Figure 4. Pooled relative hazards of all-cause and cause-specific admission for daily home hemodialysis patients in intention-to-treat and on-treatment analyses (referent: matched thrice-weekly in-center hemodialysis patients). Hazard ratios are represented by filled circles and 95% confidence intervals by solid lines. Abbreviation: VA, vascular access.
first vascular access intervention with daily hemodialysis,10 we aimed to assess the risk of hospitalization in daily HHD patients relative to comparable patients who might have initiated daily HHD therapy, but instead were treated with thrice-weekly in-center hemodialysis. We found that all-cause hospitalization risks were similar and relative risks did not vary across study eras or analytical approaches. Granular analyses of admissions revealed substantial variation. Risk of first admission was higher with daily HHD, but risk of readmission was slightly lower, a discordance due to variation across admission causes. Risk of CVD-related admission was lower with daily HHD, for first admission and readmission. However, risk of infection-related admission was higher with daily HHD due to a substantially increased risk of first admission. Risk of first vascular access dysfunction–related admission also was higher with daily HHD, although risk of readmission was lower. Cardiovascular benefits of intensive hemodialysis therapy have been reported previously. In metaanalysis, frequent (.3 sessions/wk, 2-8 h/session) or extended (3 sessions/wk, .4 h/session) hemodialysis 104
was associated with reductions in left ventricular mass and both systolic and diastolic blood pressures, decreased use of antihypertensive medications, and increased left ventricular ejection fraction.11 In the FHN trial specifically, 6 versus 3 in-center hemodialysis sessions increased low-frequency heart rate variability and both left and right ventricular endsystolic and end-diastolic volumes.12,13 These physiologic effects collectively suggest improved fluid control and pump function with daily hemodialysis. Unsurprisingly, we found that the strongest associations of daily HHD with CVDrelated admission were for principal diagnoses of heart failure and hypertensive disease, which together accounted for nearly half the CVD-related admissions among matched in-center hemodialysis patients. We also found that risks of hospitalization for cerebrovascular disease were 15% (intention-to-treat follow-up) and 25% (on-treatment follow-up) lower with daily HHD. Because blood pressure has been correlated positively with stroke risk in dialysis patients,14 the blood pressure–lowering effect of daily hemodialysis may plausibly mediate decreased stroke Am J Kidney Dis. 2015;65(1):98-108
Daily Home Hemodialysis and Hospitalization Table 2. Pooled HRs of Type-Specific Hospital Admissions for Daily Home Hemodialysis Patients in Intention-to-Treat and On-Treatment Analysis Intention-to-Treat HR (95% CI)
On-Treatment %a
HR (95% CI)
%a
Cardiovascular disease Arrhythmia Cerebrovascular disease Heart failure, fluid overload, and cardiomyopathy Hypertensive disease Ischemic heart disease Peripheral artery disease Other cardiovascular disease
0.97 0.85 0.69 0.88 0.94 1.06 1.18
(0.84-1.12) (0.71-1.02) (0.62-0.77) (0.80-0.96) (0.84-1.05) (0.95-1.18) (0.98-1.41)
10.4 5.8 20.4 24.0 16.6 16.8 5.9
1.00 0.75 0.59 0.84 0.91 1.02 1.19
(0.86-1.17) (0.60-0.93) (0.52-0.68) (0.75-0.93) (0.80-1.03) (0.90-1.15) (0.97-1.45)
11.2 5.9 18.5 24.4 16.1 17.5 6.3
Infection Bacteremia and sepsis Cardiac infection Human immunodeficiency virus Osteomyelitis Respiratory infection Urinary tract infection Vascular access infection Other infection
1.35 3.42 0.94 1.48 0.94 1.01 1.39 1.22
(1.24-1.46) (2.57-4.55) (0.65-1.37) (1.14-1.93) (0.86-1.03) (0.79-1.29) (1.28-1.50) (1.12-1.31)
24.8 3.0 0.9 2.4 17.9 2.8 22.4 25.8
1.34 3.75 0.94 1.39 0.92 0.91 1.44 1.20
(1.23-1.46) (2.78-5.07) (0.61-1.44) (1.03-1.87) (0.83-1.02) (0.67-1.23) (1.32-1.57) (1.09-1.31)
24.7 3.4 0.8 2.5 17.6 2.4 24.6 24.0
Note: The referent was matched thrice-weekly in-center hemodialysis patients. Abbreviations: CI, confidence interval; HR, hazard ratio. a Percentage of cause-specific admissions in pooled cohort of matched thrice-weekly in-center hemodialysis patients.
risk. By extension, daily hemodialysis may be a useful modality following dialysis therapy initiation when stroke risk is acutely elevated15; more relevant studies are needed. An outlier among relative risks of CVD-related admission was for principal diagnoses of other CVD. In post hoc analysis, we found that diagnoses of pulmonary embolism and aortic valve disease were chiefly responsible for apparently increased risk in daily HHD patients. Infective endocarditis constitutes a possible explanation for this association. In contrast to the protective association of daily HHD with CVD-related admission, we found an adverse association with infection-related admission. We are unaware of published studies regarding intensive hemodialysis and infection; however, we previously reported increased risk of death due to infection (HR, 1.13; 95% CI, 0.84-1.53) in daily HHD patients from 2005 through 2008.2 In this study, we found that the strongest associations of daily HHD with infectionrelated admission were for principal diagnoses of bacteremia/sepsis, cardiac infection, osteomyelitis, and vascular access infection. Several aspects of daily HHD merit discussion. First, more frequent dialysis might directly increase infection risk. In a study of Australian patients undergoing HHD for 24 or more hours weekly (n 5 286), each additional session per week was associated with a 1.56 times higher hazard of first access-related adverse event; 59% of events involved infection.16 Second, HHD may engender risks not present with in-center hemodialysis. Medicare Conditions Am J Kidney Dis. 2015;65(1):98-108
for Coverage require ESRD facilities to implement infection control practices.17 At home, no such structure exists. The dialysis area and equipment may become contaminated and patients and care partners may not follow procedures taught during training. A survey of daily HHD patients found poor care of the vascular access site: 31% did not always use clean gloves and 80% did not apply antibiotic ointments.18 HHD patients may be less likely than in-center counterparts to promptly report symptoms or receive systemic antibiotic therapy (eg, vancomycin). Third, vascular access type and cannulation technique may engender risks. A higher prevalence of catheter use in daily HHD patients could account for increased risk of infection. However, the prevalence of catheter access in US daily HHD patients in 2009 was 24%,19 similar to contemporary estimates of prevalence in US in-center hemodialysis patients.20,21 An important alternative explanation for increased risk of infection is buttonhole cannulation. A review of 4 randomized trials and 7 observational studies found increased risk of fistula-related infection (relative risks, 3.34 and 3.15, respectively) for buttonhole versus ropeladder cannulation.22 In a single-center study of HHD patients (n 5 56), adoption of buttonhole cannulation was followed by an increase in Staphylococcus aureus bacteremia with metastatic complications.23 Interestingly, we found that risk of infection-related readmission was similar in daily HHD and in-center hemodialysis patients. This might suggest that interventions (eg, retraining) occurred after a first systemic infection 105
Weinhandl et al Table 3. Absolute and Pooled Relative Rates of Hospital Admissions and Days for Daily HHD Patients in Intention-to-Treat and On-Treatment Analyses 2006-2007 Daily HHD
Intention-to-treat Mean follow-up duration (y) Admissions All-cause Cause-specific Cardiovascular disease Infection Vascular access dysfunction Other cause Admission duration (d) All-cause Cause-specific Cardiovascular disease Infection Vascular access dysfunction Other cause On-treatment Mean follow-up duration (y) Admissions All-cause Cause-specific Cardiovascular disease Infection Vascular access dysfunction Other cause Admission duration (d) All-cause Cause-specific Cardiovascular disease Infection Vascular access dysfunction Other cause
2008-2009
In-Center HD
Daily HHD
Pooled
In-Center HD
RR (95% CI)
2.10
2.05
1.53
1.54
161.9
155.2
178.0
169.3
36.4 48.5 11.0 66.1
43.5 36.2 10.4 65.1
40.3 54.4 9.8 73.4
48.4 41.3 10.1 69.4
985.1
916.0
1,025.1
995.1
1.04 (0.98-1.11)
165.1 396.9 39.6 383.5
200.3 300.0 43.6 372.1
178.1 433.2 32.4 381.4
223.3 339.1 41.3 391.5
0.81 1.29 0.84 0.99
1.66
2.00
1.26
1.51
150.3
154.2
168.3
168.9
32.8 46.6 10.9 60.0
43.6 35.7 10.4 64.5
37.3 52.7 9.4 68.9
48.4 41.0 10.2 69.3
918.9
907.1
964.3
991.0
1.01 (0.94-1.07)
145.4 382.4 39.4 351.7
199.4 296.2 43.0 368.6
164.6 422.9 27.5 349.2
222.3 338.1 41.1 389.6
0.74 1.28 0.78 0.94
1.03 (0.99-1.08) 0.83 1.32 1.01 1.02
(0.78-0.88) (1.24-1.40) (0.90-1.13) (0.97-1.09)
(0.73-0.88) (1.18-1.40) (0.71-0.99) (0.91-1.08)
1.00 (0.96-1.05) 0.77 1.30 0.99 0.98
(0.72-0.82) (1.22-1.39) (0.88-1.12) (0.92-1.04)
(0.67-0.82) (1.17-1.40) (0.66-0.93) (0.85-1.03)
Note: Admission and admission duration data for each era are expressed per 100 patient-years. Referent for pooled analysis is matched thrice-weekly in-center hemodialysis patients. Abbreviations: CI, confidence interval; HD, hemodialysis; HHD, home hemodialysis; RR, relative rate.
