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Relevantie van observationeel onderzoek in de klinische praktijk Themabijeenkomst “observationeel onderzoek” 20 september 2005.

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Presentatie over: "Relevantie van observationeel onderzoek in de klinische praktijk Themabijeenkomst “observationeel onderzoek” 20 september 2005."— Transcript van de presentatie:

1 Relevantie van observationeel onderzoek in de klinische praktijk Themabijeenkomst “observationeel onderzoek” 20 september 2005

2 Nederlandse Coöperatieve Studie naar de Adequaatheid van Dialyse

3 Presentatie NECOSAD Mogelijkheden observationeel onderzoek; voorbeelden: - HD versus PD - Vroege versus late start - Dialysedosis PD Conclusies

4 NECOSAD Initiatief van de Dialyse Groep Nederland (DGN) Eerste ideeën NECOSAD-1 (pilot-studie) NECOSAD-2 Uitgevoerd in 38 dialysecentra Gefinancierd door de Nierstichting en de Ziekenfondsraad

5 Organisatie NECOSAD Raad van Toezicht Prof. dr. G. K. van der Hem Prof. dr H. A. Koomans Prof. dr. K. M. L. Leunissen  Dr. R. van Leusen Projectleiding Dr. E. W. Boeschoten Dr. F. W. Dekker Prof. dr. R. T. Krediet Onderzoeksverpleegkundigen NECOSAD NECOSAD – verpleegkundigen in de centra Begeleidingscommissie Dr. A. J. Apperloo, Dr. J. N. M. Barendrecht, Dr. R. J. Birnie, Dr. M. Boekhout, Dr. W. H. Boer, Dr. E. F. H. van Bommel, Prof. Dr. H. R. Büller, F. Th. de Charro, Dr. C. J. Doorenbos, Dr. W. T. van Dorp, Dr. A. van Es, Dr. W. J. Fagel, Dr. G. W. Feith, Dr. C. F. M. Franssen, Dr. L. A. M. Frenken, Dr. J. A. C. A. van Geelen, Dr. P. G. G. Gerlag, Drs. J. P. M. C. Gorgels, Dr. W. Grave, Dr. R. M. Huisman, Dr. K. J. Jager, Dr. K. Jie, Drs. W. A.. H. Koning-Mulder, Dr. M. I. Koolen, Dr. T. K. Kremer Hovinga, Drs. A. T. J. Lavrijssen, Dr. A. W. Mulder, Dr. K. J. Parlevliet, Dr. J. L. C. M. van Saase, Drs. M. J. M. Schonk, Dr. M. M. J. Schuurmans, Prof. Dr. J. G. P. Tijssen, Dr. R. M. Valentijn, Dr. GH Vastenburg, Dr. C. A. Verburgh, Dr. V. M. C. Verstappen, Dr. H. H. Vincent, Dr. P. Vos.

6 Doelstellingen NECOSAD Analyse van de factoren die de uitkomst van de dialysebehandeling in Nederland bepalen Toetsen en ontwikkelen van richtlijnen voor een optimale behandeling Bijdragen aan de kwaliteit van de behandeling door terugkoppeling van centrumgebonden resultaten en het ontwikkelen van benchmarks

7 Studieopzet van NECOSAD Prospectieve observationele multi- center cohort studie bij incidente volwassen dialysepatiënten. Binnen dit cohort gerandomiseerde trial HD versus PD

8 Gegevensverzameling weken voor de start: demografie, poliklinische voorbereiding, starttherapie (+ reden), primaire nierziekte, co- morbiditeit, rookgewoonten, lengte, gewicht, RR, medicijngebruik, albumine, ureum, creatinine, GFR, kwaliteit van leven 0, 3, 6, 12, 18…..maanden dialysemodaliteit, therapiewisselingen, registratie op wachtlijst NTx, gewicht, RR, voedingstoestand, medicijngebruik, opnames, lab., dialysedosis, rGFR, Karnofsky-index, KvL.

