Originally published online as doi:10.1053/j.ajkd.2006.05.008 on July 26, 2006. ... program with 1 or more indications for using the twin-bag ... technique failure, technical problems encountered while using the system, and .... Results using ITT.
A Randomized, Multicenter, Open-Label Trial to Determine Peritonitis Rate, Product Defect, and Technique Survival Between ANDY-Disc® and UltraBag® in Patients on CAPD Hin-Seng Wong, MD, FRCP(E), Loke-Meng Ong, MRCP(UK), Teck-Onn Lim, FRCP(E), Lai-Seong Hooi, FRCP(E), Zaki Morad, FRCP(E), Rozina Ghazalli, FRCP(E), Wan Shaariah, FRCP(E), Yam-Ngo Lim, FRCP(E), Ghazali Ahmad, MMed, Bak-Leong Goh, FRCP(Glasgow), Lynster Liaw, MRCP(UK), Susan Pee, MRCP(UK), and Ming-Lee Lee, MRCP(UK) ● Background: With the various twin-bag systems available on the market, we decided to conduct a therapeutic equivalence study comparing ANDY-Disc (Fresenius Medical Care, Bad Homburg, Germany) with UltraBag (Baxter, Deerfield, IL) in patients on continuous ambulatory peritoneal dialysis (CAPD) therapy. Methods: This multicenter, open-label, parallel-group, randomized trial is designed to show the therapeutic equivalence of ANDY-Disc with UltraBag. All CAPD patients from the 6 participating centers who met inclusion/exclusion criteria were enrolled into the trial. They were randomly assigned and converted from the Y-disconnect system (Ultraset; Baxter) to the twin-bag systems. The primary outcome variable is peritonitis, and secondary outcome parameters are technique failure or product defect. Results: From April 2002 to May 2003, a total of 270 patients were recruited for this study. Overall peritonitis rates were 22.9 patient-months/episode for ANDY-Disc and 35.0 patient-months/episode for UltraBag. The overall peritonitis rate for ANDY-Disc was 53% greater compared with UltraBag, but the 95% confidence interval overlaps the prespecified margin of equivalence. There were more product defects reported with ANDY-Disc; 236 product defects compared with 17 with UltraBag. The time series of the number of product defects and peritonitis count on the ANDY-Disc arm suggests a possible cause-and-effect relationship. Conclusion: Therapeutic equivalence of ANDY-Disc to UltraBag could not be established with respect to peritonitis. There is a trend toward greater risk for peritonitis on the Andy-Disc arm. There also is a suggestive cause-and-effect relation between the occurrence of product defect and peritonitis on the ANDY-Disc arm during the early part of the trial. Am J Kidney Dis 48:464-472. © 2006 by the National Kidney Foundation, Inc. INDEX WORDS: Continuous ambulatory peritoneal dialysis (CAPD); peritonitis; ANDY-Disc; UltraBag; twin-bag system.
