October 21, 2017, Antalya

Cinacalcet treatment in

advanced CKD - is it justified?

Goce Spasovski

ERBP Advisory Board member

University of Skopje, R. Macedonia

TSN Congress

Session Objectives

From ROD to CKD-MBD in CKD patients

General issues

Guidelines

Controversies conference (updates)

Bone quality / Clinical outcome data

Cinacalcet treatment – new evidence

Efficacy - cost related evidence

When to treat – rationale

Monitoring frequency

Summary

From ROD to Mineral & Bone Disorder (MBD)

- Systemic Complication in CKD

• Mineral

• Hormonal

• Bone abnormalities,

• Vascular calcifications

• Soft tissue calcifications

CVD, fractures, mortality

From ROD to CKD-MBD: The first CKD-MBD Controversies Conference, Madrid 2005, definition of CKD-MBD.

Bone, P & Ca Management guidelines

K-DOQI Guidelines

GB Renal Association Guidelines

EDTA Guidelines

KDIGO Guidelines

Publishing the CKD-MBD Guideline

The first KDIGO clinical

practice guideline on

CKD-MBD was published

in August 2009.

After the publication…

The term traditionally used to describe the abnormalities in

bone morphology that develop in patients with CKD1

Bone abnormalities are common complications of CKD and

are found in almost all patients with stage 5 CKD

(glomerular filtration rate below 15 mL/1.73 m2/min)2

Evaluation and definitive diagnosis of renal osteodystrophy

requires a bone biopsy1

Histomorphometry is not essential for clinical diagnosis, but

should be performed in research studies1

1Moe S, et al. KI, 2006;69:1945-53; 2Malluche HH, et al. JBMR. 2011;26:1368-76; 3 KDIGO CKD-MBD WG. KI. 2009; 76 (Suppl 113):S1-130.

Renal osteodystrophy

2009 KDIGO® Definition of Renal Osteodystrophy3

• Renal osteodystrophy is an alteration of bone morphology in patients

with CKD

• It is one measure of the skeletal component of the systemic disorder of

CKD-MBD that is quantifiable by histomorphometry of bone biopsy

Bone Histology in ROD

Mixed lesion

Osteomalacia

Osteitis Fibrosa

Adynamic bone disease

Pi

PTH Secretion

Parathyroid Cell Growth

Increased CaxP & risk of

metastatic calcifications

Morbidity &

Mortality

Ca++

PTH resistance

Calcitriol

Calcitriol resistance

Consequences of Elevated Serum

Phosphorus

Treatment ABDHPTH

Spasovski G et al. Semin Dial 2009; 22(4): 357-362

GB Spasovski et al. Nephrol Dial Transpl 2003; 18: 1159-66

Normal bone38%

Mixed lesion18%

Hyperpara9%

Adynamic bone23%

Osteomalacia12%

• Prospective,• Non-randomized,

Macedonian Population• N = 84 patients• Histomorphometric criteria

according to:Salusky et al., Kidney Int.,33,1988 Parfitt et al., Calcif Tissue Int 42, 1988

N = 84

Ch

ang

ing

sp

ectr

um

of

rena

l o

ste

od

ystr

op

hy

Spectrum of Renal Bone Disease in patients with

end-stage renal bone disease not yet in dialysis

Down regulation of

PTH receptor

Insufficient PTH levels

Osteoblastic dysfunction

Uremic toxins

Decreased BFR

Relative

hypopara-

thyroidism

Al + Fe Vit.D

cinacalcet

VDR poly-

morphism

Better Pi

control

Diabetes

Older age

Malnour-

ishment

Ca receptor

expression

Extracellular Ca++

Ca load: Ca based binders

HD & CAPD dialysis fluid Ca conc.

Diabetes

Older age

Male gender

Growth factors

Al + Fe

Vit.D treatment

VDR expression

Mg++

Physiopathology of Adynamic Bone

Association in CKD patients between:MBD (abnormal mineral metabolism & bone health)

&

Fractures – decreased quality of life

VC – most important cause of morbidity

CVD – significant mortality

Clinical Relevance and Consequences

Bone health and vascular calcification relationship in chronic kidney disease

Spasovski G. Int Urol Nephrol 2007;39:1209–1216

CKD - MBD: Bone lose & fracture

United States Renal Data System data (300,000 patients)

- The relative risk for hip fracture in dialysed patients is 4.4

times (men and women) that of age-matched controls.Alem A et al. Kidney Int 2000, 58: 396-9

Disordered bone remodelling can induce

vascular calcification

High bone turnover

Low bone turnover

Phosphate

Calcium

Precipitation

in vessels and

soft tissues

Calcification

London et al. J Am Soc Nephrol 2004;15:1943–1951; Spasovski G. Int Urol Nephrol 2007;39:1209–1216

High bone turnover leads to release of Ca + P from bone. Low bone turnover hinders

their emplacement in bone. Result is cardiovascular and soft tissue calcification.

