Effect of computer-assisted European Best Practice Guideline ...

JNEPHROL 2009; 22: 662-674

ORIGINAL ARTICLE

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Effect of computer-assisted European Best Practice Guideline implementation on adherence and target attainment: ORAMA results Francesco Locatelli1, Adrian Covic2, Iain C. Macdougall3 Armin Scherhag4,5, Andrzej Wiecek6; on behalf of the ORAMA Study Group

Abstract Background: The success of guidelines depends largely on effective implementation and uptake in clinical practice. The Optimal Renal Anemia Management Assessment (ORAMA) study investigated the impact of European Best Practice Guideline (EBPG) prompting on patient outcomes. Methods: ORAMA was a prospective, international, multicenter, cluster-randomized study. Fifty-three centers in eight European countries enrolled patients with chronic kidney disease stage V receiving chronic dialysis. Patients were either anemic (hemoglobin [Hb] 11 g/ dL (110 g/L), reflecting hematological targets in the revised EPBG. Results: In this population of 599 dialysis patients, hematological targets did not differ in the presence or absence of a CDS system. There was a

Department of Nephrology, Dialysis and Renal Transplantation, A. Manzoni Hospital, Lecco - Italy 2 C. I. Parhon Hospital and University of Medicine, Gr. T. Popa, Iasi - Romania 3 Renal Unit, King’s College Hospital, London - UK 4 F. Hoffmann-La Roche Ltd., Basel - Switzerland 5I I Medical Clinic, University Hospital Mannheim, University of Heidelberg, Heidelberg - Germany 6 Department of Nephrology, Endocrinology and Metabolic Diseases, Medical University of Silesia, Katowice - Poland 1

general shift towards improved patient distribution by Hb categories while the width of the distribution curves remained unchanged. The proportion of patients with Hb >11 g/dL (110 g/L) was higher among adherers (79% and 84% with or without CDS use, respectively) than non-adherers (59% and 57%, respectively). Conclusions: ORAMA is the first international study to show that adherence to EBPG improved attainment of anemia indices. The availability of a CDS system did not affect anemia management. Key words: Chronic kidney disease, Clinical decision

support, Erythropoiesis-stimulating agents, European best practice guidelines, ORAMA, Renal anemia

Introduction Raising hemoglobin (Hb) levels in anemic patients with chronic kidney disease (CKD) using erythropoiesis-stimulating agents (ESAs) has been shown to improve a variety of parameters including patient quality of life and cardiac function (1, 2). Several studies have reported variations in the management of renal anemia between countries (3, 4). Clinical practice guidelines (4-11) that are used increasingly

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across many therapeutic areas are a means of disseminating clinical experience so that evidence-based best practice becomes standard practice, thus reducing international and regional variations in patient management. Reports assessing the impact of guidelines on patient outcomes are mixed and highlight the myriad of factors involved in assessing and bringing about change in clinical practice. The impact of the guidelines produced by the first US National Kidney Foundation Dialysis Outcomes Quality Initiative (DOQI) (12, 13) was assessed in the retrospective US Renal Data System Assessment study in 2002 (14). Results showed a correlation between ESA use and hematocrit levels, both increasing with time, but without a consistent pattern to indicate that the guidelines were responsible for the observed changes. Another study evaluated the implementation of the Caring for Australasians with Renal Impairment (CARI) guidelines (15) in 6 dialysis units across Australia, with respect to anemia management in patients on dialysis (15, 16). Considerable variation was found among units in the achievement of Hb (25%-32%), serum ferritin (65%-73%) and transferrin saturation (TSAT) targets (20%-50%). Factors associated with achieving targets included, among others, an anemia management decision aid. Improved patient outcomes, in terms of hospitalization and mortality rates, have been reported in patients meeting the clinical targets established for Hb (>11 g/dL) and dialysis efficacy (Kt/V >1.2) in the US Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines for the treatment of renal anemia in patients with CKD (17-20). In 2004, the revised European Best Practice Guidelines (EBPG) recommended hematological targets for patients with ane-

mia and CKD (21). However, it was reported in 2006 that large proportions of patients were outside proposed target ranges in spite of the availability of these guidelines (22). The same report concluded that the only way to check that guidelines improve outcomes is to emphasize implementation strategies (22). To this end, other studies have shown that guidelines have been most successful in facilities that invest in implementation initiatives (23). To facilitate the widespread implementation of guidelines, computerized clinical decision support (CDS) systems integrating decision support with computer-based patient records have been used increasingly in ambulatory and inpatient medical care settings since the 1990s (24). By comparing patient characteristics and matching these with a knowledge base, CDS systems offer guidance for specific patients and situations (25, 26).These systems are now used in a wide range of health care areas from medication management (27, 28) to improving guideline implementation (7, 29). Such systems have generally been associated with improved professional practice (8, 9), although the degree of guideline implementation varies both on an international and institutional level (30). The Optimal Renal Anaemia Management Assessment (ORAMA) is the first prospective study designed to assess attainment of the 2004 revised EBPG targets for patients with anemia and CKD with regard to guideline implementation and adherence. The design and baseline data of ORAMA have been published separately (31). A CDS system based on EBPG was used as a means of prompting physicians to follow specific guideline recommendations. This article reports the results of ORAMA in dialysis patients.

