Transcript Prezentacija HbA1c

Standardizacija/Priporočila
testiranja HbA1c ob bolniku
(Standardisation/Recommendations
of HbA1c point of care testing).
Milan Skitek
Simpozij DLM
Ljubljana, 28. maj 2012
Glikirani hemoglobini (GHB) kot
biooznačevalci
Glikirani hemoglobini (GHB) predstavljajo stabilne komponente
hemoglobina, ki se tvorijo počasi in neencimatsko med
hemoglobinom in glukozo.
HbA1c je specifična oblika GHb, ki se tvori z vezavo glukoze z
aldehidno skupino na eno ali obe končni NH2 skupini
aminokisline valina ß polipeptidne verige hemoglobina.
Glikirana HbA0 in HbA1 frakcija predstavlja z več izoformnimi
oblikami (HbA1 a1, a2, b, c, d, e) približno 7 odstotkov (%) glede
na celokupni hemoglobin, od tega je večina HbA1c.
Možnost zanesljive določitve HbA1c predstavlja največji
napredek pri oskrbi, nadzoru in zapletih ter diagnostiki
sladkorne bolezni v zadnjih 30 letih.
Metode določanja GHB
V rabi več različnih metod in analitskih sistemov, ki
temeljijo na ločitvi teh molekul na osnovi :
• naboja (elektroforeza/kapilarna in ionsko izmenjevalna
kromatografija visoke ločljivosti-HPLC, HbA1c)
• strukturnih lastnosti (afinitetna kromatografija,
celokupni glikirani hemoglobin-GHb)
• antigenskih lastnosti (imunološke metode z
monoklonalnimi protitelesi s specifično vezavo na
HbA1c).
• Rezultati so izraženi v % ali mmol/mol Hb.
Klinična standardizacija GHB
Velika variabilnost med številnimi metodami, ki so merile različne
frakcije glikiranega hemoglobina (HbA1c, HbA1 in GHb)
GHB/HbA1c lahko vodi do različnih rezultatov (tudi znotraj
istih metod različnih analitskih sistemov).
• Koncem osemdesetih in v začetku devetdesetih letih
prejšnega stoletja standardizacija na podlagi klinične
obdelave bolnikov in 2 študij (Diabetes Control and
Complications Trials-DCCT in UK Prospective Diabetes
Study-UKPDS) ter globalnega programa (National
Glycohemoglobin Standardisation Program - NGSP), ki je
zagotavljal sledljivost HbA1c z omenjenima študijama in
mrežo certificiranih laboratorijev/proizvajalcev (medicinska
sledljivost z interpretacijo laboratorijskih rezultatov, kriteriji
ukrepanja, referentnimi vrednostmi in stalnimi pred-,
analitičnimi in poanalitičnimi kazalci kakovosti oz.
napakami).
Klinična standardizacija GHB , nad.
• Poznana sta še dva lokalna programa s podobno
zasnovo kot NGSP in sicer t.i. švedski in japonski
model z manjšim obsegom in vplivom na
mednarodnem trgu.
• 1993 DCCT poročilo: intenzivna terapija zniža
retinopatije, albuminurije in neuropatije v
povprečju za več kot 50%. Stopnja glikemične
kontrole (merjene kot HbA1c) pri diabetesu tipa I
je tesno povezana z rizikom razvoja in/ali
napredovanja kroničnih diabetičnih komplikacij.
Klinična standardizacija GHB , nad.
• DCCT je postavila temelje za določitev specifičnih ciljev
zdravljenja diabetikov z uporabo HbA1c kot indeksa
povprečne glikemije
• 1998 United Kingdom Prospective Diabetes Study (UKPDS)
zagotovlja dokaze zmanjšanja rizika za diabetične
komplikacije z intenzivno kontrolo krvnega sladkorja pri
bolnikih z diabetesom tipa II.
• American Diabetes Association (ADA) izda 1994 priporočila
in cilje dobre oskrbe diabetika (HbA1c <7%), ki temeljijo na
DCCT “referenčni metodi” (kationska izmenjevalna
kromatografija-HPLC).
