IMPLEMENTATION OF THE CKD-MBD PRACTICE. Goce Spasovski, R. Macedonia

Transcription

1 IMPLEMENTATION OF THE CKD-MBD GUIDELINES Introduction INTO CLINICAL to Renagel PRACTICE Goce Spasovski, R. Macedonia Antalya, Turkey, September

2 Session Objectives Guidelines needs and controversy Evidence level Dissemination Implementation Definition of the problem of CKD-MBD clinically relevant definition and classification CKD-MBD guidelines (KDOQI / KDIGO) Treatment options hyperphosphatemia under a constant debate Phosphate binders Implementation results?!

3 Guidelines healthcare improvement Evidence level High & low (perceived as equal?) Dissemination Global the whole community Implementation Funding Audits

4 Evidence level The difficulties in measuring hard outcomes are directly attributed to a specific guideline related change in the patient outcome Implementation Frequently neglected issue!? Ideally optimize the limited health care resources Development of implementation tools

5 Evidence level Various institutions - a plethora of often parallel recommendations on similar topics - different messages KDIGO - global nephrology guidelines on a worldwide basis Whole spectrum 2006: selected topics GRADE eval.* quality of evidence balance of health benefits and harms balance of net financial benefits and costs *Guyatt G et al. BMJ 2008;336(7654):1170-3

6 Implementation - Guidelines debate Increasing knowledge - education Presentations at meetings (Congresses & CME courses) Publications and availability on websites (Free text online) blasts Quiz allotting CME points Educational materials, systematic reviews of guideline & implementation strategies The obstacles to changing practices in the professional setting in the patient the organisation of care processes Economic conditions Legal, political or cultural constraints Vanholder R et al. NDT plus 2009; 2:

7 Implementation Changing attitudes Audits - measuring the progress based at regular intervals the application of the recommendations (supra/national level) feedback system: Neutral (simple statement) Rewarding (bonus) Punitive Changing outcomes by improving patient health and quality of care Organisations to be contacted to achieve these aims: professional bodies & scientific/clinical associations specialty representative groups Funding bodies CME groups bodies representative for education of pts & health professionals Vanholder R et al. NDT plus 2009; 2:

8 Implementation (prerequisites) Recognised need for marketing, advertising, increased visibility of the particular GUIDELINE recommendation (R) Each GUIDELINE (R) should be accompanied by the proposal on the anticipated possibilities for its implementation Target group to focus upon National Societies/individual physician Patients associations/individual patient Governmental bodies Professional associations

9 CKD-MBD consensus definition & classification Mineral Hormonal Bone abnormalities, Vascular calcifications Soft tissue calcifications CVD, fractures, mortality

10 What is Precise P & Ca Management? K-DOQI Guidelines GB Renal Association Guidelines EDTA Guidelines KDIGO Guidelines on CKD-MBD

11 K/DOQI* guidelines for Bone Metabolism and Disease / Dislipidemia in Chronic Kidney Disease ( mmol/l) (< 4.4 mmol 2 /l 2 ) (< 2.56 mmol/l) (< 5.12 mmol/l) The K/DOQI guidelines have become widely accepted and are basis of many national treatment guidelines in Eastern Europe National Kidney Foundation K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Am J Kidney Dis 2003;42(Suppl 3):S1-S202. National Kidney Foundation K/DOQI Clinical Practice Guidelines for managing Dyslipidemias in Chronic Kidney Disease. Am J Kidney Dis. 2003;41(suppl 3):S1-91.

12 K/DOQI* guidelines for Bone Metabolism and Disease in Chronic Kidney Disease (> 1.8 mmol/l) Non Ca based (> 2.7 mmol/l) Non Ca based Sevelamer remains first line treatment option (Lanthanum, MCI 196) Ca based binders contraindicated in low PTH, high Ca, severe calcifications National Kidney Foundation K/DOQI Clinical Practic Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Am J Kidney Dis 2003;42(Suppl 3):S1-S202.

13 Mortality Risk Varies According to Number of Laboratory Targets* Achieved Concurrently Relative Hazard of Death (95% CI) 1,8 1,6 1,4 1,2 1,0 Three Targets (Reference) 1,00 Two Targets 1,21 1,20 1,15 One Target 1,39 1,37 1,35 No Targets 1,51 0,8 N = 22,937 All ipth & P ipth & Ca Ca & P Groups Defined by Targets Achieved P ipth Ca None Time-dependent model. *Laboratory targets from National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI ). KDOQI TM is a trademark of the National Kidney Foundation, Inc. Danese MD, et al. Clin J Am Soc Nephrol. 2008;3:

14 KDIGO Guidelines Serum phosphate Serum calcium Ca x PO4 product Target PTH level Calcium dosage Normal range no evidence for targets Normal range no evidence for targets Not a useful construct From 2 to 9 x ULN No evidence to favour any specific binder

15 KDIGO Guidelines In patients with CKD stages 3-5D and hyperphosphatemia, the recommendation a is to: Restrict calcium based phosphate binders in the presence of: Arterial calcification Adynamic bone disease (ABD) Persistently low serum PTH levels Restrict the dose of calcium based phosphate binders and/or restrict the dose of calcitriol or vitamin D analog are suggested b, in the presence of: Persistent or recurrent hypercalcemia

16 NO evidence endorsment of ERBP - NDT!

17 Why not aim for normal serum phosphate (professionals)? Explanations and Excuses... Perceived as difficult to achieve Time consuming in a busy clinic Need regular dietician input Binders are difficult to take, so... Patients find adherence difficult Our results are OK, no one else is doing any better!