TABLE I ORAMA INCLUSION AND EXCLUSION CRITERIA Inclusion criteria

Exclusion criteria

Men and women, age >18 years CKD stage 5 (dialysis: hemodialysis, CAPD or combination of both) Presence of chronic renal anemia (Hb 15 g/L Pregnancy Nonrenal anemia at enrolment Severe hyperparathyroidism (intact PTH >800 pg/mL) Hemoglobinopathies Patients enrolled in another clinical trial Patient considered unsuitable by investigator (e.g., severe comorbid illness, anticipated poor compliance)

CAPD = continuous ambulatory peritoneal dialysis; CKD = chronic kidney disease; ESA = erythropoiesis-stimulating agent; Hb = hemoglobin; PTH = parathyroid hormone. 663

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Locatelli et al: Adherence to EBPG: ORAMA study, final results

Fig. 1 - ORAMA study design. CDS = clinical decision support; CKD = chronic kidney disease; Hb = hemoglobin.

Subjects and methods Study population This study was conducted in accordance with the ICH guidelines on studies in human subjects in adherence to the Declaration of Helsinki. ORAMA enrolled adult patients with CKD (stage 5) receiving dialysis, who had chronic renal anemia (Hb 11 g/dL, serum ferritin >100 µg/L, hypochromic red cell (HRC) count 20%. Secondary end points included the following: proportion of patients who achieved at least 1 primary end point, proportion of investigatory adhering to the ORAMA CDS software, the use of iron supplementation (dose, route and administration) and the use of erythropoietic therapy (dose, route and administration). Adherence to the EBPG regardless of the use of the CDS system was evaluated in a post hoc analysis.

Statistical analysis The sample size calculation of at least 500 patients was based on detecting a difference of both 0.5 g/dL (5 g/L, [>90% power]) and 1.0 g/dL (10 g/L [>98% power]) in Hb concentration between groups (alpha = 0.05), assuming a normal distribution of the data with an interpatient coefficient of variation of 0.15 for Hb concentration, based on previous measurements in CKD patients. Primary end points for each of the 4 hematological indices were analyzed as discrete variables (target achieved or not achieved). The number of patients who met target values was expressed as a percentage of the total population at each time point. All 4 primary outcome variables were compared between study groups using analysis of variance (ANOVA) and, where appropriate, a paired Student’s t-test. Statistical significance was accepted at an alpha level below 5%. Analysis of the secondary composite end point was performed as with the primary end points. Other secondary variables (mean increase in Hb, ESA administration and iron supplementation) were examined as independent variables. Ferritin measurements were missing for 17% and TSAT/HRC count measurements were missing for 12% of all dialysis patients in the ORAMA study. Results are reported for the overall ORAMA dialysis patient population as primary analysis. Comparisons were made between patients treated at centers with or without access to the guideline-based CDS system, as well as between adherers and non-adheres at both groups of centers, as post hoc analyses.

Role of the funding source and study committees The trial was designed, implemented and overseen by the Steering Committee together with representatives of the sponsor, F. Hoffmann-La Roche Ltd. (as non-voting members of the steering committee). The sponsor identified participating centers and was responsible for the monitoring of the centers, data collection and data management. The steering committee was granted access to all study data. Interpretation of data was performed with close collaboration between the steering committee and the sponsor.

Results Demographics Baseline characteristics of the 599 patients receiving chronic dialysis enrolled in this study were as expected for a population of European dialysis patients and were generally similar between groups (Tab. II) (31). Fifty-four percent of patients were treated at centers with access to the computerized CDS. In this group, guideline prompts were adhered to in only 40% of patients, which equates to 21% of the overall ORAMA dialysis patient population. In the group without access to CDS, EBPG were followed in 48% of the patients (22% of the overall patient population). Overall, 43% of the patients were treated according to EBPG.

Hemoglobin levels Attainment of EBPG targets at baseline and at study end is summarized in Table III. Fifty percent of all patients at baseline had achieved guideline targets, i.e., >11 g/dL (110 g/L; p13 g/dL (130 g/L) increased slightly from baseline (8%) to study end (13%). The distribution of patients by Hb categories shifted upwards from baseline to study end, with the distribution curve maintaining a similar shape (Fig. 3).

Achievement of hemoglobin targets, regional differences Overall, the majority of patients (52%) had Hb in the range 10-12 g/dL (100-120 g/L) at baseline, 56% were within the 665

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TABLE II DEMOGRAPHICS AND BASELINE CHARACTERISTICS OF DIALYSIS PATIENTS BY RANDOMIZATION GROUP AND ADHERENCE

Total (N=599)

All patients by group

Adherers by group

Group A (n=321)

Group B (n=278)

Group A (n=128)

Group B (n=134)

Sex, men (%)

295 (49)

143 (45)

146 (53)

59 (46)

73 (55)

Mean age, years (SD)

59 (15)

60 (14)

57 (15)

59 (16)

59 (15)

Mean systolic blood pressure, mm Hg (SD)

134 (18)

134 (18)

134 (17)

132 (17)

134 (18)

Mean diastolic blood pressure, mm Hg (SD)

78 (10)

78 (10)

78 (10)

77 (10)

78 (10)