Analitična standardizacija GHB
Metrološka standardizacija mednarodne federacije za
klinično kemijo (IFCC) temelji na razvoju sledljivega,
referentnega kalibratorja (očiščen hemolizat z izolirano
frakcijo HbA1c in HbA0) in na razvoju definitivnih analitskih
metod (specifično določanje N-končnih ostankov beta
verige): HPLC/masne spektrometrije ali kapilarne
elektroforeze (metrološka sledljivost višjega reda s
sprejemljivim izkoristkom označene vrednosti za standard,
certificiranim referentnim materialom, referentno metodo
in akreditiranimi referentnimi laboratoriji).
Usklajevanje/povezovanje standardizacij
Primerjava rezultatov HbA1c medicinske/NGSP in
metrološke/IFCC sledljivosti dokazala značilno
razliko s sistemskim odklonom (znižanjem) IFCC
rezultatov za 1.5 do 2 % HbA1c skozi celotno
območje koncentracij:
NGSP-HbA1c (%)= 0.915 * IFCC-HbA1c (%) + 2.15%
SKITEK, Milan, ŠTER, Mateja. Standardizacija določanja in harmonizacija rezultatov HbA1C = HbA1C
standardization and harmonization. V: 2. Slovenski kongres klinične kemije z mednarodno udeležbo:
TIVADAR, Andrijana (ur.). Zbornik razširjenih povzetkov, (Farmacevtski vestnik, letn. 55, posebna št.).
Ljubljana: Slovensko farmacevtsko društvo, 2004, str. 327-328. [COBISS.SI-ID 1600881]
Standardizacija izvidov/rezultatov HbA1c
Priporočila IFCC/ IDF/ADA/EASD (Consensus Statement 2007):
• HbA1c rezultat mednarodno standardiziran na IFCC
referentni sistem
• HbA1c rezultat izražen v IFCC/SI enotah (mmol/mol Hb) in
NGSP enotah (%)
• Če “študija ocene povprečne plazemske glukoze” izračunane iz
HbA1c (ADAG ali e-AG) zadosti predhodnim specifičnim
kriterijem, lahko na izvidu prikažemo tudi ADAG kot interpretacijo
HbA1c (uspešno zaključeno 2008:
e-AG mmol/L = 1.59 X %HbA1c _ 2.59).
Standardizacija izvidov/rezultatov HbA1c, nad.
Priporočila ADA/EASD/IFCC/ISPAD (Consensus Statement 2010):
• HbA1c rezultat naj bo izražen v IFCC/SI enotah (mmol/mol Hb)
in NGSP enotah (%)
• Obe enote skupaj se uporabljata v člankih in raznih publikacijah
• Trenutno stanje: ZDA (tudi Slovenija) nadaljujejo z NGSP enotami
HbA1c(%) in dodajajo ADAG, večina evropskih dežel po vmesnem
obdobju 1 – 2 let (obe enote) prešla na IFCC/SI enote vključno s
Kanado, Avstralijo, Novo Zelandijo, Avstralijo. Japonska ostaja
pri svoji standardizaciji JDS in NGSP enotah (%).
HbA1c in diabetes diagnoza
International Expert Committee Report on the Role of
HbA1c Assay in the Diagnosis of Diabetes (2009):
• prednosti HbA1c v primerjavi z glukozo: standardiziran in
sledljiv DCCT/UKPDS/IFCC, boljši indeks celokupne
glikemije in rizika za dolgoročne komplikacije, nižja
biološka variabilnost, boljša predanalitska stabilnost,
vzorec kadarkoli brez “na tešče”, velika nihanja glukoze
brez večjega vpliva, HbA1c že uporabljan za spremljanje,
oskrbo in prilagajanje terapije
• Slabosti HbA1c v primerjavi z glukozo: interference na
variante Hb in stanja povečanega obrata eritrocitov, večji
stroški in nedostopnost v določenih delih sveta.
HbA1c in diabetes diagnoza, kriteriji
• HbA1c >= 6.5% (48 mmol/mol;
IFCC HbA1c (mmol/mol) = 10.93 x DCCT/NGSP unit (%) –
23.50 )
ALI
• FPG >= 7.0 mmol/L
ALI
• 2 urni 75 g OGTT: glukoza >= 11.0 mmol/L
ALI
• Naključna glukoza >= 11.0 mmol/L pri bolniku s klasičnimi simptomi
hiperglikemije
HbA1c testiranje samo z verificirano klinično laboratorijsko
opremo, POCT instrumenti še niso dovolj ponovljivi in pravilni
v diagnostične namene.