Arterial calcification increases mortality risk

0 arteries calcified

1 artery calcified

2 arteries calcified

3 arteries calcified

4 arteries calcified

Prospective trial in 110 dialysis patients assessing cardiovascular (CV) calcifications , mean follow up 53 months. Endpoints:

All cause and CV mortality using univariate and multivariate survival analysis. Blacher et al. Hypertension 2001;38:938–942

Presence and extent of vascular calcifications predict cardiovascular and all-

cause mortality in dialysis patients.

Probability

of survival

n=110

p<0.0001

1.00

Duration of follow-up (months)

0

0.25

0.50

0.75

0 20 40 60 80

PREVENTION OF

COMPLICATIONS OF THERAPY

. . .

OF HYPERPHOSPHATEMIA

&

MBD & ROD & VC

IN CKD PATIENTS

THERAPEUTIC APPROACH

PREVENTION OF

COMPLICATIONS OF THERAPY

• INDIVIDUALIZED COMBINATION

• Dose of Ca carbonate/acetate ”As much as needed” (AMAN)

• Non Ca-based P binders in pts at risk for VC & CVD

• Vitamin D (AMAN)

• Use Low Calcium dialysate - always

• Use aluminum (small amount, shortly)

• Vit. D analogs – upon indication

• Calcimimetics – upon indication

New Strategies in Treatment of MBD and AssociatedCardiovascular Disease in Patients with CKD - HPTH

Spasovski G, Recent Patents on Cardiovascular Drug Discovery, 2008; 3(3):222-8

Thadhani et al, JAMA 2012; 15;307(7):674-84

• At 48 weeks, the change in left ventricular mass index did not differ

between treatment groups.

• Doppler measures of diastolic function also did not differ.

• Episodes of hypercalcemia were more frequent in the paricalcitol

group compared with the placebo group.

Vitamin D therapy and cardiac structure and

function in patients with CKD: the PRIMO RCT

Effect of Cinacalcet on CVD in Pts Undergoing D

The EVOLVE Trial Investigators*

COST-EFFECTIVENESS OF THE TREATMENT WITH CINACALCET

AND VITAMIN D ANALOGS?

N Engl J Med. 2012; 367(26): 2482-94

The treatment of CKD-MBD - improvement in biochemical

parameters of the disease, hard clinical end points or

surrogate end points studies are limited.

PRIMO & EVOLVE study – negative end points (change in

left ventricular mass index and death, myocardial

infarction, unstable angina, heart failure or peripheral

vascular disease)

The results of these two randomized controlled trials with

negative primary end points require physicians to

individualize therapies for the treatment of secondary

hyperparathyroidism.

Moe & Thadhiani, 2012

Treatment of CKD-MBD after PRIMO & EVOLVE

Kaplan-Meier time-to-event curves for clinical end points. Time to the primary

composite cardiovascular end point (A), to death (B), and to severe

unremitting hyperparathyroidism (C) in the groups randomized to placebo

(dotted line, <65 years; dashed line ,>65 years) and to cinacalcet (solid line, <65

years; bold line, >65 years) by age group.

The Effects of Cinacalcet in Older and Younger Patients on

HD: The Evaluation of Cinacalcet HCl Therapy to Lower

Cardiovascular Events (EVOLVE) Trial

Parfrey et al. CJASN 2015,10: 791–799

Relative hazard (HR) of achieving a ≥30% reduction in FGF23 from baseline to

week 20 vs not achieving such a reduction on clinical outcomes (patients

randomized to cinacalcet from FGF23 cohort).

Cinacalcet, FGF-23, and CVD in HD (EVOLVE) Trial

Reduction in FGF23 Is Associated With Reduced

CVD Mortality and Morbidity

Moe et al, Circululation 2015; 132:27-39

Relative hazard (HR) of achieving a ≥50% reduction in FGF23 from baseline to

week 20 vs not achieving such a reduction on clinical outcomes (patients

randomized to cinacalcet from FGF23 cohort).

Cinacalcet, FGF-23, and CVD in HD (EVOLVE) Trial

Reduction in FGF23 Is Associated With Reduced

CVD Mortality and Morbidity

Moe et al, Circululation 2015; 132:27-39

• The ADVANCE and EVOLVE trial comparing cinacalcet vs

standard treatment on sHPTH failed to demonstrate a

significant effect on the primary end points but showed

positive signals concerning some predefined secondary

end points.