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ONTINUOUS AMBULATORY peritoneal dialysis (CAPD) is an effective therapy for patients with end-stage renal disease. Peritonitis
From the Department of Nephrology, Institute of Urology and Nephrology; Clinical Research Centre; and Department of Paediatrics, Institute of Paediatrics, Kuala Lumpur Hospital; Departments of Medicine and Paediatrics, Penang Hospital; Departments of Medicine and Paediatrics, Sultanah Aminah Hospital, Johor Bahru; Departments of Medicine and Paediatrics, Seremban Hospital; and Department of Nephrology, Selayang Hospital, Malaysia. Received November 28, 2005; accepted in revised form May 9, 2006. Originally published online as doi:10.1053/j.ajkd.2006.05.008 on July 26, 2006. Support: Supported in part by grants from Fresenius Medical Care and Baxter. Potential conflicts of interest: None. Address reprint requests to Hin-Seng Wong, MD, FRCP(E), Department of Nephrology, Kuala Lumpur Hospital, Jalan Pahang, 50586, Kuala Lumpur, Malaysia. E-mail: hswong@ hkl.gov.my © 2006 by the National Kidney Foundation, Inc. 0272-6386/06/4803-0013$32.00/0 doi:10.1053/j.ajkd.2006.05.008 464
has always been the main complication and main cause of failure in CAPD patients. Numerous advances addressed this problem, and introduction of the twin-bag system decreased peritonitis rates to 30 to 50 patient-months/episode.1-6 There are several twin-bag systems available commercially, but each has minor differences. Our experience with the Y-disconnect systems shows that minor variations in connectology could translate into marked differences in peritonitis rates.7 With the introduction of 2 different twin-bag systems into Ministry of Health hospitals (UltraBag; Baxter, Deerfield, IL and ANDY-Disc; Fresenius Medical Care, Bad Homburg, Germany), peritonitis rates of CAPD patients in these hospitals were expected to improve. A recent study had shown similar peritonitis and exit-site infection rates between the Baxter UltraBag and Fresenius Medical Care Staysafe.8 However, the effectiveness of the newly introduced Fresenius Medical Care ANDY-Disc system compared with the Baxter UltraBag is unknown. In this multicenter, randomized, controlled study,
American Journal of Kidney Diseases, Vol 48, No 3 (September), 2006: pp 464-472
A STUDY COMPARING 2 CAPD TWIN-BAG SYSTEMS
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Fig 1. The Fresenius ANDY-Disc system uses the control disc to direct dialysate flow. The Y-tubing connection is built in to the control disc that consists of a PIN system; turning the knob in the control disc from position 1 to 4 will complete the CAPD exchange cycle.
both twin-bag systems were evaluated to establish their equivalence with respect to incidences of peritonitis, technique failure, and product defect. METHODS
Study Design and Patient Selection This multicenter, open-label, parallel-group, randomized trial is designed to show the therapeutic equivalence of
ANDY-Disc (Fig 1) with UltraBag (Fig 2) for a treatment period of 12 months. New or existing patients (using the single-bag system) with end-stage renal failure in the Ministry of Health CAPD program with 1 or more indications for using the twin-bag system were recruited. These indications were patients younger than 18 years, patients who could not be trained to use the single-bag system, existing CAPD patients using the single-bag system with recurrent peritonitis, existing CAPD patients using the single-bag system who could no longer
Fig 2. The Baxter UltraBag system uses clamps situated before the Y connection to direct dialysate flow. The CAPD exchange cycle consists of draining the effluent (white clamp open, blue clamp closed), flush before fill (both clamps open), and filling fresh dialysate into the peritoneal cavity (white clamp closed, blue clamp open).
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continue with the system, and existing CAPD patients using the single-bag system who, in the opinion of the investigator, would benefit from a change to the twin-bag system. Patients currently using the twin-bag system or expected to be transferred to a nonparticipating center within the next 6 months or requiring the use of automated cycler assistance were excluded. The primary outcome variable is the incidence of peritonitis. Peritonitis is defined as the presence of at least 2 of the following conditions: abdominal pain or tenderness, presence of white blood cells in peritoneal effluent in excess of 100 cells/mL comprising at least 50% polymorphs, and positive dialysate culture result. Secondary outcome parameters are technique failure, technical problems encountered while using the system, and product defects. Technique failure is defined as transfer to hemodialysis therapy or death. Crossover to the comparator was considered withdrawal. Because of the nature of the product, blinding was not possible. The randomization list was generated separately
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for each participating center by using the random permuted block method with randomly varying block size.9 Subjects were randomly allocated to either the ANDY-Disc or UltraBag system in a 1:1 ratio. The randomization schedule was generated by using a computer program at the Clinical Research Centre. Interactive voice response central randomization service was used to provide around-the-clock randomization. Patients randomly assigned to ANDY-Disc required a change of the transfer set before conversion to the twin-bag system, whereas those randomly assigned to UltraBag started conversion by using the existing transfer set. After successful conversion from the Y-disconnect single-bag system to the twin-bag systems, patients were followed up for 12 months. A wash-in period of 1 month after conversion was allowed, assuming that the conversion process exposes patients to increased risk for peritonitis and to exclude relapsing peritonitis occurring before conversion. All reported peritonitis episodes were subjected to verification by 2 nephrologists who were independent of the site
Fig 3.