SKITEK, Milan. Screening for gestational diabetes mellitus. Clin Chem Lab Med, 2005, vol. 43, no. 6, str. 664666. [COBISS.SI-ID 1746801],
Izboljšave določanja HbA1c
Evolucija NGSP certifikacijskih kriterijev za
proizvajalce:
• 1996: Evaluacijski protokoli EP9 (odklon) in EP5
(ponovljivost <=5%); HbA1c območje 4-14%
• 1999: Sprememba iz EP9 na Bland/Altman oceno
primerljivosti (95% meja zaupanja znotraj ± 1% HbA1c)
• 2002: Zvišanje kriterijev za ponovljivost iz <=5% na <=4%)
• 2007: Zvišanje kriterijev za oceno primerljivosti iz ± 1% na
± 0.85% HbA1c (oženje območja na 4-12%)
• 2010: Zvišanje kriterijev za oceno primerljivosti iz ± 0.85%
na ± 0.75% HbA1c (oženje območja na 4-10%).
Izboljšave določanja HbA1c, nad.
Evolucija kriterijev sprejemljivosti (odklon od
referenčnih vrednosti) College of American
Pathologists (CAP) zunanjih presoj (PT) za
laboratorije*:
•
•
•
•
•
2007: Začetek PT z dovoljeno mejo odstopanja ± 15% HbA1c
2008: Dovoljena meja odstopanja se zniža na ± 12% HbA1c
2009: Dovoljena meja odstopanja se zniža na ± 10% HbA1c
2010: Dovoljena meja odstopanja se zniža na ± 8% HbA1c
2011-2012: Dovoljena meja odstopanja se zniža na ± 6%
HbA1c.
*Klinično značilna razlika v območju 6-9% HbA1c je ± 10%.
Izboljšave določanja HbA1c, nad.
Zmanjševanje interferenc:
• Zavedanje dejstva interferenc pri določanju HbA1c
(globalno HbS najpogostejša varianta, sledijo HbE,
HbC in HbD)
• Evaluacija interferenc za vsako analitsko metodo
• Priporočeno uporabljati analitske metode
dokazano brez interferenc (več kot 20%
laboratorijev uporablja metode z različnimi
interferencami).
The National Academy
Of Clinical Biochemistry
Presents
LABORATORY MEDICINE PRACTICE
GUIDELINES
EVIDENCE BASED PRACTICE FOR
POINT OF CARE TESTING
2006
Does the provision of the HbA1c result at the point of care lead to an
improved patient (clinical) outcome, when compared with central
laboratory testing? (Literature Search 42)
Guideline 68: We conclude that there is good evidence to support
the use of POCT for HbA1c in both the primary and secondary care
setting. The benefit comes from the diabetes specialist having the
result at the time of the patient consultation. This recommendation
assumes that the POCT is implemented under proper conditions e.g.
trained and certificated operators, quality control and quality
assurance and with an analytical system comparable with that used
in the central laboratory. The evidence base would benefit from
studies conducted over a longer period of time.
Strength/consensus of recommendation: A
Level of evidence: I and II (two randomized controlled trials and two
controlled trials ).
Does the provision of the HbA1c result at the point of care lead to an
economic benefit, when compared with central laboratory testing?
(Literature Search 42)
Guideline 69: We conclude that there is some evidence to show that
POCT testing for HbA1c will lead to an economic benefit. However the
data are limited and more detailed studies are required which should
focus on the wider benefit of POCT i.e. beyond the immediate costs of
providing the test and the change in clinic attendance. The evidence
would benefit from studies conducted (and impacts judged) over a
longer period of time.
Strength/consensus of recommendation: B
Level of evidence: II (randomised controlled trial and control trial, but
small numbers).
Laurence CO et al. BMC Health Services Research 2010, 10:165; “The incremental
cost-effectivenes ratio for POCT was found to be unfavourable for INR but
somewhat favourable for ACR, while substantial uncertainty still surrounds POCT
for HbA1c and lipids as the non-standard intermediate outcome indicator”.
