| Abstract | Cilj istraživanja
Cilj ovog specijalističkog rada je analizirati podatke iz kliničkih ispitivanja i registara te
relevantne smjernice europskih stručnih društava vezano za oralne antikoagulanse koji nisu
antagonisti vitamina K (NOAK-i) u bolesnika s fibrilacijom atrija (FA) i kroničnom bubrežnom
bolesti (KBB).
Materijali i metode
Literatura je pretraživana prema temi i predmetu istraživanja, autorima i časopisu, od općih
prema specijaliziranim člancima pri čemu su odabrani članci relevantni za problematiku ovog
specijalističkog rada. Ciljana pretraga provedena je putem baza kao što su PubMed, baza
lijekova hrvatske Agencije za lijekove i medicinske proizvode te Clinicaltrials.gov. Relevantne
smjernice europskih stručnih društava također su detaljno istražene.
Rezultati
Bolesnici s FA-om i KBB-om imaju povećan pobol i smrtnost, što je povezano s njihovim
paradoksalno povećanim rizikom tromboembolizma i krvarenja, kako je pokazano u nekoliko
registara. To čini izazovnim stratifikaciju rizika i liječenje antikoagulansima. Tri NOAK-a ušla
su na hrvatsko tržište tijekom posljednjeg desetljeća. Subanalize njihovih temeljnih ispitivanja
pokazale su usporedivu učinkovitost uz povoljan profil sigurnosti u podskupini bolesnika s
FA-om i blagim do umjerenim KBB-om, što je u skladu s nalazima u općoj populaciji. U
subanalizama je pokazano i da rivaroksaban i dabigatran bolje čuvaju bubrežnu funkciju
nego varfarin, što je potvrđeno u kliničkoj praksi iz američke administrativne baze podataka.
Za apiksaban su nađeni neutralni rezultati i u subanalizi temeljnog ispitivanja i u navedenoj
bazi podataka. Očekivano, nađeno je više retrospektivnih analiza baza podataka (uglavnom
iz SAD-a) nego prospektivnih ispitivanja. Općenito, učinkovitost i sigurnost NOAK-a u
bolesnika s FA-om i KBB-om potvrđene su u kliničkoj praksi. Varijacije bubrežne funkcije u
bolesnika s FA-om liječenih NOAK-om nisu rijetke, stoga je potrebno pomno praćenje i
prilagodba doze prema potrebi. Doziranje NOAK-a koje nije u skladu s uputom o lijeku vodi
ka lošijim ishodima. CKD-EPI jednadžba, koja je preporučena za procjenu GFR-a, u kliničkoj
praksi nije naširoko upotrebljavana. Ako bi se u propisivanju ovih novih lijekova eGFR
izveden iz MDRD jednadžbe upotrebljavao umjesto preporučene Cockcroft-Gault formule,
mnogi stariji bolesnici s FA-om pogrešno bi postali za njih pogodni, ili bi primili previsoku
dozu. Dvije retrospektivne studije ispitale su upotrebu apiksabana u bolesnika s FA-om i
bubrežnom bolešću krajnjeg stadija. Jedno japansko ispitivanje pokazalo je da NOAK-i mogu
biti atraktivna opcija za katetersku ablaciju bolesnika s FA-om i KBB-om. EHRA upitnik
pokazao je da je u kliničkoj praksi prepoznata važnost praćenja bubrežne funkcije u
bolesnika s FA-om. U bolesnika s blagim do umjerenim KBB-om, FA je uglavnom zbrinjavan
sukladno preporukama smjernicama, no više podataka potrebno je za vođenje bolesnika s
FA-om i teškim KBB-om ili na bubrežnoj nadomjestnoj terapiji.