Trial profile.
A STUDY COMPARING 2 CAPD TWIN-BAG SYSTEMS
reporting the peritonitis and blinded to subject treatment assignment. Only verified peritonitis episodes were included for analysis. Peritonitis episodes occurring during the wash-in period were excluded from analysis.
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termined margin of equivalence. For power of 0.8 and ␣ of 0.05 (1 sided), the required sample size was 132 patients/ arm.
RESULTS
Statistics Incidence rate ratio (IRR), the ratio of peritonitis rates of patients using ANDY-Disc to those using UltraBag, was used to compare the 2 twin-bag systems. A Poisson model was used to estimate IRR. The combined treatment effect was estimated by taking the average of individual centers’ effects weighted by the inverse of individual centers’ variance.10,11 STATA software package (Stata Corp, College Station, TX) was used for analysis.12 The margin of equivalence between ANDY-Disc and UltraBag was accepted as an IRR of 0.8 to 1.2. Upper and lower limits of the 95% confidence interval (CI) of IRR of peritonitis using ANDY-Disc compared with UltraBag must lie within these limits by both per-protocol and intention-totreat analyses to conclude therapeutic equivalence.13 The sample size required was based on an expected peritonitis rate of 0.05 episodes/patient-month and the prede-
Two hundred seventy CAPD patients were screened and randomly assigned, with 135 patients in each arm. Two patients in the ANDYDisc arm were excluded from the study. One subject withdrew his consent and the other subject required use of an automated cycler. Two hundred twelve patients completed the study, and 56 patients died or converted to hemodialysis treatment (Fig 3) during the study period. There was a lower baseline peritonitis rate and a higher percentage of self-care CAPD patients in the ANDY-Disc group, but these were not statistically significant. The other baseline characteristics were very similar between groups, including
Table 1. Demographics and Baseline Characteristics Characteristics
ANDY-Disc (n ⫽ 133)
UltraBag (n ⫽ 135)
P
Median age (y) Age ⬍ 12 y (pediatric) Male Primary renal disease Unknown Diabetic nephropathy Glomerulonephritis Obstructive nephropathy or calculi Others Comorbidity Diabetes Hypertension Impaired vision Ischemic heart disease Cerebrovascular disease Quality-of-life score of 10 Baseline peritonitis rate, episode/patient-month (patient-mo/episode peritonitis) Peritoneal dialysis regimen 4 exchanges/d Assistance required on CAPD Laboratory tests results Hemoglobin (g/dL) Urea (mg/dL) Creatinine (mg/dL) Albumin (g/dL) Baseline clearance Dialysis creatinine clearance (L/wk) Renal creatinine clearance (mL/min) Weekly urea Kt/V (total)
44 (4-81) 9 (7) 60 (45)
46 (2-71) 14 (10) 69 (51)
0.3910 0.2923 0.3258
44 (33) 40 (30) 30 (23) 10 (8) 7 (5)
49 (36) 38 (28) 21 (16) 14 (10) 13 (10)
0.5806 0.7284 0.1443 0.4137 0.1738
43 (32) 107 (79) 6 (4) 23 (17) 8 (6) 86 (63.7)
0.9331 0.3492 0.4082 0.6557 0.1300 0.4942
0.033 (30.4)
0.2160
130 (97.7) 32 (24)
131 (99.2) 40 (30)
0.7166 0.3037
9.9 ⫾ 1.9 49.6 ⫾ 22.4 9.11 ⫾ 3.46 3.34 ⫾ 0.64
9.8 ⫾ 1.9 48.7 ⫾ 22.7 8.47 ⫾ 3.04 3.25 ⫾ 0.64
0.6258 0.464 0.808 0.2339
61.6 (15-122) 0.6 (0-18.7) 2.1 (1-11.1)
59.5 (20-116) 0.9 (0-8.5) 2.2 (1.1-5)
0.179 0.272 0.714
43 (32) 99 (74) 9 (7) 20 (15) 3 (2) 90 (67.7) 0.026 (38)
NOTE. Values expressed as median (range), number (percent), and mean ⫾ SD. To convert serum creatinine in mg/dL to mol/L, multiply by 88.4; urea nitrogen in mg/dL to mmol/L, multiply by 0.357; albumin and hemoglobin in g/dL to g/L, multiply by 10.