Does patient self testing for HbA1c lead to an
improved patient (clinical) outcome, when
compared with central laboratory testing?
(Literature Search 42)
Guideline 70: We cannot make a
recommendation here because no studies have
been reported.
Strength/consensus of recommendation: I
Level of evidence: III (no studies addressing
the question)
What is the optimal frequency of HbA1c testing? Does more frequent
testing lead to better outcomes? (Literature Search 42)
Guideline 71: There are no studies that have investigated the
optimal frequency of POCT for HbA1c and therefore we can only
recommend that the guidelines generated from studies using a
laboratory service for the measurement of HbA1c are adopted in the
POCT setting. There are no studies that have formally investigated
the frequency of measurement of HbA1c – in any setting. We
therefore recommend that HbA1c testing is performed between 2
and 4 times per year in line with the patient’s individual requirements.
It is recommended that more frequent testing is required in those
patients with extremely elevated HbA1c levels and less frequently in
those with levels approaching the reference range.
Strength/consensus of recommendation: I
Level of evidence: III (opinion of respected authorities based on
clinical experience)
NHS; Purchasing and Supply Agency,
Centre of Evidence-based Purchasing
Buyer’s guide
POCT devices for the measurement of
HbA1c and low concentration albumin
in urine.
CEP 08057
June 2009
Ali POCT instrumenti zagotavljajo zadostno
zanesljivost (ponovljivost, pravilnost/specifičnost,
sledljivost, robustnost itd.) v primerjavi z referentno
in rutinsko tehnologijo.
The analysers (5) included in this guide could be
used in a diabetic clinic setting within
secondary care and some are suitable for use within
primary care if demand is sufficient. Any grade of
appropriately trained staff could use these devices
with one exception which required laboratory trained
staff. Axis Shield now market the NycoCard only for
laboratory use since the procedure includes pipetting
which is a laboratory skill.
Limited technical evaluation
•
Twenty one venous whole blood patient samples, preserved with
EDTA, were analysed in duplicate for HbA1c on each of the five
analysers
•
Analyses were performed according to the IFUs in a well lit
laboratory. Quality control samples were measured on each device
at the beginning and end of each analytical session
•
The samples had been previously measured in a clinical laboratory
on a Menarini 8160 HPLC analyser
•
Regression analysis was performed to compare each POCT
method with the laboratory method. Confidence intervals are an
indication of imprecision. Average bias of the results relative to the
laboratory method was calculated only if the bias was similar
across the measured range of the results
•
The results are presented together with the manufacturers’
claimed performance
Results
The in2it results gave the best agreement with laboratory results. At
concentrations close to the recommended targets HbA1c of 6.5 7.5%, Afinion, DCA Vantage and in2it analysers provided results
within 0.5% HbA1c of the laboratory result. The DCA Vantage
performed well up to 8.5% HbA1c but overestimated at higher
concentrations. A1cNow + results had a negative bias which
exceeded the 0.5% expected with the use of EDTA preserved
samples. Accuracy data for most analysers agreed moderately
well with manufacturers’ quoted performance, the largest
differences being shown by the A1cNow+ and the DCA Vantage.
The Afinion samples showed the lowest imprecision as indicated
by the confidence intervals.
The cutoff table shows % HbA1c underestimation by A1cNow+ and
overestimation by NycoCard.
All the analysers have NGSP certification for 2008 and therefore have
acceptable performance. The analysers demonstrating the best
analytical performance in this study were the in2it, Afinion and
DCA Vantage (Overall rating: Good for a quantitative system).
Razprava, zaključki, perspektive
Samo nekaj RC študij in veliko tehničnih/evaluacijskih študij in
primerjav HbA1c-POCT s centralnim laboratorijem oz.
referenčno/rutinsko tehnologijo v zadnjih 20 letih.