111 (19) 107 (18)

61 (19) 66 (21)

44 (16) 40 (14)

24 (19) 19 (15)

19 (14) 18 (13)

173 (29) 52 (9) 98 (16)

86 (27) 20 (6) 63 (20)

82 (29) 30 (11) 34 (12)

41 (32) 12 (9) 20 (16)

40 (30) 19 (14) 12 (9)

101 (17)

46 (14)

54 (19)

20 (16)

32 (24)

153 (26) 297 (50)

79 (25) 160 (51)

67 (25) 130 (48)

32 (25) 67 (52)

30 (22) 67 (50)

ACE inhibitors, no. (%)

246 (41)

128 (40)

109 (39)

51 (40)

56 (42)

Beta blockers, no. (%)

235 (39)

113 (35)

114 (41)

38 (30)

63 (47)

Other antihypertensive medication, no. (%)

226 (38)

107 (33)

112 (40)

42 (33)

59 (44)

Patients on hemodialysis, no. (%)

567 (95)

308 (96)

259 (93)

-

-

Mean length of dialysis, months (SD)

50 (51)

44 (46)

57 (56)

-

-

Kt/V, mean (SD)

1.35 (0.23)

1.36 (0.21)

1.33 (0.25)

-

-

Kt/V >1.2, no. (%)

261 (73)

150 (79)

111 (66)

-

-

3 92 5

3 90 7

2 95 3

-

-

Cause of chronic renal failure

Diabetic nephropathy, no. (%) Hypertensive nephrosclerosis, no. (% Glomerulonephritis, no. (%) Polycystic kidney disease, no. (%) Pyelonephritis/interstitial nephritis, no. (%) Other cause, no. (%)

Most frequent concomitant diseases Diabetes mellitus, no. (%) Cardiovascular disease, no. (%) Use of concomitant medications at baseline

Frequency of hemodialysis/week Twice, % Three times, % Four or more times, %

Group A included patients with computerized clinical decision support (CDS) access; Group B, patients without CDS access. ACE = angiotensin-converting enzyme; Hb = hemoglobin; no. = number of patients; SD = standard deviation; Kt/V = dialysis efficacy. 666

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Fig. 2 - EBPG target attainment in all patients and according to access to guideline prompts (access to clinical decision support [CDS]) at study end. Hb = hemoglobin; HRC = hypochromic red cell count; NS = nonsignificant difference between groups with and without guideline prompts; TSAT = transferrin saturation.

range 11-13 g/dL (110-130 g/L) at study end. There was no major difference in the distribution curve shape between patients treated in centers with or without CDS access. Achievement of major hematological targets was mostly independent of region: the proportion of patients from East and West Europe attaining serum ferritin >100 ng/mL and HRC 20% was similar in groups with or without CDS (Tab. IV).

Adherence to EBPG A

B Fig. 3 - Distribution of patients across hemoglobin (Hb) categories at baseline and study end. A) Dialysis patients treated at centers with no clinical decision support (CDS) access. B) Adherent patients.

In the subgroup of patients whose treatment followed EBPG at both study visits (n=128, [21%] in the group with CDS access and n=134 [22%] in the group without CDS access), mean Hb at study end was 11.9 g/dL (119 g/L) and 12.1 g/dL (121 g/L), respectively, with 79% and 84% achieving Hb >11 g/dL (110 g/L). In contrast, Hb >11 g/dL (110 g/L) was achieved only in 59% and 57% of patients whose treatment did not adhere to guidelines. Thirty-four percent of patients whose treatment followed EBPG in the group with CDS and 29% in the group without CDS access had Hb 11-12 g/dL (110-120 g/L). Twelve percent and 18% of patients in these groups, respectively, had Hb >13 g/dL (130 g/L). The mean Hb and the proportion of patients who attained Hb targets were generally higher when guidelines were followed compared with those patients whose treatment did not adhere to guidelines (Tab. III).

Iron indices Overall, a high proportion of patients achieved iron targets both at baseline and at visit 4 (Tab. III). The proportion of patients with serum ferritin >100 ng/mL increased from 85% at baseline to 91% at study end, with no significant 667

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difference between study groups or between Western and Eastern European countries (Tab. IV). At baseline, 82% of patients had TSAT >20% or HRC 100 ng/mL or HRC 20% already at baseline, the difference at visit 4 was relatively small except in Western European patients from the group with CDS access (Tab. IV).

ESA use Ninety-six percent of the dialysis patients were receiving ESA treatment for a mean of 9 months prior to baseline. The proportion of patients receiving ESA and the percentages of ESA treatments administered intravenously (i.v.) or subcutaneously (s.c.) remained stable over the course of the study (Tab. V). The weekly combined dose was slightly higher in the group with CDS access than in the group without CDS access. ESA-related guideline prompts were only adhered

TABLE III PROPORTION OF DIALYSIS PATIENTS ACHIEVING HEMATOLOGICAL TARGETS BY RANDOMIZATION GROUP AND ADHERENCE All patients by group

All dialysis patients

Group A

Group B

Baseline

11.1 (1.4)

11.0 (1.3)

11.2 (1.4)

Visit 4

11.7 (1.3)

11.6 (1.3)

11.7 (1.3)

Baseline

297 (50)