Ketteler et al. KI 2015 Mar;87(3):502-28

Should patients with CKD stage 5D & biochemical

evidence of sHPTH be prescribed calcimimetic therapy?

An ERA-EDTA position statement

What do the guidelines say?

No guidelines on this subject (KDOQI, CARI, RA, NICE) have

been produced on this topics since the release of the EVOLVE

results.

Recommendations ERBP

1. We do not recommend routine use of calcimimetic therapy to

improve survival in patients with CKD stage 5D and

biochemical evidence of secondary hyperparathyroidism (1A).

2. There is insufficient evidence whether parathyroidectomy or

medical intervention with cinacalcet or standard care or a

combination thereof should be preferred to control secondary

hyperparathyroidism in patients with CKD stage 5D.

Goldsmith et al. NDT; 2015; 30: 698–700

Topic #3: Bone Quality

3.2.1 In patients with CKD stages 3–5D, it is reasonable

to perform a bone biopsy in various settings including,

but not limited to: unexplained fractures, persistent

bone pain, unexplained hypercalcemia, unexplained

hypophosphatemia, possible aluminum toxicity, and

prior to therapy with bisphosphonates in patients with

CKD–MBD (not graded)

Argument:

Secondary analyses in osteoporosis trials

New therapies – denosumab and teriparatide

Revision Yes No

Bone histomorphometry before and after long-term

treatment with cinacalcet in dialysis patients with sHPT

• Cinacalcet is indicated for lowering parathyroid hormone

(PTH) in dialysis patients with sHPT, but its effects on bone

remain unclear.

• The effect of cinacalcet on renal bone disease among

patients undergoing dialysis has yet to be characterized

adequately

• The multicenter, single-arm BONAFIDE study characterized

the skeletal response to cinacalcet in adult dialysis patients

with plasma PTH ≥300 pg/mL, serum calcium ≥8.4 mg/dL

(2.1 mmol/L), bone-specific alkaline phosphatase (BALP)

>20.9 ng/mL and biopsy-proven high-turnover bone disease.

Behets, Spasovski et al. Kidney International; 2015;87(4):846-56

Study design and treatment schema

146 adult dialysis patients with plasma PTH (PTH) ≥300 pg/mL, serum

calcium ≥8.4 mg/dL, and bone-specific alkaline phosphatase (BALP)

>20.9 ng/mL underwent bone biopsy during screening.

Behets, Spasovski et al. Kidney International; 2015;87(4):846-56

Comparison of PTH level at baseline and

end of study (median-IQR-range)

The median (interquartile

range; IQR) PTH at

baseline was 985 (674,

1621) pg/mL, and values

decreased nominally to 480

(268, 798) pg/mL, or by a

median (IQR) percent

change of -48.3% (-68.8%, -

26.5%), after treatment with

cinacalcet, p<0.001

BFR – same pattern!

Behets, Spasovski et al. Kidney International; 2015;87(4):846-56

Two Years of Cinacalcet Decreased PTgl. Vol. & Ser.

PTH in HDP With Advanced sHPTH Yamada et al. TAD 2015; 19(4):367–77

Diameter of PT gl Measured by CT as an Indicator

for Response to Cinacalcet in HDP with SHPTH

Hong et al. Kidney Blood Press Res 2015;40:277-287

Measurement of parathyroid gland (PTG) volume and diameter on high-resolution US and PTG

diameter on CT before cinacalcet therapy. Study 1 - cutoff values of imaging parameters; study

2, we reevaluated the clinical and radiologic risk factors for response of cinacalcet treatment.

A, B: Parathyroid gland volume and diameter measured by US. The PTG was diffusely

hypoechoic and hypervascularized on color Doppler US.

C: Measurement of parathyroid gland diameter by CT.

Hong et al. Kidney Blood Press Res 2015;40:277-287

Comparison of clinical and biochemical parameters between responders and non-

responders to cinacalcet treatment in a single center (1)

Diameter of PT gl Measured by CT as an Indicator

for Response to Cinacalcet in HDP with SHPTH

Hong et al. Kidney Blood Press Res 2015;40:277-287

Clinical factors influencing the response to cinacalcet treatment in SHPT in a multicenter study (2)

Diameter of PT gl Meas. by CT - Indicator for Response to Cinacalcet in SHPTH

PTH-dependence of the effectiveness of

cinacalcet in HDP with SHPTH

Akizawa et al. Sci Rep. 2016 Apr 13;6:19612

Survival of people with CKD and SHPT

remains controversial, in part because a

recent randomized trial excluded patients with

iPTH <300 pg/ml. Prospective case-cohort

and cohort study on 8229 pts with CKD stage

5D requiring maintenance hemodialysis who

had SHPT on important clinical outcomes.by

baseline iPTH category

Adjusted associations between cinacalcet use

and clinical outcomes, computed using marginal

structural models, stratified by baseline iPTH

category.