in daily HHD patients. Alternatively, infections might have been inadequately treated in the hospital,24 such that dialysis frequency after discharge had little influence on readmission risk. In either case, the risk of infection in daily HHD patients probably is modifiable. History is illustrative: peritonitis rates declined sharply between 1980 and 1995 with continued innovation in peritoneal dialysis therapy.25 Although HHD is not new per se, HHD programs in many ESRD facilities are young. Patients, providers, and researchers should increase their vigilance in monitoring infection in HHD patients. The increased hazard of first vascular access dysfunction–related admission with daily HHD is qualitatively similar to the increased hazard (HR, 1.76) of first access intervention with 6 versus 3 sessions per week in the FHN trial,10 albeit smaller in magnitude. Notably, we found that risk of readmission for 106
access dysfunction was lower in daily HHD, though with substantial uncertainty. The corresponding HR of all access interventions in the FHN trial was 1.35,3 implying approximately equal risk of repeat interventions in the treatment arms. Reasons for the relative risk discordance between first and subsequent interventions are unclear. This study has some limitations. First, it is observational. Matching cannot reduce confounding attributable to unmeasured factors. Uncontrolled differences in disease severity (as measured by serum concentrations), nutrition, socioeconomic status, and initial vascular access type may underlie observed relative risks. Second, we lacked data regarding dialysis frequency, duration, and dose in daily HHD patients. Some study patients may have used the NxStage System One for nocturnal treatment. Third, we used diagnosis codes to classify admissions. The principal Am J Kidney Dis. 2015;65(1):98-108
Daily Home Hemodialysis and Hospitalization
codes on inpatient claims determine diagnosisrelated group assignments and, by extension, Medicare reimbursement. Thus, principal codes may not accurately reflect morbidity. Fourth, this study should be interpreted in the context of Medicare beneficiaries undergoing daily HHD with the NxStage System One versus in-center hemodialysis. Our comparisons may not apply to other payers in the United States, intensive hemodialysis with other machines, or in-center hemodialysis delivery in other countries. In conclusion, we found that overall hospitalization risk was similar in daily HHD and in-center hemodialysis patients. However, risks of CVD- and infection-related admission were lower and higher, respectively, in daily HHD patients. Because CVD is the leading cause of death in hemodialysis patients,1 the protective association of daily HHD with CVD is important. The adverse association of daily HHD with infection constitutes a safety concern that requires attention to infection control practices in the home, promptness of infection treatment, and cannulation technique. Because infection is the second leading cause of death in hemodialysis patients1 and infection-induced inflammation may precipitate cardiovascular events,26 interventions to reduce infection risk may broadly improve outcomes in daily HHD patients. The clinical success of daily HHD likely depends on patients and providers recognizing the advantages and challenges of this increasingly popular modality.
ACKNOWLEDGEMENTS The authors thank Chronic Disease Research Group colleagues Delaney Berrini, BS, for manuscript preparation and Nan Booth, MSW, MPH, ELS, for manuscript editing. Aspects of this work were presented in abstract form at the 34th Annual Dialysis Conference, Atlanta, GA, February 8-11, 2014. The data reported here have been supplied by the USRDS. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as official policy or interpretation of the US government. Support: This work was supported by a restricted grant from NxStage Medical Inc, Lawrence, MA. The interpretation and reporting of these data are the responsibility of the authors, who retained final authority over manuscript content. Financial Disclosure: Dr Collins has provided consulting services to NxStage Medical Inc. The other authors declare that they have no other relevant financial interests. Contributions: Research idea and study design: EDW, KMN, DTG, AJC; data acquisition: AJC; data analysis/interpretation: EDW, DTG; statistical analysis: EDW; supervision or mentorship: AJC. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. EDW takes responsibility that this study has been reported honestly, accurately, and transparently; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.