157 (49)

140 (50)

Visit 4

374 (69)

193 (67)

181 (70)

Baseline

149 (25)

91 (28)

58 (21)

Visit 4

170 (31)

88 (31)

82 (32)

Baseline

46 (8)

17 (5)

29 (10)

Visit 4

72 (13)

37 (13)

35 (14)

Baseline

489 (85)

255 (84)

221 (85)

Visit 4

490 (91)

253 (90)

237 (93)

Adherers by group

p Value (A vs. B)

Group A

Group B

11.4 (1.3)

11.8 (1.3)

11.9 (1.1)

12.1 (1.1)

82 (64)

99 (74)

95 (79)

106 (84)

48 (38)

38 (28)

41 (34)

37 (29)

10 (8)

20 (15)

15 (12)

23 (18)

105 (83)

116 (89)

99 (92)

112 (93)

87 (81)

111 (84)

104 (88)

106 (85)

Mean Hb, g/dL (SD)

0.134

Hb >11 g/dL, no. (%)

NA

Hb 11-12 g/dL, no. (%)

NA

Hb >13 g/dL, no. (%) NA

Serum ferritin >100 ng/mL, no. (%)

0.359

HRC 20%, no. (%) Baseline

439 (82)

206 (79)

222 (86)

Visit 4

480 (85)

253 (86)

227 (85)

0.812

Group A included patients with computerized clinical decision support (CDS) access; Group B, patients without CDS access. Visit 4 was at study end; 11 g/dL = 110 g/L. Hb = hemoglobin; HRC = hypochromic red cell count; NA = not applicable; TSAT = transferrin saturation. 668

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TABLE IV PROPORTION OF DIALYSIS PATIENTS ACHIEVING HEMATOLOGICAL TARGETS IN WESTERN AND EASTERN EUROPEAN COUNTRIES Total

Western

Western

Eastern

p Value*

Baseline

11.8 (1.2)

10.6 (1.3)

Visit 4

12.1 (1.3)

11.3 (1.3)

Baseline

201 (76)

96 (29)

Visit 4

201 (83)

173 (57)

Eastern

Group A

Group B

Group A

Group B

11.6 (1.2)

12.0 (1.2)

10.6 (1.3)

10.6 (1.2)

12.0 (1.3)

12.2 (1.3)

11.3 (1.2)

11.3 (1.2)

98 (71)

103 (81)

59 (32)

37 (25)

98 (82)

103 (84)

95 (57)

78 (57)

110 (86)

122 (95)

152 (84)

105 (75)

88 (98)

116 (96)

148 (89)

108 (91)

72 (69)

107 (84)

134 (85)

126 (87)

98 (85)

103 (85)

138 (87)

113 (86)

Mean Hb, g/dL (SD) 11 g/dL, no. (%) 100 ng/mL, no. (%) Baseline

232 (91)

257 (80)

Visit 4

204 (97)

256 (90)

0.013

HRC 20%, no. (%) Baseline

179 (77)

260 (86)

Visit 4

201 (85)

251 (86)

NA

Group A included patients with computerized clinical decision support (CDS) access; group B, patients without CDS access. Visit 4 was at study end; 11 g/dL = 110 g/L. Hb = hemoglobin; HRC = hypochromic red cell count; NA = not applicable; TSAT = transferrin saturation. *p Value, Western vs. Eastern patients; by t-test.

TABLE V ESA USAGE All dialysis patients

Group A

Group B

Baseline (n=599)

Visit 4 (n=547)

Visit 4 (n=289)

Visit 4 (n=258)

% patients receiving ESA % i.v./s.c.

96 43/57

95 45/55

96 46/54

94 43/57

Mean weekly combined IV dose*

7,606 (n=250)†

7,960 (n=232)†

8,398 (n=127)†

7,431 (n=105)†

Mean weekly combined SC dose

6,309 (n=326)†

7,228 (n=285)†

8,000 (n=147)†

6,406 (n=138)†

Group A included patients with computerized clinical decision support (CDS) access; Group B, patients without CDS access. Data are for visit 4 (at study end) unless otherwise stated. EPO = epoetin; ESA = erythropoiesis-stimulating agent; i.v. = intravenous; s.c. = subcutaneous. *ESA weekly doses were compiled for all agents (EPO alfa, EPO beta, darbepoetin alfa) applying the conventional conversion factor 1 μg = 200 IU; 75% of patients were on EPO beta. † Data for some patients were missing. 669

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TABLE VI IRON USAGE All dialysis patients

Group A

Group B

Baseline (n=599)

Visit 4 (n=547)

Visit 4 (n=289)

Visit 4 (n=258)

% patients receiving iron

65 (391)

59 (324)

63 (182)

55 (142)

% patients on i.v./oral/ both/none

55/8/2/35

51/7/2/41

52/8/3/37

49/5/1/45

Group A included patients with computerized clinical decision support (CDS) access; Group B, patients without CDS access. Data are for visit 4 (at study end) unless otherwise stated. i.v. = intravenous.

to in 67% of study visits, and adherence did not significantly affect ESA administration rate/route (data not shown). Overall, there were no major regional differences in ESA treatment. The choice of agents was similar, with a higher usage of darbepoetin alpha in Western Europe than in Eastern Europe (data not shown). Intravenous administration was preferred in Western European countries, where it was used in 55%-56% of the patients throughout the study, while s.c. administration was the preferred option in Eastern European countries (64%67% of patients). The weekly combined dosage administered was similar in Western and Eastern European countries.