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using ANDY-Disc, 72% of reported peritonitis episodes were verifiable, whereas 77% of peritonitis episodes in patients using UltraBag were verified. Percentages of verified peritonitis episodes in the 2 groups were similar (P ⫽ 0.52). Twelve patients using ANDY-Disc experienced more than 1 episode of peritonitis, whereas in the UltraBag arm, there were 10 patients (P ⫽ 0.63). Types of organisms cultured in the 107 verified peritonitis episodes are listed in Table 2. There was no significant difference in type of organisms cultured between the 2 groups. Verified peritonitis rates varied widely by centers, ranging from 13 to 55.4 patient-months/ episode for ANDY-Disc and 16.4 to 132 patientmonths/episode for UltraBag. Overall peritonitis rates were 22.9 patient-months/episode for ANDY-Disc and 35.0 patient-months/episode for UltraBag (P ⫽ 0.033). Risk for peritonitis using ANDY-Disc was 53% greater compared with UltraBag. IRR was used to measure treatment effect. This was estimated based on the Poisson model. Data showed no significant departure from model assumption. The point estimate of the IRR was greater than 1 in all centers except center 4. IRRs of peritonitis using ANDY-Disc compared with UltraBag were 2.09 (95% CI, 0.97 to 4.5), 4.41 (95% CI, 0.52 to 37.8), 2.25 (95% CI, 0.41 to 12.3), 0.63 (95% CI, 0.22 to 1.77), 1.26 (95% CI, 0.61 to 2.62), and 1.94 (95% CI, 0.78 to 4.87) for centers 1, 2, 3, 4, 5, and 6 with per-protocol
Table 2. Type of Culture by Treatment Type of culture
ANDY-Disc
UltraBag
Total
No growth Corynebacterium species Actinomyces species Staphylococcus aureus Methicillin-resistant S aureus Staphylococcus coagulase negative/Staphyloccus epidermidis Methicillin-resistant S epidermidis Enterococcus/Streptococcus group D/Streptococcus faecalis Streptococcus others Escherichia coli Klebsiella species Pseudomonas aeroginosa, others Cinetobacter species Enterobacter species Candida albicans, others Others Missing Total
13 1 1 5 1
11 0 0 6 4
24 1 1 11 5
14
5
19
2
1
3
1 3 4 5
1 3 2 2
2 6 6 7
7 2 2 0 1 2 64
3 0 1 1 1 2 43
10 2 3 1 2 4 107
percentages of pediatric patients, numbers of assisted CAPD patients, and patient quality of life14,15 (Table 1). Peritonitis Of 145 episodes of peritonitis reported, 107 (74%) were verified independently. Of patients . . |
6 |
Centre
5 4
|
|
|
|
|
|
p-value=0.156
p-value=0.535
p-value=0.379
|
p-value=0.349
3
|
|
|
p-value=0.175
2
|
|
|
1
|
|
All .5
.8
|
1.2
|
|
|
p-value=0.059
p-value=0.033
5 IRR, log scale
10
20
30 40
Fig 4. Treatment effect (IRR) by center and pooled estimate (per-protocol analysis).