Am J Kidney Dis. 2015;65(1):98-108
SUPPLEMENTARY MATERIAL Table S1: Definitions of causes and types of admission. Table S2: Characteristics of daily HHD patients and thriceweekly in-center HD candidate records. Table S3: Relative rates of type-specific hospital admissions and days for daily HHD patients. Note: The supplementary material accompanying this article (http://dx.doi.org/10.1053/j.ajkd.2014.06.015) is available at www. ajkd.org
REFERENCES 1. Collins AJ, Foley RN, Chavers B, et al. US Renal Data System 2013 annual data report. Am J Kidney Dis. 2014;63(1)(suppl 1): e1-e420. 2. Weinhandl ED, Liu J, Gilbertson DT, Arneson TJ, Collins AJ. Survival in daily home hemodialysis and matched thrice-weekly in-center hemodialysis patients. J Am Soc Nephrol. 2012;23(5):895-904. 3. Chertow GM, Levin NW, Beck GJ, et al. In-center hemodialysis six times per week versus three times per week. N Engl J Med. 2010;363(24):2287-2300. 4. Suri RS, Nesrallah GE, Mainra R, et al. Daily hemodialysis: a systematic review. Clin J Am Soc Nephrol. 2006;1(1):33-42. 5. Johansen KL, Zhang R, Huang Y, et al. Survival and hospitalization among patients using nocturnal and short daily compared to conventional hemodialysis: a USRDS study. Kidney Int. 2009;76(9): 984-990. 6. Quan H, Sundararajan V, Halfon P, et al. Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data. Med Care. 2005;43(11):1130-1139. 7. D’Agostino RB Jr. Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med. 1998;17(19):2265-2281. 8. Austin PC. Using the standardized difference to compare the prevalence of binary variable between two groups in observation research. Comm Stat Simul Comput. 2009;38(6):1228-1234. 9. Prentice RL, Williams BJ, Peterson AV. On the regression analysis of multivariate failure time data. Biometrika. 1981;68(2): 373-379. 10. Suri RS, Larive B, Sherer S, et al. Risk of vascular access complications with frequent hemodialysis. J Am Soc Nephrol. 2013;24(3):498-505. 11. Susantitaphong P, Koulouridis I, Balk EM, Madias NE, Jaber BL. Effect of frequent or extended hemodialysis on cardiovascular parameters: a meta-analysis. Am J Kidney Dis. 2012;59(5):689-699. 12. Chan CT, Chertow GM, Daugirdas JT, et al. Effects of daily hemodialysis on heart rate variability: results from the Frequent Hemodialysis Network (FHN) Daily Trial. Nephrol Dial Transplant. 2014;29(1):168-178. 13. Chan CT, Greene T, Chertow GM, et al. Effects of frequent hemodialysis on ventricular volumes and left ventricular remodeling. Clin J Am Soc Nephrol. 2013;8(12):2106-2116. 14. Seliger SL, Gillen DL, Tirschwell D, Wasse H, Kestenbaum BR, Stehman-Breen CO. Risk factors for incident stroke among patients with end-stage renal disease. J Am Soc Nephrol. 2003;14(10):2623-2631. 15. Murray AM, Seliger S, Lakshminarayan K, Herzog CA, Solid CA. Incidence of stroke before and after dialysis initiation in older patients. J Am Soc Nephrol. 2013;24(7):1166-1173. 16. Jun M, Jardine MJ, Gray N, et al. Outcomes of extended-hours hemodialysis performed predominantly at home. Am J Kidney Dis. 2013;61(2):247-253. 107
Weinhandl et al 17. Health Care Financing Administration Federal Register. Conditions for coverage of suppliers of end-stage renal disease (ESRD) facilities. Fed Regist. 2008;73:20370-20484. https://www. cms.gov/Regulations-and-Guidance/Legislation/CFCsAndCoPs/ downloads/esrdfinalrule0415.pdf. Accessed June 3, 2014. 18. Spry LA, Burkart JM, Holcroft CC, Glickman DG. Anonymous survey among home hemodialysis patients and nursing staff regarding vascular access site use and care [abstract]. Hemodial Int. 2014;18(1):220-256. 19. Nesrallah GE, Suri RS, Moist LM, et al. International Quotidian Dialysis Registry: annual report 2009. Hemodial Int. 2009;13(3):240-249. 20. Arbor Research Collaborative for Health, Ann Arbor, Michigan. 2012 Annual Report of the Dialysis Outcomes and Practice Patterns Study: Hemodialysis Data 1997-2011 (DOPPS). 2012. http://www.dopps.org/annualreport/. Accessed June 3, 2014. 21. US Renal Data System. USRDS 2009 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. Bethesda, MD: National Institute of Diabetes
108
and Digestive and Kidney Diseases, National Institutes of Health; 2009. 22. Muir CA, Kotwal SS, Hawley CM, et al. Buttonhole cannulation and clinical outcomes in a home hemodialysis cohort and systematic review. Clin J Am Soc Nephrol. 2014;9(1): 110-119. 23. Nesrallah GE, Cuerden M, Wong JH, Pierratos A. Staphylococcus aureus bacteremia and buttonhole cannulation: longterm safety and efficacy of mupirocin prophylaxis. Clin J Am Soc Nephrol. 2010;5(6):1047-1053. 24. Anderson DJ, Moehring RW, Sloane R, et al. Bloodstream infections in community hospitals in the 21st century: a multicenter cohort study. PLoS One. 2014;9:e91713. 25. Bloembergen WE, Port FK. Epidemiological perspective on infections in chronic dialysis patients. Adv Renal Replace Ther. 1996;3(3):201-207. 26. Foley RN. Infections and cardiovascular disease in patients with chronic kidney disease. Adv Chronic Kidney Dis. 2006;13(3): 205-208.
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Editorial, p. 6
I
n the United States, 5,535 patients were treated with home hemodialysis (HHD) at the end of 2011, the largest year-end count since 1985.1 Most HHD patients are prescribed either 5 or 6 dialysis sessions per week.2 Daily hemodialysis improves some parameters of cardiovascular function. In the FHN (Frequent Hemodialysis Network) trial, a 12-month From the 1Chronic Disease Research Group, Minneapolis Medical Research Foundation; and 2Department of Medicine, University of Minnesota, Minneapolis, MN. Received February 3, 2014. Accepted in revised form June 9, 2014. Originally published online July 29, 2014. Address correspondence to Eric D. Weinhandl, MS, Chronic Disease Research Group, Minneapolis Medical Research Foundation, 914 S 8th St, Ste S4.100, Minneapolis, MN 55404. E-mail: [email protected] 2014 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2014.06.015 98
regimen of 6 versus 3 in-center hemodialysis sessions per week significantly decreased left ventricular mass and systolic blood pressure.3 In an earlier review, daily hemodialysis was associated with decreased systolic or mean arterial blood pressure in 10 of 11 studies.4 Although cardiovascular disease (CVD) is a leading cause of hospitalization in dialysis patients, limited data about hospitalization risk with daily hemodialysis have been published. In the FHN trial, hemodialysis frequency did not alter the risk of the composite end point of death or first hospitalization unrelated to vascular access.3 In an observational study of daily HHD (n 5 43) versus thrice-weekly in-center hemodialysis, admission rates were similar in the treatment groups.5 Because inpatient care imposes a substantial burden on hemodialysis patients and their payers, larger studies of hospitalization risk with daily hemodialysis are needed. We assessed hospitalization risk among Medicare beneficiaries treated with daily HHD versus thriceweekly in-center hemodialysis. Daily HHD patients initiated use of the NxStage System One (NxStage Am J Kidney Dis. 2015;65(1):98-108
Daily Home Hemodialysis and Hospitalization
Medical Inc) from 2006 through 2009. Matched incenter hemodialysis patients were identified from the US Renal Data System (USRDS) database. Our primary aim was to compare the hazard of all-cause admission in daily HHD versus thrice-weekly incenter hemodialysis. Secondary aims were to compare the hazards of first admission, readmission, and causespecific admission and rates of hospital admissions and days.
METHODS Protection of Human Participants Daily HHD patient data were obtained through a data licensing agreement between NxStage Medical Inc and the Chronic Disease Research Group. Data were linked to the USRDS database by USRDS staff under data use agreements with the National Institute of Diabetes and Digestive and Kidney Diseases; the agreements stipulated confidentiality rules and security regulations. Study approval was obtained from the Hennepin County Medical Center Human Subjects Research Committee (Minneapolis, MN).
Study Cohort Daily HHD patients were identified from a registry of NxStage System One users maintained by NxStage Medical Inc. Each registry record included first and last names, date of birth, race, sex, beginning and ending dates of System One use, and the prescribed number of dialysis runs per week. Beginning dates ranged from January 1, 2006, through December 31, 2009, and ending dates (when observed) occurred as late as December 31, 2010. Almost all records (97.3%) were linked to patients in the USRDS database. We stratified patients by year of daily HHD initiation: 2006-2007 (era 1) or 2008-2009 (era 2). We retained 3,480 patients with 5 or 6 prescribed dialysis sessions per week and Medicare as primary payer on and during the 3 months preceding the date of daily HHD initiation (Fig 1). For each era, the source cohort of thrice-weekly in-center hemodialysis patients comprised those who were treated and had Medicare primary payer coverage for one or more days during the era (era 1, n 5 403,210; era 2, n 5 414,916). For each such patient, we constructed one record from each date (including off-dialysis dates) during the era when the patient was treated with in-center hemodialysis and had Medicare primary payer coverage on and during the 3 months preceding that date (era 1, n 5 114,343,334; era 2, n 5 126,538,807). We hereafter refer to each such patient-day as an in-center hemodialysis candidate record.