9 Database Per ondergebracht bij Hans Mak Instituut

10 Ingevroren materiaal Op elk meetmoment afname van spijtmateriaal (serum, urine en dialysaat) Vanaf 2000 werden ook bloedmonsters voor genotypering ingevroren

11 Inclusion NECOSAD - 2

12 Baseline Characteristics Necosad-2 HD PD Number %1184 (68)545 (32) % Male6063 Age (sd)62,1 (14,5)53,6 (14,6) Prim. Kidney Dis.:Diabetes (%)1516 Glomerulonephr. (%)1118 Vascular (%)2114 Co-morbidity:Low (%)3253 Medium (%)3529 High (%)3318

13 Presentatie NECOSAD Mogelijkheden observationeel onderzoek; voorbeelden: - HD versus PD - Vroege versus late start - Dialysedosis PD Conclusies

14 Survival in HD and PD Several studies show small and opposing differences between HD and PD for survival and for quality of life Variability - due to methodological differences such as type of statistical models, case-mix and follow-up? - or due to an absence of a true difference between HD and PD ?

15

16 Design & Aim A randomized controlled trial (RCT) within a prospective cohort Compare survival and quality of life between Hemodialysis and Peritoneal dialysis patients

17 Study design Patients without medical, social or logistic objections were invited Patients were educated about HD and PD Informed consent Patients were randomized by telephone service: HD or PD Patients were treated according to usual local care

18 Study design Primary outcome: QALY in first 2 years QALY: quality of the time spent on dialysis Patients evaluated their own quality with EuroQol

19 EuroQol Best imaginable state Worst imaginable state

20 Example: QALY-scores after 2-yrs †

21 Study design Difference of 10 QALY-points clinical relevant Calculated sample size: 100 patients 50 HD patients 50 PD patients

22 Trial profile

23

24 Mean (SD) QALY-scores after 2 yrs. i.t.t. HD patients:59.1 (11.7) PD patients:54.0 (18.9) Difference HD and PD: 5.1 (p = 0.41) Difference after adjustment: 2.1 (p = 0.63) (adjusted for: age, comorbidity, primary kidney disease)

25 Deceased after 5-year follow-up Years Total HD (50%) PD (25%)

26 Survival (i.t.t.)

27 Hazard ratio’s after 5 years follow-up i.t.t.

28 Number changed modality after 5-yr follow-up Years012345Total HD (11%) PD (35%)

29 Conclusions from the RCT HD versus PD In terms of QALY scores HD and PD are equivalent Better survival on PD compared to HD over the first 5 years in i.t.t. analysis Incident dialysis patients may benefit from starting on PD

30 Termorshuizen et al. Hemodialysis and peritoneal dialysis: comparison of adjusted mortality rates according to the duration of dialysis: analysis of the NECOSAD 2 study. JASN 2003;14: Design & Aim Prospective cohort study of patients new on dialysis treatment Compare mortality rates between HD and PD patients

31 Patient characteristics – 3 months * p<0.05 HD vs PD

32 Patient characteristics (cont’d) * p<0.05 HD vs PD

33 Unadjusted death rates and RR of death HD – PD cohort study

34 Multivariate analysis HD compared with PD Adjusted for: ( age, gender, comorbidity, prim kidney dis, SGA, Hb, Alb, renal Kt/v baseline) Time period (mo) as treatedITT Adj HR 95% CI 3 to – – to – – to – – to – – 0.73

35 Conclusions from the prospective cohort study During the first 2 years lower mortality rates in PD patients < 60 yr After 2 years tendency towards greater relative mortality rates for PD patients, especially in PD patients > 60 yr Indication of a survival benefit of long-term PD patients after switching to HD

36 From: Lysacht M et al. ASAIO Trans, 1991

37 Significant risk factors for the decline of GFR during the 1 st year on dialysis relative riskeffect on index GFR (mL/min) HD vs PD Diastolic BP (10 mm Hg  ) Proteinuria (g/day) From: Jansen MAM et al. Kidney Int, 2002

38 Dialysis related mechanisms responsible for the decline in rGFR (adjusted for baseline GFR, age, sex, PKD, comorbidity) ß p HD: hypotensive episodes PD: dehydration Jansen et al KI 2002;62:

39 Presentatie NECOSAD Mogelijkheden observationeel onderzoek; voorbeelden: - HD versus PD - Vroege versus late start - Dialysedosis PD Conclusies

40 Lancet 2001:358:

41 NECOSAD analysis Korevaar et al Lancet 2001;358: Consecutive new ESRD patients > 18 yrs in 29 dialysis centres Exclusion of patients without predialysis care and with malignancies GFR 0-4 weeks before start dialysis Timely start defined according to DOQ1

42 Initiation guideline DOQI Am J Kidney Dis 1997 Timely initiation 1. renal Kt/V urea  2.0/week 2. Renal Kt/V urea < 2.0, but BMI  20 kg/m² and nPNA  0.8/kg/day Late initiation: all other patients

43 Patient characteristics at start late (n=94)timely (n=159) age (yrs) male (%) BMI (kg/m²) GFR (ml/min/1.73 m³) * Kt/V urea (per week) * % HD * = p < 0.05

44

45 Comparison between timely and late starters Timely starters have a 2.5 month longer survival on dialysis after 3 years, but Timely starters begin dialysis 4.1 to 8.3 months earlier in the time course of their disease No effect of an early start of dialysis on survival

46 Comparison between timely and late starters  No effect of a timely start of dialysis on survival  Effect on quality of life?

47 Korevaar et al Am J Kidney Dis 2002;39:

48 Conclusions Early start of dialysis NKF-DOQI targets on the start of dialysis were not evidence based An earlier start of chronic dialysis in patients with end-stage renal disease than currently applied in developed countries is not warranted

49 Presentatie NECOSAD Mogelijkheden observationeel onderzoek; voorbeelden: - HD versus PD - Vroege versus late start - Dialysedosis PD Conclusies

50 Ademex study (Paniagua R. et al. J Am Soc Nephrol, 2002) 965 Mexican patients with peritoneal creatinine clearance < 60 L/week/1.73 m 2. Control: 4 x 2L CAPD treated: pCCr > 60 L/week/1.73 m 2. No differences in baseline characteristics. Minimum follow-up: 2 years.

51 ADEMEX: Treatment Characteristics p<.001

52 ADEMEX: Primary Outcome p= RR(Treated:Control)= % CI: (0.80, 1.24)

53 Conclusion ADEMEX No difference in survival between patients having a weekly creatinin clearance 60L/week What should the minimal target be?

54 PD adequacy - Necosad

55 PD adequacy - NECOSAD Inclusion: PD patients 3-months after the start of dialysis treatment Age > 18 years Informed consent

56 Patient characteristics (N=413)

57 Follow-up

58 Survival

59 Unfavourable effect Favourable effect effect on QOL * * *

60 Anuric PD patients (N=130)

61 Anuric patients* ref * Adjusted for age, time on dialysis, comorbidity, SGA, serum albumin, hemoglobin

62 Anuric patients –cut off point: 1.7 * Adjusted for age, time on dialysis, comorbidity, SGA, serum albumin, hemoglobin ref

63 Anuric patients – 2 cut off points * Adjusted for age, time on dialysis, comorbidity, SGA, serum albumin, hemoglobin ref

64 PD adequacy All PD pts: No effect of dialysis dose on mortality or on QOL Effect of residual renal function on mortality and QOL  Anuric patients: Kt/V ≤ 1.5 → increased mortality risk

65 Presentatie NECOSAD Mogelijkheden observationeel onderzoek; voorbeelden: - HD versus PD - Vroege versus late start - Dialysedosis PD Conclusies

66 Hierarchy of study designs (Levels of evidence) 1.Randomized Controlled Trial 2.Prospective cohort 3.Retrospective cohort 4.… Main purpose of randomization is to prevent selection bias (=confounding by indication or prognosis)

67 Conclusions In many clinical situations RCT’s are very difficult to perform because of obvious ethical reasons Therefore observational studies have to provide the evidence Carefully designed large prospective controlled cohort studies with wide variations in patient- and treatment characteristics are required.


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