18 Can we do better (patients)? Patients need time and explanation Need to be engaged... Need to understand what they are aiming for Need to understand what phosphate binders do Need to understand timing and dosage of binders Need to know what to do if adherence difficult Also need to know if phosphate control is beneficial!

19 Mineral Metabolism and Mortality Risk in the DOPPS Hyperphosphatemia is the most frequent abnormality. Around 90% of dialysis patients on phosphate binders, still 35% out of KDOQI targets. Prospective observational cohort study patients with ESRD on hemodialysis. Outcomes: Adjusted hazard ratios (HR) for all-cause and cardiovascular mortality using Cox models. Tentori F et al. Am J Kidney Dis. 2008;52:

20 Mineral Metabolism and Mortality Risk in the DOPPS Disorders of mineral metabolism are associated with increased mortality Prospective observational cohort study patients with ESRD on hemodialysis. Outcomes: Adjusted hazard ratios (HR) for all-cause and cardiovascular mortality using Cox models. Tentori F et al. Am J Kidney Dis 2008;52:

21 Vascular events in healthy older women on calcium supplementation p=0,01 Myocardial infarction and the composite endpoint occurred more frequently in the calcium group Randomized, placebo controlled trial in 1471 healthy postmenopausal women to determine the effect of calcium supplementation on myocardial infarction, stroke, and sudden death in healthy postmenopausal women. Bolland MJ et al. BMJ 2008;336:262-6

22 Risk Factors Associated With Cardiac Calcification in Young Dialysis Patients Coronary No Calcification Calcification Factor (n=14) (n=25) P - value Ca from 6456 ± ± calcium binders (mg/day) Serum Ca (mmol/l) 2.4 ± ± Serum P (mmol/l) 2.2 ± ± Ca P (mmol 2 /L 2 ) 5.2 ± ± Age (years) 26 ± 3 15 ± 5 <0.001 Mean duration of dialysis (years) 14 ± 5 4 ± 4 < HD patients 7 30 years 60 controls years EBT scans at baseline and after months Goodman WG et al. N Engl J Med. 2000; 342:

23 INDIVIDUAL THERAPEUTIC APPROACH PREVENTION OF COMPLICATIONS OF THERAPY... OF HYPERPHOSPHATEMIA & MBD & ROD & VC IN CKD PATIENTS

24 Reducing Calcium Load With a Calcium-free Phosphate Binder Total Elemental Calcium Intake (average g/wk) g/wk Phosphate binder: 3-5 g/day (20-30% resorption) 1300 mg/day Dialysate: 1.25 moll/l - net influx mg calcium / HD Diet: intake 600 mg calcium per day Calcium Binder* 4.3 g/wk Calcium-Free, Metal-Free Binder Binder (dose 5 g/day) Dialysate (2.5 meq/l) Diet (600 mg/day) Bleyer AJ et al. Am J Kidney Dis. 1999;33: Data on file, Genzyme Corporation Hsu CH. Am J Kidney Dis. 1997;29:

25 Mortality effect of coronary calcification and phosphate binder choice (Sevelamer) 1.00 Survival Distribution Function Calcium Renagel P= Months No. at Risk Calcium Renagel Treatment with sevelamer was associated with a significant survival benefit. There were 11 deaths in the sevelamer and 23 in the Calcium group. Follow up of a randomized, prospective, open label, multicenter study over a median of 44 months (RIND). 127 patients randomized to either sevelamer or Ca. Prespecified secondary endpoint. Block GA et al. Kidney Int 2007;71:

26 DCOR: All-Cause Mortality Cumulative Incidence of All-Cause Mortality Calcium Sevelamer Time on Study (Years) Results of the DCOR trial were inconclusive for the primary end-point of allcause mortality across the entire patient cohort (RR 0.91; p = 0.3) Prospective, randomized trial in 2103 prevalent dialysis patients receiving either sevelamer or Ca-containing phosphate binders. Max. follow up 45 months. Primary endpoint: All cause survival. Secondary endpoints: Cause-specific mortality, all-cause and cause-specific hospitalization, medicare expenditures. Suki W et al. Kidney Int 2007;72:

27 DCOR: Mortality risk reduction with Renagel Risk reduction [%] % -22% p = 0,02-34% All patients Patients 65 Patients on study 2 yrs A mortality benefit for patients treated with Renagel was shown in subgroups: Patients older than 65 (predefined) and patients on study for more than 2 years Prospective, randomized trial in 2103 prevalent dialysis patients receiving either sevelamer or Ca-containing phosphate binders. Max. follow up 45 months. Primary endpoint: All cause survival. Secondary endpoints: Cause-specific mortality, all-cause and cause-specific hospitalization, medicare expenditures. Suki W et al. Kidney Int 2007; 72:

28 Hospitalisation rate by binder choice Rate per patient-year Sevelamer Calcium HR* p* First hospitalisations 0,96 0,97 ns Multiple hospitalisations 1,70 1,91 0,89 0,02 Days in hospital 12,3 13,9 0,88 0,03 Almost every patient was hospitalised once per year. Renagel treated patients were hospitalized less frequently and spent less time in the hospital. Preplanned secondary analysis of DCOR for mortality, morbidity, and hospitalization end points, using Centers for Medicare & Medicaid Services data. St. Peter WL et al. Am J Kidney Dis 2008;51: *Adjusted for demographic variables and prestudy cardiovascular comorbidity

29 New Strategies in Treatment of MBD and Associated CVD in Patients with CKD Spasovski G, Recent Patents on Cardiovascular Drug Discovery, 2008; 3(3):222-8 Cost-effectiveness - Good value for money!? Huybrechts KF, Caro JJ, Wilson DA, O Brien JA. Health and economic consequences of sevelamer use for hyperphosphatemia in patients on hemodialysis. Value Health 2005; 8: Lack of outcome data favorable enough to justify widespread utilisation CA White, J Jaffey, P Magner. Cost of applying the K/DOQI guidelines for bone metabolism and disease to a cohort of chronic hemodialysis patients. Kidney International (2007) 71, The yearly cost of implementation of the K/DOQI guidelines for 416 pts. at this center (University of Ottawa) was estimated at $ (American dollars). Given the significant cost, widespread adoption of the K/DOQI CPGs for Bone Metabolism and Disease should await the publication of compelling data demonstrating significant improved outcomes in patients treated with sevelamer.

30 Type of treatment for hyperphosphataemia and related outcomes

31 Type of treatment for hyperphosphataemia and related outcomes

32 Type of treatment for hyperphosphataemia and related outcomes Benefits and Harms of Phosphate Binders in CKD: A Systematic Review of Randomized Controlled Trials The primary advantage for more recently developed phosphate binders (lanthanum carbonate and sevelamer) is a DECREASE IN HYPERCALCEMIA IN DIALYSIS PATIENTS. Sankar D. Navaneethan, MD, MPH, Suetonia C. Palmer, MBChB, Jonathan C. Craig, MBChB, PhD, Grahame J. Elder, PhD, and Giovanni F.M. Strippoli, MD, PhD, MPH, MM Full adoption of sevelamer and lanthanum by government drug American reimbursement Journal of agencies Kidney Diseases, in place Vol 54, of No calcium 4 (October), salts 2009: would pp lead to a LARGE INCREASE IN HEALTH CARE EXPENDITURE. Limitations: Few long-term studies of the efficacy of phosphate binders on mortality and musculoskeletal morbidity, significant heterogeneity for many surrogate outcomes, and suboptimal reporting of study methods to determine trial quality. This can be justified only by presenting evidence for improved clinical outcomes of these agents compared with calcium salts. Additionally, it should be remembered that to date NO CLINICAL TRIAL HAS SHOWN A SURVIVAL ADVANTAGE FOR CALCIUM SALTS (COMPARED WITH PLACEBO OR OTHER AGENTS) Conclusion: Currently, there are insufficient data to establish the comparative superiority of non calcium binding agents over calcium-containing phosphate binders for such important patient-level outcomes as all-cause mortality and cardiovascular end points. Additional trials are still required to examine the differential effects of phosphate-binding agents on these end points and the mineral homeostasis pathway. PARACHUTE STORY!?

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34 IMPLEMENTATION STRATEGIES Reduction of Calcium Load and successful P control Individualized program do not harm!

35 Spasovski G. Int Urol Nephrol 2011 Dec 16. [Epub ahead of print]

36 Improved P control through a sustained education, monitoring & evaluation process Conclusion: The guidelines implementation process should be a continuous and self-monitored process, with the help of periodic surveys.

37 CKD-MBD Guidelines - Is there any confusion? Evidence Guidelines Implementation Data from systematic reviews & meta analysis

38 Summary: CKD - MBD guidelines implementation Continuous education through interactive sessions, and monitoring & evaluation of the stuff is essential as an implementation strategy Mild and stepwise treatment" could be a better option than overzealous treatment in order to "do no harm" for patients health The individualization of the CKD-MBD management should be successful even in the absence of modern new treatments Nephrologists in developing countries should ask for advanced treatment options in accordance with the guidelines at least for a small subset of patients where standard therapy does not work Professionals should be dedicated to implement the knowledge into the clinical practice and to convince the authorities for best treatment options as main goal for our patients

39 Implementation of the CKD-MBD guidelines could save Bones, Blood vessels & the Heart!