Iron use The proportions of patients receiving iron orally and i.v. remained relatively stable during the study (Tab. VI). A higher proportion of patients treated by physicians with CDS access received iron compared with those treated by physicians with no access to the computerized CDS (63% vs. 55%, respectively). The proportions of patients receiving iron i.v., orally or by both routes were not affected by computerized CDS access. In adherent patients from the group with CDS access, iron use (57%) and the proportions of iron administered i.v. and orally (i.v.: 48%, oral: 7%) were similar to those for the ORAMA dialysis patients treated at centers with no CDS access (iron use: 55%; i.v.: 49%; oral: 5%; Tab. VI).

Discussion ORAMA compared clinical outcomes in patients with renal anemia whose treatment did or did not adhere to EBPG and whose investigators had or did not have access to a CDS system. An overall improvement in

anemia indices was observed in all ORAMA patients, irrespective of whether they had access to a CDS system or not, and in general, physician access to a computerized CDS system did not markedly influence the attainment of Hb targets or improve guideline achievement. The overall improvement in achievement of target indices observed in this study may be due to a “Hawthorne Effect” (study effect): in this case, an increased awareness of anemia management and guidelines by physicians through their involvement in the clinical study. This effect of study enrollment resulting in better outcomes, regardless of the intervention investigated in a study, has been reported previously (33). ORAMA demonstrates that adherence to EBPG increases the proportion of patients attaining target anemia indices. However, results from this study also suggest there was no significant difference in mean Hb levels in patients over 6-8 months when investigators adhered to or did not follow the promptings of the CDS software. These results suggest that although access to a computerized CDS system alone does not improve anemia management, the use of a CDS system in combination with active adherence to guidelines may improve anemia management in this population of dialysis patients. It should be noted that adherence to CDS guideline prompts may have selected the best patients (for example, those without comorbidities or intercurrent illness). An important result from the ORAMA study is that, despite the software system fulfilling all of the criteria for a CDS, including the delivery of guideline prompts, adherence to the guidelines remained poor. Only 41% of patients within the CDS access group actually received the treatment recommended by the guideline prompts. The possible reasons for

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non-adherence to guidelines have been discussed in the recent literature and include a reluctance to change clinical practice when there is no perception of a need for change (this could indicate a lack of awareness of performance versus guideline targets), economic restrictions that differ between institutions and between countries, and a patient population with certain comorbidities and/or concomitant therapies that may render them less likely to respond to guideline-recommended treatments (34-37). The relatively high instance of non-adherence in the ORAMA study points to the existence of a patient population to whom current guidelines are not applied and draws attention to the difficulties associated with global guideline implementation. A systematic review of computerized CDS systems identified 4 features that independently improve clinical practice, and the ORAMA CDS system met all 4 requirements: (i) “automatic provision of decision support as part of clinical workflow”; (ii) “provision of decision support at the time and location of decision making”; (iii) “provision of recommendations rather than just assessment”; and (iv) “computerbased decision support” (8). The data from ORAMA do not exclude the possibility that a CDS system may be beneficial to some patients, e.g., those with low Hb. However, such a CDS system would need to be adapted to country-specific anemia management schemes to ensure compliance and the resulting benefits. More research into the effect of country-adapted CDS systems on specific populations is needed. In addition to assessing the level of guideline target attainment and the impact on this of a CDS system, ORAMA was conceived with the aim of reducing the proportion of European CKD patients with low Hb (13 g/dL (130 g/L), coupled with the fact that prompts to reduce ESA dose were often not followed, suggest that less importance was placed on an upper Hb target and that nephrologists focused predominantly on bringing about an increase in Hb. It should also be noted that ORAMA was conducted before the availability of the updated KDOQI guidelines 2006-2007 and the Kidney Disease Improving Global Outcomes (KDIGO) and Anaemia Working Group of European Renal Best Practice (ERBP) position papers (42, 43). In the ORAMA dialysis patient population, mean Hb in-