Data Elements For each daily HHD patient, we identified age, race, sex, primary cause of end-stage renal disease (ESRD), ESRD duration, ESRD Network, dual enrollment in Medicare and Medicaid, comorbid conditions, body mass index, recent catheter insertion, cumulative hospital days, kidney transplant wait-list registration, dialysis provider affiliation, and cumulative doses of epoetin alfa, darbepoetin alfa, intravenous iron, and intravenous vitamin D sterols. Age, ESRD duration, ESRD Network, dual enrollment, wait-list registration, and provider affiliation were defined at daily HHD initiation (index date). Body mass index was ascertained from the final outpatient dialysis claim during the 3 months preceding the index date, or in lieu of claims with body mass index data, from the ESRD Medical Evidence Report (Centers for Medicare & Medicaid Services [CMS] form CMS-2728). Catheter insertions, hospital days, and intravenous drug doses were ascertained from all claims, inpatient claims, and outpatient dialysis claims, respectively, during the 3 months preceding the index date. Am J Kidney Dis. 2015;65(1):98-108
Figure 1. Sample size, daily home hemodialysis (DHHD) patients in the study cohort, with iterative application of inclusion criteria. Era 1, 2006-2007; era 2, 2008-2009. Abbreviation: USRDS, US Renal Data System.
Comorbid conditions were defined from the Medical Evidence Report and all claims during the 6 months preceding the index date; we required one or more Medicare Part A or 2 or more Part B claims with relevant diagnosis codes to define conditions.6 For each in-center hemodialysis candidate record, we identified all aforementioned factors analogously. Regarding follow-up data, we ascertained dates of death, kidney transplantation, cessation of in-center hemodialysis therapy, and loss of Medicare primary payer coverage from USRDS data. Hospitalization dates were ascertained from inpatient claims. Using principal diagnosis and procedure codes on claims, we categorized each hospitalization into 1 of 4 causes: CVD, infection, vascular access dysfunction unrelated to infection, or other cause. CVD was divided into 7, and infection into 8, mutually exclusive types. Codes defining admission causes and types are listed in Table S1 (provided as online supplementary material).
Matching Algorithm We used propensity score matching.7 We fit a logistic regression model of daily HHD initiation in the pooled set of daily HHD patients and in-center hemodialysis candidate records for each era to address the possibility of differential confounding between eras. Predictors included main effects for characteristics listed in Table 1, ESRD Network, and number of days between the first day of the era and date of either daily HHD initiation or in-center hemodialysis patient-day. All continuous factors were parameterized as quadratic polynomials. From the fitted model, we calculated the logit of the estimated probability of daily HHD initiation in each daily HHD patient and in-center hemodialysis candidate record. We ordered daily HHD patients by index date and arbitrarily within index date and applied a greedy matching algorithm in the specified order. For each daily HHD patient with propensity score logit equal to s, we identified the index date, ESRD duration (,1 or $1 year), hospitalization history (0 or .0 day), and dialysis provider affiliation (DaVita or other). We retained in-center hemodialysis candidate records on the day of the index date and with the same values of each aforementioned factor; we required exact matching for these factors because we hypothesized that each strongly predicted either daily HHD initiation or hospitalization risk. From this subset, we selected the 5 candidate records with 99
Weinhandl et al Table 1. Characteristics of Daily HHD and Matched Thrice-Weekly In-Center HD Patients Pooled Eras Characteristic
Era 1, 2006-2007
In-Center HD
No. in sample
3,480
17,400
1,396
6,980
Ageb (y)
53.4
53.6
52.5
52.5
0.0%
Race Black Nonblack
26.8% 73.2%
27.0% 73.0%
27.8% 72.2%
27.5% 72.5%
0.6% 0.6%
Sex Female Male
34.7% 65.3%
34.4% 65.6%
36.2% 63.8%
36.5% 63.5%
29.5% 21.4% 27.0%
30.5% 21.6% 26.2%
26.7% 20.8% 29.1%
22.1%
21.6%
23.4%
b
ESRD duration (y) Dual Medicare/Medicaid enrollmentc Comorbid conditionsc Cardiovascular conditions Cardiac disease, NOS Cerebrovascular disease Congestive heart failure Hypertension Ischemic heart disease Peripheral arterial disease Pulmonary heart disease Noncardiovascular conditions Cancer Chronic pulmonary disease Coagulopathy Dementia or psychosis Diabetes Fluid or electrolyte disorders Hemiplegia HIV or AIDS Iron deficiency anemia Liver disease Malnutrition Body mass indexb (kg/m2) Catheter insertiond Hospitalizationd Any hospitalization Cumulative hospitalized days Kidney transplant wait-list registrationb Affiliation of dialysis providerb DaVita Dialysis Clinic Inc Fresenius Medical Care Small dialysis organization Independent dialysis provider Hospital-based dialysis provider Unknown affiliation
In-Center HD
ASDa
Daily HHD
Primary cause of ESRD Diabetes Hypertension Glomerulonephritis or cystic kidney disease Other or unknown cause
Daily HHD
Era 2, 2008-2009 ASDa
Daily HHD
In-Center HD
2,084
10,420
54.0
54.3
1.6%
26.2% 73.8%
26.7% 73.3%
1.3% 1.3%
0.6% 0.6%
33.7% 66.3%
33.1% 66.9%
1.3% 1.3%
27.6% 20.2% 28.8%
2.1% 1.3% 0.6%
31.4% 21.7% 25.7%
32.5% 22.5% 24.5%
2.2% 1.9% 2.7%
23.3%
0.3%
21.2%
20.5%
1.6%
5.8
5.4
6.5
6.2
4.8%
5.4
4.9
7.1%
29.0%
29.0%
26.4%
26.6%
0.5%
30.7%
30.5%
0.4%
31.7% 8.9% 34.8% 40.4% 29.3% 24.2% 2.0%
32.2% 9.2% 35.7% 41.0% 29.8% 24.2% 1.9%
29.2% 9.0% 31.9% 37.2% 25.9% 22.8% 1.3%
29.0% 9.3% 33.1% 37.6% 26.3% 22.9% 1.1%
0.4% 1.3% 2.3% 0.9% 0.9% 0.3% 1.6%
33.3% 8.9% 36.8% 42.5% 31.6% 25.2% 2.4%
34.4% 9.0% 37.5% 43.3% 32.3% 25.0% 2.5%
2.3% 0.8% 1.4% 1.5% 1.4% 0.5% 0.3%
10.3% 11.6% 6.4% 2.4% 46.1% 43.3% 0.9% 1.4% 83.5% 4.1% 7.4%
10.4% 11.6% 6.5% 2.3% 47.4% 43.4% 0.9% 1.4% 83.3% 4.3% 7.2%
9.7% 10.3% 6.7% 2.2% 41.7% 41.8% 0.9% 1.9% 81.9% 4.4% 8.5%
10.0% 10.5% 6.8% 2.1% 42.7% 41.5% 0.8% 2.0% 81.8% 4.5% 8.2%
1.1% 0.5% 0.4% 0.9% 2.0% 0.6% 0.5% 0.8% 0.3% 0.4% 1.1%
10.8% 12.5% 6.2% 2.5% 49.0% 44.3% 0.9% 1.1% 84.6% 3.9% 6.6%
10.7% 12.4% 6.3% 2.5% 50.6% 44.5% 1.0% 1.0% 84.2% 4.2% 6.5%
0.4% 0.3% 0.3% 0.2% 3.3% 0.3% 0.7% 0.3% 1.2% 1.1% 0.2%
28.5
28.6
27.9