A STUDY COMPARING 2 CAPD TWIN-BAG SYSTEMS Table 3. Product Defect by Treatment Arm
Product Defects
ANDY-Disc (n ⫽ 132)
UltraBag (n ⫽ 133)
66 52 14 118 114 4 25
8 5 3 3 2 1 4
20
Not applicable
5 2
1 1
All defects with dialysate bag Leaking bag Others All defects with drainage bag Leaking Others Defects with tubing Defects with control disc (for Andy-Disc only) Defects with disconnection cap for transfer set Defects with transfer set
analysis, respectively (Fig 4). Results using ITT analysis were similar. The equivalence of ANDY-Disc compared with UltraBag with regard to peritonitis rate could not be shown because the overall IRR estimate (95% CI) overlaps the prespecified margin of equivalence of ⫾20%. Secondary End Points Product defects. Product defects occurred more frequently with ANDY-Disc. Two hundred thirty-six product defects were reported withANDYDisc compared with 17 with UltraBag. The most common defects encountered with ANDYDisc were leakage of the drainage and dialysate bags, accounting for 78% of total defects reported (Table 3).
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Graphs of product defects and peritonitis counts with calendar time for ANDY-Disc and UltraBag are shown in Figs 5 and 6, respectively. Change in peritonitis count with time for ANDY-Disc appears to follow and mirror changes in the number of product defects (Fig 5). Cross-correlation between product defects and peritonitis for ANDYDisc by using time series reporting showed a moderately strong positive correlation between product defect and peritonitis at lags 0 and 3. No correlation of peritonitis and product defect was noted in the UltraBag arm. Despite a higher number of product defects on the ANDY-Disc arm, most patients were either very or moderately satisfied with the system assigned, and few reported difficulties using the systems. Technique failure. Technique failure rates at 3, 6, and 12 months for ANDY-Disc were 3%, 7%, and 21%, and for UltraBag, 4%, 9%, and 18%, respectively. The 2 main reasons for technique failure were death and conversion from CAPD to hemodialysis therapy. There were no significant differences in these events between the 2 systems. However, there appears to be a divergence in technique survival beyond 6 months, with better survival in the UltraBag arm, but this did not reach statistical significance (Fig 7). DISCUSSION
This study was conducted to evaluate 2 disconnect CAPD systems: Fresenius ANDY-Disc and
Peritonitis, ANDY-disc
30
Product defect, ANDY-disc
Count
25
20
15
10
5
0 May-02
Fig 5. defect.
Jun-02
July-02
Aug-02
Sept-02
Oct-02
Nov-02
Dec-02
Jan-03
Feb-03
Mar-03
Apr-03 May-03 Jun-03 Month-Year on trial
July-03
Aug-03
Sept-03
Oct-03
Nov-03
Dec-03
Jan-04
Feb-04
Mar-04
Apr-04
May-04
Relationship between product defect and peritonitis for ANDY-Disc. (Œ), Peritonitis count; (⌬), product
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WONG ET AL
Peritonitis, UltraBag
Product defect, UltraBag
30
Count
25
20
15
10
5
0 May-02
Fig 6.
Jun-02
July-02
Aug-02
Sept-02
Oct-02
Nov-02
Dec-02
Jan-03
Feb-03
Mar-03
Apr-03 May-03 Jun-03 Month-Year on trial
July-03
Aug-03
Sept-03
Oct-03
Nov-03
Dec-03
Jan-04
Feb-04
Mar-04
Apr-04
May-04
Relationship between product defect and peritonitis for UltraBag. (Œ), Peritonitis; (⌬), product defect.