creased in both groups over the course of the study, and the proportion of patients achieving the EBPG target of Hb >11 g/dL (110 g/L) increased from 50% to 69%, an improvement that compares favorably with figures reported previously in observational studies in European dialysis patients such as the Dialysis Outcomes and Practice Patterns Study (DOPPS; 56%) and the European Survey on Anaemia Management (ESAM 2003; 53%) (3, 4). This general increase in Hb levels can also be seen in the upward shift of the patient distribution by Hb category, supported by the higher proportion of patients with Hb >13 g/dL at study end compared with baseline (Fig. 3). Overall, attainment of iron targets was relatively good and improved over the course of the study. The number of missing ferritin and TSAT/HRC count measurements in the ORAMA study was comparable to the previously published DOPPS results (3) suggesting that reporting of iron was, and continues to be, suboptimal across Europe. As iron deficiency is a major cause of low responsiveness to ESA therapy, the monitoring of iron status is important in this patient population and could be further emphasized in future guidelines (44). There was a slight decrease in the use of iron over the course of the study. Neither the physician’s access to the computerized CDS system nor adherence to the EPBG influenced this trend. The EBPG recommend that iron be given to all patients with CKD in order to reach or maintain serum ferritin >100 mg/L, HRC 20%), or reticulocyte Hb content >29 pg/cell (21). Iron usage in ORAMA was similar to that reported in the 2004 DOPPS of 5 European countries, where 60% of hemodialysis patients received iron therapy. The slight decrease in iron usage over the course of the ORAMA study may reflect iron treatment being discontinued once Hb targets were reached (3). In ORAMA, a lower proportion of iron was administered i.v. than in the 2004 DOPPS (55% vs. 60%). The possible side effects of i.v. iron treatment raise concerns. However, when administered according to guidelines, i.v. iron is considered a safe and more effective treatment than oral iron (44, 45). Patients with adequate iron status respond better to ESA, which permits a lower ESA dose and can result in net savings. Such economic benefits may offset the increased costs associated with i.v. iron administration (46, 47). Given the seemingly suboptimal level of iron reporting across Europe, this is an area where guidelines could possibly be improved and the economic implications of effective iron management emphasized. An overall improvement in anemia indices was observed in all dialysis patients enrolled in the ORAMA study. This improvement was independent of the use of a CDS system. 671

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In patients whose treatment followed the EBPG, anemia indices were generally improved, with a higher proportion of patients achieving target Hb levels than those whose treatment did not follow guidelines. However, the data from the ORAMA study also show that adherence to guidelines is generally low even with a CDS system, potentially because the CDS system cannot address financial constraints and regional variations in clinical practice. Overall, the ORAMA results support the use of clinical best practice guidelines such as the EBPG which are designed to optimize patient care and treatment outcomes.

Acknowledgements We would like to thank all study investigators and clinical monitors of the study for their commitment to the collection of high-quality data (see “Appendix”). Statistical analyses were provided by GDS Services.

Appendix

ORAMA steering committee Adrian Covic, MD, PhD. Dialysis and Transplantation Center, Parhon University Hospital, Iasi, Romania Francesco Locatelli, MD, FRCP. Department of Nephrology, Dialysis and Renal Transplantation, A. Manzoni Hospital, Lecco, Italy Iain C Macdougall, MD, PhD. Renal Unit, King’s College Hospital, London, UK Andrzej Wiecek, MD, PhD. Department of Nephrology, Endocrinology and Metabolic Diseases, Medical University of Silesia, Katowice, Poland

Principal investigators Bulgaria: Peter Shikov (Pazardjik); Dimitar Nikolov (Plovdiv); Boriana Deliyska (Sofia); Dobrin Paskalev (Varna); Pencho Simeonov (Sofia) Croatia: Zarko Belavic (Karlovac); Barbic Jerko (Osijek); Ninoslov Leko (Slavonski Brod); Ivan Bogadi (Varazdin) Germany: Roland E. Winkler (Rostock); Martin Buhl (Berlin); Eckhard Wilbrandt (Heringen); Martin Edinger (Eschwege); Margit Mall (Halle); Christoph Dammerboer (Herzberg); Holger Urzowski (Finsterwalde); Daniela Flender (Sinsheim); Gabriele Kunowski (Heilbronn); Alexander Müller (Weinheim); Hans Anschütz (Groß Gerau); Gerhard Prager (Bad König); Johann-Borwin Lüth (Hannover) Italy: Francesco Locatelli (Lecco); Natale Gaspare De

Santo (Napoli); Cosimo Lodeserto (Taranto); Mario Bonomini (Chieti); Gina Meneghel (Dolo); Mauro Ragaiolo (Ascoli Piceno); Giovanni Cancarini (Brescia); Ugo Rotolo (Palermo) Latvia: L. Zepa (Rezekne); G. Saumane-Baza (Valmiera); G. Ritovs (Riga); R. Rozentals (Riga) Poland: Andrzej Rydzewski (Warszawa); Danuta AntczakJedrzejczak (Gorzow); Wlodzimierz Ratajewski (Kalisz); Andrzej Wiecek (Katowice); Dorata Frankiewicz (Konin); Olech Mazur (Koszalin); Bogdanowicz Grazyna (Opole); Andrzej Kosicki (Przemysl); Antoni Sydor (Tarnow); Marek Muszytowski (Torun) Romania: Adrian Covic (Iasi); Gabriel Mircescu (Bucharest) Serbia & Montenegro: Marina Mugosa Ratkovic (Podgorica); Steva Pljesa (Zemun); Vidosava Nesic (Belgrade); Nada Dimkovic (Belgrade); Svobodan Curic (Novi Sad); Marina Lazarevic (Kragujevac); Zoran Kovacevic (Belgrade)

Financial support: This study was sponsored by F. Hoffmann-La Roche Ltd. IRB/EC approval for this study was obtained from all participating centers. Conflict of interest statement: None of the authors have a conflict of interest to declare, but would like to make the following disclosures: Francesco Locatelli has received honoraria for lectures and panels from F. Hoffmann-La Roche Ltd, Amgen, Dompé, Shire Pharmaceuticals and Affymax. Adrian Covic has received honoraria for lectures and advisory boards for F. Hoffmann-La Roche Ltd. and for advisory boards for Fresenius Medical Care. Iain C. Macdougall has received research grants/consultancy fees, speaker fees and honoraria from Ortho Biotech, F. Hoffmann-La Roche Ltd. and Amgen, as well as consultancy fees and honoraria from Shire and Affymax. Armin Scherhag is an employee of F. Hoffmann-La Roche Ltd. Andrzej Wiecek has received travel grants and honoraria and has participated in clinical trials supported by F. Hoffmann-La Roche Ltd, Janssen-Cilag, Amgen, Affymax and Fibrogen.