27.9
1.2%
29.0
29.0
0.2%
8.4%
8.9%
6.7%
7.2%
1.7%
9.6%
10.1%
1.9%
25.1% 10.0
25.1% 10.5
22.8% 9.5
22.8% 9.5
0.0% 0.3%
26.7% 10.5
26.7% 11.2
0.0% 5.2%
34.6%
32.9%
37.0%
35.9%
2.4%
33.0%
30.9%
4.6%
44.8% 1.8% 4.0% 12.9% 23.9% 11.9% 0.7%
44.8% 1.9% 3.4% 13.0% 24.3% 12.0% 0.5%
38.3% 2.6% 3.9% 10.6% 28.5% 15.3% 0.9%
38.3% 2.7% 3.3% 11.0% 28.9% 15.3% 0.6%
0.0% 0.7% 3.5% 1.1% 0.9% 0.2% 3.5%
49.2% 1.3% 4.0% 14.4% 20.8% 9.6% 0.6%
49.2% 1.4% 3.5% 14.4% 21.3% 9.8% 0.5%
0.0% 0.5% 2.7% 0.2% 1.1% 0.7% 1.4%
(Continued)
100
Am J Kidney Dis. 2015;65(1):98-108
Daily Home Hemodialysis and Hospitalization Table 1 (Cont’d). Characteristics of Daily HHD and Matched Thrice-Weekly In-Center HD Patients Pooled Eras
Era 1, 2006-2007
Era 2, 2008-2009
Daily HHD
In-Center HD
Daily HHD
In-Center HD
ASDa
Daily HHD
In-Center HD
ASDa
80.3% 218,618
79.7% 220,732
78.6% 233,420
78.0% 235,317
1.4% 1.8%
81.5% 208,702
81.0% 210,963
1.3% 1.1%
Darbepoetin alfa exposured Any exposure Cumulative dose (mg)
13.5% 560
13.1% 544
14.7% 697
14.2% 700
1.4% 4.7%
12.7% 468
12.5% 440
0.8% 4.5%
IV iron exposured Any exposure Cumulative dose (mg)
71.3% 775
71.0% 786
66.7% 743
65.1% 743
3.3% 0.0%
74.3% 796
74.9% 814
1.2% 2.9%
IV vitamin D sterol exposured Any exposure Cumulative dosee (mg)
63.5% 141
63.4% 139
62.1% 146
62.1% 147
0.1% 1.1%
64.4% 138
64.3% 134
0.2% 4.2%
Characteristic
Epoetin alfa exposured Any exposure Cumulative dose (IU)
Note: Unless otherwise indicated, values are given as means. Abbreviations: ASD, absolute standardized difference; ESRD, end-stage renal disease; HD, hemodialysis; HHD, home hemodialysis; HIV, human immunodeficiency virus; IV, intravenous; NOS, not otherwise specified. a Difference between daily HHD and matched in-center HD patients, in percentage of 1 standard deviation. b On index date. c During the 6 months preceding the index date. d During the 3 months preceding the index date. e In paricalcitol-equivalent units, with dose conversion ratios of 4.62 for calcitriol and 1.49 for doxercalciferol.
the smallest absolute differences between s and the logit of their respective propensity scores. After a patient was selected, other candidate records derived from that patient were removed from further matching consideration.
Statistical Analysis We calculated mean summaries of measured factors in daily HHD and matched in-center hemodialysis patients by era. We assessed the match quality with absolute standardized differences; differences , 10% indicate sufficient similarity to obviate adjustment.8 We used both intention-to-treat and on-treatment approaches during follow-up. In the former, we followed up patients from the index date (daily HHD patients) or date of in-center hemodialysis (matched patients) to the earliest of death, kidney transplantation, loss of Medicare primary payer coverage, and December 31, 2009 (era 1) or December 31, 2010 (era 2). In the latter, we added the date exactly 2 months after cessation of daily HHD therapy (daily HHD patients) or in-center hemodialysis (matched patients) to the list of dates on which follow-up may end; the 2-month extension after a change in dialytic modality assigned late admissions to the first modality. To compare the risk of hospitalization between daily HHD and in-center hemodialysis patients, we used 3 analytical techniques. First, we calculated the cumulative incidence of first admission and readmission (given live discharge following admission due to the corresponding cause, as applicable). Regarding readmission, each discharge constituted an observation for follow-up; we imposed no upper bound on time between discharge and subsequent readmission. Death and kidney transplantation were classified as competing risks. We repeated analyses for all-cause and causespecific admission. Second, we used the Prentice-WilliamsPeterson conditional gap-time model to estimate relative hazards of all-cause, cause-specific, and type-specific admission for daily HHD versus in-center hemodialysis patients.9 Heuristically, the Prentice-Williams-Peterson model is a stratified Cox model in which each stratum groups follow-up time that is preceded by the same Am J Kidney Dis. 2015;65(1):98-108
number of discharges. Specifically, stratum 1 includes time from the beginning of follow-up to the first admission or the end of follow-up; stratum 2 includes time from the first discharge to the second admission or the end of follow-up; and so on. The structure of the model accounts for changes in admission hazard functions after each additional discharge; in the study cohort, admission hazard increased with each additional discharge. We estimated hazard ratios (HRs) under assumptions of homogeneous and heterogeneous associations for first admission and subsequent readmission. Third, we calculated absolute and relative rates of hospital admissions and days. We used Poisson regression to estimate relative rates and repeated analyses for all-cause and cause-specific admission. We fit Prentice-Williams-Peterson and Poisson models separately by era and used sandwich covariance estimation to account for intrapatient correlation among repeated observations. We calculated pooled HR and relative rate estimates by calculating mean values of era-specific estimates; standard errors of pooled estimates were calculated under an assumption of independence between era-specific estimates.
RESULTS Descriptive Analysis We identified 1,396 and 2,084 daily HHD patients in eras 1 and 2, respectively. Mean ages were 52.5 years in era 1 and 54.0 years in era 2, 72.2% and 73.8% of patients were of nonblack race, and 63.8% and 66.3% were men, respectively (Table 1). Mean ESRD duration at daily HHD initiation was 6.5 years in era 1 and 5.4 years in era 2. From era 1 to era 2, most comorbid condition metrics increased among daily HHD patients. Compared with in-center hemodialysis patients, daily HHD patients were younger, healthier, and less likely to be concurrently enrolled in 101
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Figure 2. Cumulative incidence estimates of first (A) all-cause, (B) cardiovascular-related, (C) infectionrelated, (D) vascular access dysfunction–related, and (E) other cause–related admission in intention-to-treat analysis. Abbreviations: DHHD, daily home hemodialysis; IHD, in-center hemodialysis.