Baxter UltraBag. Baseline characteristics of the 2 arms were well balanced, except for more self-care patients and lower peritonitis rates on the ANDY-Disc arm. The peritonitis rate improved in the UltraBag group, decreasing from 30.4 to 35 patient-months/episode of peritonitis, whereas in the ANDY-Disc cohort, peritonitis rate deteriorated from 38 to 22.9 patient-months/ episode of peritonitis. This was unexpected because conversion from the conventional Ydisconnect system with a single bag to the doublebag disconnect system was expected to improve peritonitis rates significantly.2-4,6 However, this should be interpreted with caution because baseline peritonitis episodes were collected retrospec-
tively, unverified, and may be underreported. Baseline peritonitis episodes were collected to show similar baseline peritonitis rates in the 2 groups and were not intended to be used to test for equivalence. Peritonitis rates varied widely among the 6 centers. A similar pattern was seen in our first multicenter CAPD trial,7 in which a significant treatment-center interaction was found. In the Malaysian Dialysis and Transplant Registry 2005 report, wide center variations also were reported in terms of patient survival, technique survival, peritonitis rates, and dialysis adequacy among CAPD centers in this country.16 In this study, the wide center variation could be caused by differ-
1
Technique survival
.9 UltraBag
ANDY-disc .8
.7 0
3
6 Time [months]
9
12
Fig 7. CAPD technique survival (0 to 12 months) by treatment arms (P > 0.05).
A STUDY COMPARING 2 CAPD TWIN-BAG SYSTEMS
ent CAPD practices, different percentages of pediatric patients in each center, and different baseline characteristics of patients recruited for this study. Although we did not find a similar interaction in this study, the analysis likely is lacking in power. Overall peritonitis rates with both systems were greater than the rate reported in the literature.1,2 This probably is a reflection of the high-risk patients recruited for the trial. Risk for peritonitis using ANDY-Disc was 53% greater compared with UltraBag. Although the 95% CI overlaps the margin of equivalence, the apparent increased rate is of concern to clinicians treating CAPD patients. The greater peritonitis rate will translate to increased morbidity and mortality of patients and treatment costs. Our results seem to differ from those of the trial with the Fresenius Staysafe system.8 This trial reported no significant difference between Baxter UltraBag and Staysafe, but it was not designed to test for equivalence and numbers were smaller. Furthermore, the Fresenius Staysafe system studied by Li et al8 is very similar to the Fresenius ANDY-Disc in terms of design and connectology, but the material is different. Product defects were reported more frequently with ANDY-Disc, predominantly with leaks from drainage and dialysate bags. More product defects were detected as the number of patients recruited increased. There appears to be a downward trend in product defects in the last quarter of the study period. This may occur because of a change in manufacturing process after feedback from the investigators during the progress meeting in February 2003. Drainage bag leakage is of particular concern because this results in a break in the closed system. There are insufficient data to establish the relationship between drainage bag leakage and peritonitis in individual centers. The link between dialysate bag leakage and peritonitis is tenuous because patients should have identified the leak and discarded the product before use. However, microscopic leaks may not be detected. The relationship between other product defects and peritonitis is unclear. There was a greater technique failure rate in the ANDY-Disc group at the end of the study, probably because of the greater peritonitis rate in the ANDY-Disc group. Although technique failure rates of the 2 groups diverge with time, the differ-
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ence in technique survival at 1 year between the 2 groups did not reach statistical significance. In conclusion, therapeutic equivalence of ANDY-Disc to UltraBag could not be shown in this trial because of small sample size. There was a trend toward a greater peritonitis rate with ANDY-Disc. ACKNOWLEDGMENT The authors thank Fresenius Medical Care and Baxter for the support of this research; the Clinical Research Centre, Hospital Kuala Lumpur, for overseeing and auditing this trial; and the Director General of Health Malaysia for the permission to publish this report.
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13. Jennison C, Turnbull BW: Repeated confidence intervals for group sequential clinical trials. Control Clin Trials 5:33-45, 1984 14. Spitzer WD, Dobson AJ, Hall J, et al. Measuring the quality of life of cancer patients, a concise QL index for use by physicians. J Chronic Dis 34:585-597, 1981
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15. Lim TO, Morad Z: Reliability, validity and discriminatory ability of Spitzer’s QL index in dialysis patients. Med J Malaysia 53:392-400, 1998 16. Lim YN, Lim TO: 13th Report of the Malaysian Dialysis and Transplant Registry 2005. Malaysia, National Renal Registry, 2006