Nekaj ključnih ugotovitev:
•
HbA1c se lahko dandanes določa s hitrimi, avtomatiziranimi
in povezljivimi POCT instrumenti
•
Ponovljivost meritev se izboljšuje in je pri nekaterih
instrumentih že enakovredna referenčno/rutinski tehnologiji
•
Problem ostaja odklon od pravih vrednosti in interference
(HbS itd.) in s tem povezana referentna območja ter v
nekaterih sredinah kompetentnost/usposobljenost kadrov
•
Ekonomska podprtost HbA1c-POCT je še vprašljiva in zavisi
od političnih odločitev, koliko je posamezna družba
pripravljena investirati v dolgoročno spremljanje bolnikov.
Razprava, zaključki, perspektive
New POCT system “Banalyst M” using a microfluidic chip achieves
simultaneous rapid diagnosis of HbAlc and Glu
Banalyst® M, a new microblood analyzing system for POCT, comprises a μTAS
(Micro Total Analysis System) chip (l30 mm, w62 mm, t12 mm) and a compact
desktop measuring instrument, and measures and mixes samples in a chip with micro
channels. Unlike the Banalyst reported at the same academic conference, Banalyst®
M measures maximum 5 items by one chip. “Banalyst M HbA1c/Glu” recently
developed measures hemoglobin A1c (HbA1c) and glucose (Glu) simultaneously
from only a 10 μL whole blood sample. Using this chip, system was evaluated at
Kyushu University Hospital.
CLINICAL CHEMISTRY, Vol. 57, No. 10, Supplement, 2011
Razprava, zaključki, perspektive, nad.
Novel Cellular Hemoglobin A1c Control - A Commutable Control
Across HPLC, Immunoassay and Boronate Affinity Methods
Commercial A1c controls are noncellular which do not test the entire analytical
system of the instrument, including
the lysing step. Lysate based A1c controls are also reported to give erroneous results.2
Streck A1c-Cellular® is the only cellular control which has intact RBC. Therefore,
Streck A1c control tests the entire assay procedure. Streck A1c control is also
commutable across different A1c analyzers of all methodologies. The importance of
commutable calibrators is emphasized in order to harmonize the clinical instruments.3
The aim of the present study is to compare the performance of Streck A1c controls
with the other commercial controls and establish its commutability across different
A1c methodologies.
CLINICAL CHEMISTRY, Vol. 57, No. 10, Supplement, 2011
Primer
In preliminary recommendations published today (18 October 2011) by NICE,
exenatide prolonged release suspension for injection (Bydureon, Eli Lilly) is
recommended in triple therapy regimens (in combination with metformin
and a sulphonylurea, or metformin and a thiazolidinedione) as a treatment
option for people with type 2 diabetes, when control of blood glucose
remains or becomes inadequate (HbA1c of 7.5% or above, or other higher
level agreed with the individual), and the person has:
•
a body mass index (BMI) of 35 kg/m2 or higher in those of European family
origin (with appropriate adjustment for other ethnic groups) and specific
psychological or medical problems associated with high body weight, or
•
a BMI below 35 kg/m2, and therapy with insulin would have significant
occupational implications or weight loss would benefit other significant
obesity-related comorbidities.
Treatment with exenatide prolonged release suspension for injection in a triple
therapy regimen should only be continued if a beneficial metabolic response
has been shown (defined as a reduction of at least 1 percentage point in HbA1c
and a weight loss of at least 3% of initial body weight at 6 months).
Primer - vprašanje
Kakšna mora biti analitična variabilnost
(standardna deviacija) analitskega sistema,
da bi zagotovil zaznavo znižanja
koncentracije HbA1c (zaradi uporabe
GLP-1 agonista exenatida) za najmanj 8.0
mmol/mol Hb (cca 1 %, NGSP) na nivoju
5.0% rizika (biološka variabilnost HbA1c
znotraj osebka kot standardna deviacija je
0.1 mmol/mol)?
Primer - izračun
P(%)
10
5
2
1
0.2
0.1
z
1.65 1.96 2.33 2.58 3.09 3.29
(x1 - x2) – m 1-2
z =
-----------------s1,2
S = 3.43 mmol/mol
SA = 3.4 mmol/mol (pri 62.8 mmol/mol oz. 8.5%
HbA1c znaša 5.4 % kot KV%).
Fast is fine (and image op.avt.), but
accuracy (and patient benefit
op.avt.) is everything.
Wyatt Earp
HVALA ZA POZORNOST!