Medicaid (Table S2). In both eras, matching balanced all measured factors between daily HHD and in-center hemodialysis patients; standardized differences were uniformly ,10%. Cumulative Incidence of Admission and Readmission Figures 2 and 3 show cumulative incidences of first admission and readmission, respectively. With intention-to-treat follow-up, cumulative incidence of first admission for daily HHD versus in-center hemodialysis was 62.8% versus 58.3% after 1 year and 80.2% versus 74.9% after 2 years (Fig 2A). After 1 year, cumulative incidence of cause-specific admission was 24.1% versus 26.7% for CVD (Fig 2B), 29.5% versus 22.9% for infection (Fig 2C), 7.8% versus 7.2% for vascular access dysfunction (Fig 2D), and 36.1% versus 34.1% for other causes (Fig 2E). With intentionto-treat follow-up, cumulative incidence of readmission (after discharge) for daily HHD versus in-center hemodialysis was 81.8% versus 82.6% after 1 year and 90.2% versus 90.3% after 2 years (Fig 3A). After 1 year, cumulative incidence of cause-specific readmission was 47.1% versus 55.0% for CVD (Fig 3B), 53.5% versus 51.1% for infection (Fig 3C), 22.8% versus 31.5% for vascular access dysfunction (Fig 3D), and 60.8% versus 62.6% for other causes (Fig 3E). 102
Relative Hazards of Admission and Readmission Figure 4 shows relative hazards of admission, first admission, and readmission. With intention-to-treat follow-up, the pooled HR of admission for daily HHD versus in-center hemodialysis patients was 1.01 (95% confidence interval [CI], 0.98-1.03); for first admission and readmission, the corresponding HRs were 1.14 (95% CI, 1.09-1.19) and 0.96 (95% CI, 0.94-0.99), respectively. With on-treatment followup, results were similar. However, there was substantial variation by cause. With intention-to-treat follow-up, the pooled HR of CVD-related admission was 0.89 (95% CI, 0.86-0.93), and corresponding HRs for first admission and readmission were 0.91 and 0.87, respectively. In contrast, the pooled HR of infection-related admission was 1.18 (95% CI, 1.131.23), and corresponding HRs for first admission and readmission were 1.35 and 1.03, respectively. Pooled HRs for vascular access dysfunction–related and other cause–related admission were 1.01 (95% CI, 0.931.09) and 1.02 (95% CI, 0.99-1.06), respectively; for both, HRs of first admission were greater than 1, and HRs of readmission were less than 1. With on-treatment follow-up, results from cause-specific admission analyses were similar. For all comparisons in Fig 4, HRs in eras 1 and 2 did not differ significantly (P . 0.05). Am J Kidney Dis. 2015;65(1):98-108
Daily Home Hemodialysis and Hospitalization
Figure 3. Cumulative incidence estimates of (A) all-cause, (B) cardiovascular-related, (C) infectionrelated, (D) vascular access dysfunction–related, and (E) other cause–related readmission, given discharge following admission due to the corresponding cause, in intention-to-treat analysis. Abbreviations: DHHD, daily home hemodialysis; IHD, in-center hemodialysis.
Relative hazards of type-specific admission are shown in Table 2. With intention-to-treat follow-up, HRs of heart failure, fluid overload, and cardiomyopathy (0.69) and hypertensive disease (0.88) were significant (P , 0.05) among CVD-related types. Among infection-related types, HRs of bacteremia/ sepsis (1.35), cardiac infection (3.42), osteomyelitis (1.48), vascular access infection (1.39), and other infection (1.22) were significant. Absolute and Relative Rates of Hospitalization Absolute and relative rates of hospital admissions and days are shown in Table 3. With intention-to-treat follow-up, admission rates for daily HHD patients in eras 1 and 2 were 161.9 and 178.0 admits per 100 patient-years, respectively, and corresponding day rates were 985.1 and 1025.1 days per 100 patient-years. For daily HHD versus in-center hemodialysis, relative rates of admissions and days were 1.03 (95% CI, 0.99-1.08) and 1.04 (95% CI, 0.98-1.11), respectively. Corresponding relative rates of cause-specific admissions were 0.83 (95% CI, 0.78-0.88) for CVD, 1.32 (95% CI, 1.24-1.40) for infection, 1.01 (95% CI, 0.90-1.13) for vascular access dysfunction, and 1.02 (95% CI, 0.97-1.09) for other causes. Relative rates of causespecific days were concordant with relative rates Am J Kidney Dis. 2015;65(1):98-108
of admissions. Results with on-treatment follow-up were similar. Absolute and relative rates of typespecific hospital admissions and days are shown in Table S3. Competing Risks With intention-to-treat follow-up, kidney transplantation rates were 7.1 and 7.0 events per 100 patient-years in daily HHD and in-center hemodialysis patients, respectively. Corresponding death rates were 13.1 and 13.5 events per 100 patient-years. With on-treatment follow-up, death rates were 12.4 and 13.6 events per 100 patient-years in daily HHD and in-center hemodialysis patients, respectively. Corresponding dialytic modality change rates were 21.3 and 2.0 events per 100 patient-years. Most changes among daily HHD patients were conversions to incenter hemodialysis, and all changes among incenter hemodialysis patients were conversions to peritoneal dialysis therapy.
DISCUSSION In light of accumulating data indicating improved cardiovascular function with daily hemodialysis, a report of increased risk of infection-related death with daily HHD,2 and a trial finding of shortened time to 103
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Figure 4. Pooled relative hazards of all-cause and cause-specific admission for daily home hemodialysis patients in intention-to-treat and on-treatment analyses (referent: matched thrice-weekly in-center hemodialysis patients). Hazard ratios are represented by filled circles and 95% confidence intervals by solid lines. Abbreviation: VA, vascular access.
first vascular access intervention with daily hemodialysis,10 we aimed to assess the risk of hospitalization in daily HHD patients relative to comparable patients who might have initiated daily HHD therapy, but instead were treated with thrice-weekly in-center hemodialysis. We found that all-cause hospitalization risks were similar and relative risks did not vary across study eras or analytical approaches. Granular analyses of admissions revealed substantial variation. Risk of first admission was higher with daily HHD, but risk of readmission was slightly lower, a discordance due to variation across admission causes. Risk of CVD-related admission was lower with daily HHD, for first admission and readmission. However, risk of infection-related admission was higher with daily HHD due to a substantially increased risk of first admission. Risk of first vascular access dysfunction–related admission also was higher with daily HHD, although risk of readmission was lower. Cardiovascular benefits of intensive hemodialysis therapy have been reported previously. In metaanalysis, frequent (.3 sessions/wk, 2-8 h/session) or extended (3 sessions/wk, .4 h/session) hemodialysis 104
was associated with reductions in left ventricular mass and both systolic and diastolic blood pressures, decreased use of antihypertensive medications, and increased left ventricular ejection fraction.11 In the FHN trial specifically, 6 versus 3 in-center hemodialysis sessions increased low-frequency heart rate variability and both left and right ventricular endsystolic and end-diastolic volumes.12,13 These physiologic effects collectively suggest improved fluid control and pump function with daily hemodialysis. Unsurprisingly, we found that the strongest associations of daily HHD with CVDrelated admission were for principal diagnoses of heart failure and hypertensive disease, which together accounted for nearly half the CVD-related admissions among matched in-center hemodialysis patients. We also found that risks of hospitalization for cerebrovascular disease were 15% (intention-to-treat follow-up) and 25% (on-treatment follow-up) lower with daily HHD. Because blood pressure has been correlated positively with stroke risk in dialysis patients,14 the blood pressure–lowering effect of daily hemodialysis may plausibly mediate decreased stroke Am J Kidney Dis. 2015;65(1):98-108
Daily Home Hemodialysis and Hospitalization Table 2. Pooled HRs of Type-Specific Hospital Admissions for Daily Home Hemodialysis Patients in Intention-to-Treat and On-Treatment Analysis Intention-to-Treat HR (95% CI)
On-Treatment %a
HR (95% CI)
%a
Cardiovascular disease Arrhythmia Cerebrovascular disease Heart failure, fluid overload, and cardiomyopathy Hypertensive disease Ischemic heart disease Peripheral artery disease Other cardiovascular disease
0.97 0.85 0.69 0.88 0.94 1.06 1.18
(0.84-1.12) (0.71-1.02) (0.62-0.77) (0.80-0.96) (0.84-1.05) (0.95-1.18) (0.98-1.41)
10.4 5.8 20.4 24.0 16.6 16.8 5.9
1.00 0.75 0.59 0.84 0.91 1.02 1.19
(0.86-1.17) (0.60-0.93) (0.52-0.68) (0.75-0.93) (0.80-1.03) (0.90-1.15) (0.97-1.45)
11.2 5.9 18.5 24.4 16.1 17.5 6.3
Infection Bacteremia and sepsis Cardiac infection Human immunodeficiency virus Osteomyelitis Respiratory infection Urinary tract infection Vascular access infection Other infection
1.35 3.42 0.94 1.48 0.94 1.01 1.39 1.22
(1.24-1.46) (2.57-4.55) (0.65-1.37) (1.14-1.93) (0.86-1.03) (0.79-1.29) (1.28-1.50) (1.12-1.31)
24.8 3.0 0.9 2.4 17.9 2.8 22.4 25.8
1.34 3.75 0.94 1.39 0.92 0.91 1.44 1.20
(1.23-1.46) (2.78-5.07) (0.61-1.44) (1.03-1.87) (0.83-1.02) (0.67-1.23) (1.32-1.57) (1.09-1.31)
24.7 3.4 0.8 2.5 17.6 2.4 24.6 24.0
Note: The referent was matched thrice-weekly in-center hemodialysis patients. Abbreviations: CI, confidence interval; HR, hazard ratio. a Percentage of cause-specific admissions in pooled cohort of matched thrice-weekly in-center hemodialysis patients.