Proportion of patients receiving cinacalcet

continuously over the study period, stratified

by baseline iPTH category.

PTH-dependence of the effectiveness of

cinacalcet in HDP with SHPTH

Akizawa et al. Sci Rep. 2016 Apr 13;6:19612

Survival of people with CKD and SHPT

remains controversial, in part because a

recent randomized trial excluded patients with

iPTH <300 pg/ml. Prospective case-cohort

and cohort study on 8229 pts with CKD stage

5D requiring maintenance hemodialysis who

had SHPT on important clinical outcomes.by

baseline iPTH category

Adjusted associations between cinacalcet use

and clinical outcomes, computed using marginal

structural models, stratified by baseline iPTH

category.

When analyses were restricted to patients

with iPTH levels ≥ 300 pg/ml (an inclusion

criterion of the EVOLVE study), cinacalcet

initiation was associated with a lower

incidence of cardiovascular hospitalization

or death due to any cause (adjusted RR

0.71, 95% CI 0.53–0.94).

Etelcalcetide vs Cinacalcet on PTH in HDP

With sHPTH A Randomized Clinical Trial

Etelcalcetide IV & oral

placebo (n = 340) or oral

cinacalcet and IV placebo

(n = 343) for 26 weeks.

The IV study drug was

administered 3 times

weekly with hemodialysis;

the oral study drug was

administered daily.

Among patients receiving

HD with moderate to

severe sHPTH, the use of

etelcalcetide was not

inferior to cinacalcet

in reducing serum PTH

concentrations over 26

weeks.

Block et al. JAMA. 2017;317(2):156-164

A Randomized Study Comparing PTx vs Cinacalcet

for Hypercalcemia in KTx pts with sHPTH

Cruzado et al. JASN 27: 2487–2494, 2016

KTx pts. with hypercalcemia and elevated

iPTH concentration, transplanted >6months

before the study and had an eGFR 30 ml/min.

The primary end point - proportion of patients

with normocalcemia at 12 months. Secondary

end points - serum iPTH concentration,

phosphate, BMD, vascular calcification, renal

function, patient and graft

survival, and economic cost.

30 pts cinacalcet (n=15) or subtotal PTx (n=15).

At 12months, ten of 15 patients in the cinacalcet

group and 15 of 15 patients in the PTx group

(P=0.04) normocalcemic.

Subtotal PTx had a higher proportion of patients

achieving normocalcemia and iPTH normaliz.

(A) Serum calcium,

(B) iPTH,

(C) Phosphate

the reduction of iPTH was greater in the PTx

group than in the cinacalcet group.

Frequency of monitoring CKD-MBD in sHPTH pts:

assoc. with achievements and adjusted therapy

Japanese multicenter cohort study on 3276 HDP with sHPTH.

Yokoyama et al. NDT 2017: Epub ahead of print

Conclusion: increasing frequency of measurements is helpful when serum marker levels exceed

the target range, partially via adjustment in the therapeutic regimen.

No evidence that frequent measurements helps if mineral levels are already within target ranges.

JOURNAL OF MEDICAL ECONOMICS, 2017 VOL. 20, NO. 10, 1110–1115

Analyses such as the one presented cannot be the only criterion for setting a

price, but such analyses are meant to inform the price that may be considered

efficient by society at large. Models are never suitable to capture all aspects that

should be considered for decision-making.

Kidney Int. 2017 Jul;92(1):26-36

Summary - Research Recommandations -

sHPTH

Parathyroidectomy remains a valid treatment option

especially in cases when PTH lowering therapies fail,

Recom. 4.2.5 from 2009 KDIGO-CKD-MBD guideline

Placebo controlled trials with calcimimetics versus

standard therapy for the treatment of SHPT in patients

with CKD stage 5D with emphasis on those at greatest

risk (e.g. older, CVD)

Prospective pts-centered RCTs with the new parenteral

calcimimetics (etelcalcitide) surrogate outcomes (primary

endpoints: mortality, cardiovascular events; secondary

endpoints: FGF23, LVH progression, calcification)

RCTs evaluating Calcimimetic vs vitamin D therapies on

the specific reduction of FGF23 as a therapeutic endpoint

Increasing freq. of CKD-MBD parameters measurements

Even the best treatment option are not perfect

“Do no harm and prevent complications”