Address for correspondence: Francesco Locatelli, Department of Nephrology, Dialysis and Renal Transplantation A. Manzoni Hospital Via Dell‘Eremo, 9/11 I-23900 Lecco Italy [email protected]

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JNEPHROL 2009; 22:662-674

References 1.

2. 3.

4.

5. 6.

7.

8.

9.

10.

11.

12.

13.

14.

Pisoni RL, Bragg-Gresham JL, Young EW, et al. Anemia management and outcomes from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis. 2004;44:94-111. London GM. Left ventricular hypertrophy: why does it happen? Nephrol Dial Transplant. 2003;18(Suppl 8):viii2-viii6. Locatelli F, Pisoni RL, Combe C, et al. Anaemia in haemodialysis patients of five European countries: association with morbidity and mortality in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant. 2004;19:121-132. Jacobs C, Frei D, Perkins AC. Results of the European Survey on Anaemia Management 2003 (ESAM 2003): current status of anaemia management in dialysis patients, factors affecting epoetin dosage and changes in anaemia management over the last 5 years. Nephrol Dial Transplant. 2005;20:3-24. ICH. Harmonised tripartite guideline: guideline for good clinical practice, adopted 1997. www.ich.org. Oxman AD, Schunemann HJ, Fretheim A. Improving the use of research evidence in guideline development: Part 16: evaluation. Health Res Policy Syst. 2006;4:28. Durieux P, Nizard R, Ravaud P, Mounier N, Lepage E. A clinical decision support system for prevention of venous thromboembolism: effect on physician behavior. JAMA. 2000;283:2816-2821. Kawamoto K, Lobach DF. Clinical decision support provided within physician order entry systems: a systematic review of features effective for changing clinician behavior. AMIA Annu Symp Proc. 2003;361-365. Garg AX, Adhikari NK, McDonald H, et al. Effects of computerized clinical decision support systems on practitioner performance and patient outcomes: a systematic review. JAMA. 2005;293:1223-1238. Portoles J, Krisper P, Choukroun G, de Francisco AL. Exploring dosing frequency and administration routes in the treatment of anaemia in CKD patients. Nephrol Dial Transplant. 2005;20(Suppl 8):viii13-viii17. Patkar V, Hurt C, Steele R, et al. Evidence-based guidelines and decision support services: a discussion and evaluation in triple assessment of suspected breast cancer. Br J Cancer. 2006;95:1490-1496. National Kidney Foundation. NKF-K/DOQI clinical practice guidelines for anemia of chronic kidney disease: update 2000. Am J Kidney Dis. 2001;37:182-238. National Kidney Foundation. NKF-DOQI clinical practice guidelines for the treatment of anemia of chronic renal failure. National Kidney Foundation Dialysis Outcomes Quality Initiative. Am J Kidney Dis. 1997;30:192-240. Collins AJ, Roberts TL, St Peter WL, Chen SC, Ebben J, Constantini E. United States Renal Data System assessment of the impact of the National Kidney Foundation-Dialysis

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25. 26.

27.

28.

29.

30.

Outcomes Quality Initiative guidelines. Am J Kidney Dis. 2002;39:784-795. Pollock C, McMahon L. The CARI guidelines: biochemical and haematological targets guidelines: haemoglobin. Nephrology (Carlton). 2005;10(Suppl 4):S108-S115. Irving MJ, Craig JC, Gallagher M, et al. Implementing iron management clinical practice guidelines in patients with chronic kidney disease having dialysis. Med J Aust. 2006;185:310-314. Amaral S, Hwang W, Fivush B, Neu A, Frankenfield D, Furth S. Association of mortality and hospitalization with achievement of adult hemoglobin targets in adolescents maintained on hemodialysis. J Am Soc Nephrol. 2006;17:2878-2885. Plantinga LC, Fink NE, Jaar BG, et al. Attainment of clinical performance targets and improvement in clinical outcomes and resource use in hemodialysis care: a prospective cohort study. BMC Health Serv Res. 2007;7:5. Port FK, Pisoni RL, Bragg-Gresham JL, et al. DOPPS estimates of patient life years attributable to modifiable hemodialysis practices in the United States. Blood Purif. 2004;22:175-180. Rocco MV, Frankenfield DL, Hopson SD, McClellan WM. Relationship between clinical performance measures and outcomes among patients receiving long-term hemodialysis. Ann Intern Med. 2006;145:512-519. Locatelli F, Aljama P, Barany P, et al. Revised European Best Practice Guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant. 2004;19:1-47. Arenas MD, varez-Ude F, Gil MT, et al. Application of NKF-K/ DOQI clinical practice guidelines for bone metabolism and disease: changes of clinical practices and their effects on outcomes and quality standards in three haemodialysis units. Nephrol Dial Transplant. 2006;21:1663-1668. Hysong SJ, Best RG, Pugh JA. Clinical practice guideline implementation strategy patterns in Veterans Affairs primary care clinics. Health Serv Res. 2007;42:84-103. Wu R, Peters W, Morgan MW. The next generation of clinical decision support: linking evidence to best practice. J Healthc Inf Manag. 2002;16:50-55. Friedman C, Wyatt J. Evaluation methods in medical informatics. New York: Springer-Verlag; 1997. Grimshaw J, Freemantle N, Wallace S, et al. Developing and implementing clinical practice guidelines. Qual Health Care. 1995;4:55-64. Rochon PA, Field TS, Bates DW, et al. Clinical application of a computerized system for physician order entry with clinical decision support to prevent adverse drug events in long-term care. CMAJ. 2006;174:52-54. Samore MH, Bateman K, Alder SC, et al. Clinical decision support and appropriateness of antimicrobial prescribing: a randomized trial. JAMA. 2005;294:2305-2314. Steele AW, Eisert S, Davidson A, et al. Using computerized clinical decision support for latent tuberculosis infection screening. Am J Prev Med. 2005;28:281-284. Brand C, Landgren F, Hutchinson A, Jones C, Macgregor