risk. By extension, daily hemodialysis may be a useful modality following dialysis therapy initiation when stroke risk is acutely elevated15; more relevant studies are needed. An outlier among relative risks of CVD-related admission was for principal diagnoses of other CVD. In post hoc analysis, we found that diagnoses of pulmonary embolism and aortic valve disease were chiefly responsible for apparently increased risk in daily HHD patients. Infective endocarditis constitutes a possible explanation for this association. In contrast to the protective association of daily HHD with CVD-related admission, we found an adverse association with infection-related admission. We are unaware of published studies regarding intensive hemodialysis and infection; however, we previously reported increased risk of death due to infection (HR, 1.13; 95% CI, 0.84-1.53) in daily HHD patients from 2005 through 2008.2 In this study, we found that the strongest associations of daily HHD with infectionrelated admission were for principal diagnoses of bacteremia/sepsis, cardiac infection, osteomyelitis, and vascular access infection. Several aspects of daily HHD merit discussion. First, more frequent dialysis might directly increase infection risk. In a study of Australian patients undergoing HHD for 24 or more hours weekly (n 5 286), each additional session per week was associated with a 1.56 times higher hazard of first access-related adverse event; 59% of events involved infection.16 Second, HHD may engender risks not present with in-center hemodialysis. Medicare Conditions Am J Kidney Dis. 2015;65(1):98-108
for Coverage require ESRD facilities to implement infection control practices.17 At home, no such structure exists. The dialysis area and equipment may become contaminated and patients and care partners may not follow procedures taught during training. A survey of daily HHD patients found poor care of the vascular access site: 31% did not always use clean gloves and 80% did not apply antibiotic ointments.18 HHD patients may be less likely than in-center counterparts to promptly report symptoms or receive systemic antibiotic therapy (eg, vancomycin). Third, vascular access type and cannulation technique may engender risks. A higher prevalence of catheter use in daily HHD patients could account for increased risk of infection. However, the prevalence of catheter access in US daily HHD patients in 2009 was 24%,19 similar to contemporary estimates of prevalence in US in-center hemodialysis patients.20,21 An important alternative explanation for increased risk of infection is buttonhole cannulation. A review of 4 randomized trials and 7 observational studies found increased risk of fistula-related infection (relative risks, 3.34 and 3.15, respectively) for buttonhole versus ropeladder cannulation.22 In a single-center study of HHD patients (n 5 56), adoption of buttonhole cannulation was followed by an increase in Staphylococcus aureus bacteremia with metastatic complications.23 Interestingly, we found that risk of infection-related readmission was similar in daily HHD and in-center hemodialysis patients. This might suggest that interventions (eg, retraining) occurred after a first systemic infection 105
Weinhandl et al Table 3. Absolute and Pooled Relative Rates of Hospital Admissions and Days for Daily HHD Patients in Intention-to-Treat and On-Treatment Analyses 2006-2007 Daily HHD
Intention-to-treat Mean follow-up duration (y) Admissions All-cause Cause-specific Cardiovascular disease Infection Vascular access dysfunction Other cause Admission duration (d) All-cause Cause-specific Cardiovascular disease Infection Vascular access dysfunction Other cause On-treatment Mean follow-up duration (y) Admissions All-cause Cause-specific Cardiovascular disease Infection Vascular access dysfunction Other cause Admission duration (d) All-cause Cause-specific Cardiovascular disease Infection Vascular access dysfunction Other cause
2008-2009
In-Center HD
Daily HHD
Pooled
In-Center HD
RR (95% CI)
2.10
2.05
1.53
1.54
161.9
155.2
178.0
169.3
36.4 48.5 11.0 66.1
43.5 36.2 10.4 65.1
40.3 54.4 9.8 73.4
48.4 41.3 10.1 69.4
985.1
916.0
1,025.1
995.1
1.04 (0.98-1.11)
165.1 396.9 39.6 383.5
200.3 300.0 43.6 372.1
178.1 433.2 32.4 381.4
223.3 339.1 41.3 391.5
0.81 1.29 0.84 0.99
1.66
2.00
1.26
1.51
150.3
154.2
168.3
168.9
32.8 46.6 10.9 60.0
43.6 35.7 10.4 64.5
37.3 52.7 9.4 68.9
48.4 41.0 10.2 69.3
918.9
907.1
964.3
991.0
1.01 (0.94-1.07)
145.4 382.4 39.4 351.7
199.4 296.2 43.0 368.6
164.6 422.9 27.5 349.2
222.3 338.1 41.1 389.6
0.74 1.28 0.78 0.94
1.03 (0.99-1.08) 0.83 1.32 1.01 1.02
(0.78-0.88) (1.24-1.40) (0.90-1.13) (0.97-1.09)
(0.73-0.88) (1.18-1.40) (0.71-0.99) (0.91-1.08)
1.00 (0.96-1.05) 0.77 1.30 0.99 0.98
(0.72-0.82) (1.22-1.39) (0.88-1.12) (0.92-1.04)
(0.67-0.82) (1.17-1.40) (0.66-0.93) (0.85-1.03)
Note: Admission and admission duration data for each era are expressed per 100 patient-years. Referent for pooled analysis is matched thrice-weekly in-center hemodialysis patients. Abbreviations: CI, confidence interval; HD, hemodialysis; HHD, home hemodialysis; RR, relative rate.
in daily HHD patients. Alternatively, infections might have been inadequately treated in the hospital,24 such that dialysis frequency after discharge had little influence on readmission risk. In either case, the risk of infection in daily HHD patients probably is modifiable. History is illustrative: peritonitis rates declined sharply between 1980 and 1995 with continued innovation in peritoneal dialysis therapy.25 Although HHD is not new per se, HHD programs in many ESRD facilities are young. Patients, providers, and researchers should increase their vigilance in monitoring infection in HHD patients. The increased hazard of first vascular access dysfunction–related admission with daily HHD is qualitatively similar to the increased hazard (HR, 1.76) of first access intervention with 6 versus 3 sessions per week in the FHN trial,10 albeit smaller in magnitude. Notably, we found that risk of readmission for 106
access dysfunction was lower in daily HHD, though with substantial uncertainty. The corresponding HR of all access interventions in the FHN trial was 1.35,3 implying approximately equal risk of repeat interventions in the treatment arms. Reasons for the relative risk discordance between first and subsequent interventions are unclear. This study has some limitations. First, it is observational. Matching cannot reduce confounding attributable to unmeasured factors. Uncontrolled differences in disease severity (as measured by serum concentrations), nutrition, socioeconomic status, and initial vascular access type may underlie observed relative risks. Second, we lacked data regarding dialysis frequency, duration, and dose in daily HHD patients. Some study patients may have used the NxStage System One for nocturnal treatment. Third, we used diagnosis codes to classify admissions. The principal Am J Kidney Dis. 2015;65(1):98-108
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codes on inpatient claims determine diagnosisrelated group assignments and, by extension, Medicare reimbursement. Thus, principal codes may not accurately reflect morbidity. Fourth, this study should be interpreted in the context of Medicare beneficiaries undergoing daily HHD with the NxStage System One versus in-center hemodialysis. Our comparisons may not apply to other payers in the United States, intensive hemodialysis with other machines, or in-center hemodialysis delivery in other countries. In conclusion, we found that overall hospitalization risk was similar in daily HHD and in-center hemodialysis patients. However, risks of CVD- and infection-related admission were lower and higher, respectively, in daily HHD patients. Because CVD is the leading cause of death in hemodialysis patients,1 the protective association of daily HHD with CVD is important. The adverse association of daily HHD with infection constitutes a safety concern that requires attention to infection control practices in the home, promptness of infection treatment, and cannulation technique. Because infection is the second leading cause of death in hemodialysis patients1 and infection-induced inflammation may precipitate cardiovascular events,26 interventions to reduce infection risk may broadly improve outcomes in daily HHD patients. The clinical success of daily HHD likely depends on patients and providers recognizing the advantages and challenges of this increasingly popular modality.