Zaključak
Zaštita bolesnika s FA-om i KBB-om od razornih posljedica moždanog udara može biti
izazovna budući da su oni povećanog rizika i za tromboembolizam i za krvarenja. Potrebna
je dodatna edukacija o važnosti korištenja CKD-EPI jednadžbe za procjenu GFR-a, koja je
pokazala pouzdanost kroz široki spektar stadija KBB-a. Međutim, u kontekstu liječenja
NOAK-ima, bubrežnu funkciju treba procijeniti računajući CrCl korištenjem Cockcroft–Gault
metode, koja je korištena u većini ispitivanja s NOAK-ima. U bolesnika liječenih NOAK-ima
bubrežnu funkciju treba redovito pratiti, najmanje jednom godišnje, kako bi se otkrile
promjene u bubrežnoj funkciji i sukladno tome prilagodila doza. U usporedbi s varfarinom,
upotreba NOAK-a mogla bi biti povezana s manjim rizikom od štetnih bubrežnih ishoda
povezanih s vaskularnom kalcifikacijom i akutnom varfarinskom nefropatijom. Buduća
ispitivanja potrebna su kako bi utvrdila je li utjecaj na pogoršanje bubrežne funkcije
specifičan za učinak određenog lijeka. Upotreba doza NOAK-a koje nisu u skladu s uputom o
lijeku povezana je s lošijm ishodima. Potrebna su dodatna ispitivanja o optimalnom doziranju
NOAK-a i učestalosti praćenja bolesnika s FA-om i KBB-om. Potrebna su randomizirana
ispitivanja s oralnim antikoagulansima u bolesnika na hemodijalizi, kao i kontrolirana
ispitivanja s NOAK-ima u teškom KBB-u. Dodatno, potrebna su istraživanja s oralnim
antikoagulansima u bolesnika nakon transplantacije bubrega. Mnogo toga ostaje za naučiti o
optimalnoj upotrebi NOAK-a u bolesnika s FA-om i KBB-om. Uska suradnja između
kardiologa i nefrologa ili multidisciplinarni timovi mogli bi poboljšati skrb bolesnika s FA-om i
uznapredovalim KBB-om. |
| Abstract (english) | Objectives
The aim of this paper is to analyze data from clinical trials and registries together with
relevant guidelines of the European scientific societies related to non-vitamin K antagonst
oral anticoagulants (NOACs) in patients with atrial fibrillation (AF) and chronic kidney disease
(CKD).
Materials and Methods
Literature search was done by topic and subject of research, authors and journals, from
general to specialized articles relevant to the issues of this paper. The targeted search was
carried out via on-line databases such as PubMed, medicinal products database of the
Croatian Agency for Medicinal Products and Medical Devices and Clinicaltrials.gov. Relevant
guidelines of the European scientific societies were also searched in detals.
Results
AF patients with CKD have increased morbidity and mortality which is related to their
paradoxically increased risk of both thromboembolism and bleeding as shown in few
registries. This makes risk stratification and treatment with anticoagulants challenging.
Three NOACs have been introduced to Croatian market within the last decade. Subanalyses
from their landmark trials have shown comparable efficacy with favourable safety profile in
subset of AF patients with mild to moderate CKD, consistent with findings in general
population. In subanalyses it has been shown that rivaroxaban and dabigatran better
preserve renal function than warfarin which was confirmed in clinical practice from the US
administrative database. For apixaban more neutral results were found in both subanalysis
from landmark trial and the respective database. As expected, more retrospective database
analyses (predominantly from the US) were found than prospective studies. In general,
efficacy and safety of NOACs in AF patients with CKD has been confirmed in clinical
practice. Variation of kidney function in AF patients treated with NOACs is not rare and
diligent follow up should be employed with dose adjustment if needed. NOAC dosing
inconsistent with product label leads to worse outcomes. CKD-EPI equation which is
recommended for estimation of GFR is not widely used in clinical practice. If MDRD-derived
eGFR was used instead of recommended Cockcroft-Gault in prescribing these new agents,
many elderly patients with AF would either incorrectly become eligible for them or would
receive too high dose. Two retrospective studies examined the use of apixaban in AF
patients with end stage kidney disease. One Japanese study has shown NOACs could be
attractive option for catheter ablation of AF patients with CKD. EHRA survey has shown that
the importance of renal function monitoring in AF patients is well recognized in clinical
practice. In patients with mild-to-moderate CKD, AF is mostly managed according to the
guideline recommendations, but more data are needed to guide the management of AF in
patients with severe CKD or renal replacement therapy.
Conclusion
Protecting AF patients with CKD from the devastating consequences of stroke can be
challenging since they are at increased risk for both thromboembolism and bleeding.
Additional education is needed on the importance of using CKD-EPI equation for estimation
of GFR which showed to be reliable accross the wide spectrum of CKD stages. However, in
the context of NOAC treatment, renal function should be estimated by calculating the CrCl
using the Cockcroft-Gault method, which was used in most NOAC trials. In patients treated
with NOACs kidney function should be monitored regularly, at least yearly, to detect changes
in renal function and adapt the dose accordingly. Compared to warfarin, NOACs might be
related to the lower risk of adverse renal outcomes related to vascular calcification and acute
warfarin nephropathy. Future studies are needed to establish wether the impact on
deterioration of kindey function is specific for the effect of certain drug. The use of NOAC
doses inconsistent with drug labelling has been associated with worse outcomes. Additional
research is needed on optimal NOAC dosing and frequency of follow up for patients with AF
and CKD. Randomized trials with OACs in patients on hemodialysis, as well as controlled
trials with NOACs in severe CKD are needed. Moreover, research is needed with OACs in
patients after kidney transplantation. Much remains to be learned on the optimal use of
NOACs in AF patients with CKD. Close collaboration of cardiologist and nephrologist or
multidisciplinary teams could improve care of AF patients with advanced CKD. |