673

Locatelli.indd 673

11-09-2009 12:26:27


31.

32.

33.

34.

35.

36.

37.

38.

39.

L, Campbell D. Clinical practice guidelines: barriers to durability after effective early implementation. Intern Med J. 2005;35:162-169. Locatelli F, Covic A, Macdougall IC, Wiecek A; on behalf of the ORAMA Study Group. ORAMA: a study to investigate EBPG impact on renal anaemia - design and baseline data. J Nephrol. 2008;21:592-603. Wiecek A, Covic A, Locatelli F, Macdougall IC. Renal anemia: comparing current Eastern and Western European management practice (ORAMA). Ren Fail. 2008;30:267-276. Brimble KS, Rabbat CG, McKenna P, Lambert K, Carlisle EJ. Protocolized anemia management with erythropoietin in hemodialysis patients: a randomized controlled trial. J Am Soc Nephrol. 2003;14:2654-2661. Guidelines for exercise testing: a report of the American College of Cardiology/American Heart Association Task Force on Assessment of Cardiovascular Procedures (Subcommittee on Exercise Testing). J Am Coll Cardiol. 1986;8:725-738. Hayward RS, Wilson MC, Tunis SR, Bass EB, Guyatt G. Usersí guides to the medical literature: Part VIII: how to use clinical practice guidelines. A. Are the recommendations valid? The Evidence-Based Medicine Working Group. JAMA. 1995;274:570-574. Sox HC Jr, Garber AM, Littenberg B. The resting electrocardiogram as a screening test: a clinical analysis. Ann Intern Med. 1989;111:489-502. Goetz LL, Nelson AL, Guihan M, et al. Provider adherence to implementation of clinical practice guidelines for neurogenic bowel in adults with spinal cord injury. J Spinal Cord Med. 2005;28:394-406. Berns JS. Should the target hemoglobin for patients with chronic kidney disease treated with erythropoietic replacement therapy be changed? Semin Dial. 2005;18:22-29. Gomez JM, Carrera F. What should the optimal target hemoglobin be? Kidney Int Suppl. 2002;80:39-43.

40. Paoletti E, Cannella G. Update on erythropoietin treatment: should hemoglobin be normalized in patients with chronic kidney disease? J Am Soc Nephrol. 2006;17:S74-S77. 41. Spiegel DM. Anemia management in chronic kidney disease: what have we learned after 17 years? Semin Dial. 2006;19:269-272. 42. Locatelli F, Covic A, Eckardt KU, Wiecek A, Vanholder R. Anaemia management in patients with chronic kidney disease: a position statement by the Anaemia Working Group of European Renal Best Practice (ERBP). Nephrol Dial Transplant. 2009;24:348-354. 43. Locatelli F, Nissenson AR, Barrett BJ, et al. Clinical practice guidelines for anemia in chronic kidney disease: problems and solutions: a position statement from Kidney Disease Improving Global Outcomes (KDIGO). Kidney Int. 2008;74:1237-1240. 44. Horl WH. Iron therapy for renal anemia: how much needed, how much harmful? Pediatr Nephrol. 2007;22:480-489. 45. Macdougall IC, Tucker B, Thompson J, Tomson CR, Baker LR, Raine AE. A randomized controlled study of iron supplementation in patients treated with erythropoietin. Kidney Int. 1996;50:1694-1699. 46. Singh AK, Hertello P. The benefits of IV iron therapy in treating anemia in patients with renal disease and comorbid cardiovascular disease. Nephrol Nurs J. 2005;32:199-206. 47. Vankova S, Safarova R, Horackova M, et al. [Clinical and economic significance of iron replacement in anemia treated with recombinant human erythropoietin in patients on hemodialysis] [article in Czech]. Cas Lek Cesk. 2001;140:209-213. Received: January 14, 2009 Accepted: February 26, 2009 © Società Italiana di Nefrologia

674

Locatelli.indd 674

11-09-2009 12:26:27