ACKNOWLEDGEMENTS The authors thank Chronic Disease Research Group colleagues Delaney Berrini, BS, for manuscript preparation and Nan Booth, MSW, MPH, ELS, for manuscript editing. Aspects of this work were presented in abstract form at the 34th Annual Dialysis Conference, Atlanta, GA, February 8-11, 2014. The data reported here have been supplied by the USRDS. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as official policy or interpretation of the US government. Support: This work was supported by a restricted grant from NxStage Medical Inc, Lawrence, MA. The interpretation and reporting of these data are the responsibility of the authors, who retained final authority over manuscript content. Financial Disclosure: Dr Collins has provided consulting services to NxStage Medical Inc. The other authors declare that they have no other relevant financial interests. Contributions: Research idea and study design: EDW, KMN, DTG, AJC; data acquisition: AJC; data analysis/interpretation: EDW, DTG; statistical analysis: EDW; supervision or mentorship: AJC. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. EDW takes responsibility that this study has been reported honestly, accurately, and transparently; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.
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SUPPLEMENTARY MATERIAL Table S1: Definitions of causes and types of admission. Table S2: Characteristics of daily HHD patients and thriceweekly in-center HD candidate records. Table S3: Relative rates of type-specific hospital admissions and days for daily HHD patients. Note: The supplementary material accompanying this article (http://dx.doi.org/10.1053/j.ajkd.2014.06.015) is available at www. ajkd.org
REFERENCES 1. Collins AJ, Foley RN, Chavers B, et al. US Renal Data System 2013 annual data report. Am J Kidney Dis. 2014;63(1)(suppl 1): e1-e420. 2. Weinhandl ED, Liu J, Gilbertson DT, Arneson TJ, Collins AJ. Survival in daily home hemodialysis and matched thrice-weekly in-center hemodialysis patients. J Am Soc Nephrol. 2012;23(5):895-904. 3. Chertow GM, Levin NW, Beck GJ, et al. In-center hemodialysis six times per week versus three times per week. N Engl J Med. 2010;363(24):2287-2300. 4. Suri RS, Nesrallah GE, Mainra R, et al. Daily hemodialysis: a systematic review. Clin J Am Soc Nephrol. 2006;1(1):33-42. 5. Johansen KL, Zhang R, Huang Y, et al. Survival and hospitalization among patients using nocturnal and short daily compared to conventional hemodialysis: a USRDS study. Kidney Int. 2009;76(9): 984-990. 6. Quan H, Sundararajan V, Halfon P, et al. Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data. Med Care. 2005;43(11):1130-1139. 7. D’Agostino RB Jr. Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med. 1998;17(19):2265-2281. 8. Austin PC. Using the standardized difference to compare the prevalence of binary variable between two groups in observation research. Comm Stat Simul Comput. 2009;38(6):1228-1234. 9. Prentice RL, Williams BJ, Peterson AV. On the regression analysis of multivariate failure time data. Biometrika. 1981;68(2): 373-379. 10. Suri RS, Larive B, Sherer S, et al. Risk of vascular access complications with frequent hemodialysis. J Am Soc Nephrol. 2013;24(3):498-505. 11. Susantitaphong P, Koulouridis I, Balk EM, Madias NE, Jaber BL. Effect of frequent or extended hemodialysis on cardiovascular parameters: a meta-analysis. Am J Kidney Dis. 2012;59(5):689-699. 12. Chan CT, Chertow GM, Daugirdas JT, et al. Effects of daily hemodialysis on heart rate variability: results from the Frequent Hemodialysis Network (FHN) Daily Trial. Nephrol Dial Transplant. 2014;29(1):168-178. 13. Chan CT, Greene T, Chertow GM, et al. Effects of frequent hemodialysis on ventricular volumes and left ventricular remodeling. Clin J Am Soc Nephrol. 2013;8(12):2106-2116. 14. Seliger SL, Gillen DL, Tirschwell D, Wasse H, Kestenbaum BR, Stehman-Breen CO. Risk factors for incident stroke among patients with end-stage renal disease. J Am Soc Nephrol. 2003;14(10):2623-2631. 15. Murray AM, Seliger S, Lakshminarayan K, Herzog CA, Solid CA. Incidence of stroke before and after dialysis initiation in older patients. J Am Soc Nephrol. 2013;24(7):1166-1173. 16. Jun M, Jardine MJ, Gray N, et al. Outcomes of extended-hours hemodialysis performed predominantly at home. Am J Kidney Dis. 2013;61(2):247-253. 107
Weinhandl et al 17. Health Care Financing Administration Federal Register. Conditions for coverage of suppliers of end-stage renal disease (ESRD) facilities. Fed Regist. 2008;73:20370-20484. https://www. cms.gov/Regulations-and-Guidance/Legislation/CFCsAndCoPs/ downloads/esrdfinalrule0415.pdf. Accessed June 3, 2014. 18. Spry LA, Burkart JM, Holcroft CC, Glickman DG. Anonymous survey among home hemodialysis patients and nursing staff regarding vascular access site use and care [abstract]. Hemodial Int. 2014;18(1):220-256. 19. Nesrallah GE, Suri RS, Moist LM, et al. International Quotidian Dialysis Registry: annual report 2009. Hemodial Int. 2009;13(3):240-249. 20. Arbor Research Collaborative for Health, Ann Arbor, Michigan. 2012 Annual Report of the Dialysis Outcomes and Practice Patterns Study: Hemodialysis Data 1997-2011 (DOPPS). 2012. http://www.dopps.org/annualreport/. Accessed June 3, 2014. 21. US Renal Data System. USRDS 2009 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. Bethesda, MD: National Institute of Diabetes
108
and Digestive and Kidney Diseases, National Institutes of Health; 2009. 22. Muir CA, Kotwal SS, Hawley CM, et al. Buttonhole cannulation and clinical outcomes in a home hemodialysis cohort and systematic review. Clin J Am Soc Nephrol. 2014;9(1): 110-119. 23. Nesrallah GE, Cuerden M, Wong JH, Pierratos A. Staphylococcus aureus bacteremia and buttonhole cannulation: longterm safety and efficacy of mupirocin prophylaxis. Clin J Am Soc Nephrol. 2010;5(6):1047-1053. 24. Anderson DJ, Moehring RW, Sloane R, et al. Bloodstream infections in community hospitals in the 21st century: a multicenter cohort study. PLoS One. 2014;9:e91713. 25. Bloembergen WE, Port FK. Epidemiological perspective on infections in chronic dialysis patients. Adv Renal Replace Ther. 1996;3(3):201-207. 26. Foley RN. Infections and cardiovascular disease in patients with chronic kidney disease. Adv Chronic Kidney Dis. 2006;13(3): 205-208.
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