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VARNOST IN UČINKOVITOST NOVIH ANTIKOAGULACIJSKIH ZDRAVIL PRI BOLNIKIH Z ATRIJSKO FIBRILACIJO – PROSPEKTIVNA KLINIČNA RAZISKAVA
Šinigoj, Petra (Author), Mavri, Alenka (Mentor) More about this mentor... This link opens in a new window

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Abstract
Ozadje: V velikih randomiziranih raziskavah so se neposredna peroralna antikoagulacijska zdravila (NOAK) izkazala kot varna in učinkovita v zdravljenju bolnikov z atrijsko fibrilacijo (AF) in so hitro prešla v klinično uporabo. Prve analize kakovosti zdravljenja v klinični praksi se že pojavljajo, a med njimi je le malo podatkov o varnosti njihove uporabe pri starostnikih in o potrebnosti laboratorijskega nadzora ob zapletih zdravljenja. Metode dela: V prospektivno opazovalno raziskavo smo vključili zaporedne bolnike z AF, ki smo jim od leta 2012 do marca 2017 v Antikoagulacijski (AK) ambulanti Kliničnega oddelka za žilne bolezni Univerzitetnega kliničnega centra Ljubljana uvedli in vodili zdravljenje z dabigatranom (N = 1308), rivaroksabanom (N = 1102) in apiksabanom (N = 850). Bolnike smo spremljali s pomočjo računalniškega programa Trombo. Ocenili smo pojavnost krvavitev in trombemboličnih zapletov. V drugi del raziskave smo vključili 44 bolnikov z AF, ki smo jim uvedli zdravljenje z dabigatranom v obeh odmerkih. V ravnotežnem stanju smo v razmaku enega meseca pri vsakemu bolniku s tekočinsko kromatografijo s tandemsko masno spektrometrijo (LC-MS/MS) določili dve vrednosti najmanjše in dve vrednosti največje koncentracije dabigatrana ter jih primerjali s posredno ocenjenimi koncentracijami s pomočjo nekaterih koagulacijskih preiskav. Bolnike smo spremljali 12 mesecev in preverili, ali so vrednosti koncentracij povezane z zapleti AK zdravljenja. Rezultati: Povprečni čas spremljanja je bil 621 ± 464 dni. Pojavnost velikih krvavitev je bila ob zdravljenju z dabigatranom 1,5 %/leto, z rivaroksabanom 2,6 %/leto in z apiksabanom 2,5 %/leto, pojavnost možganskih kapi in sistemskih embolij pa ob zdravljenju z dabigatranom 0,9 %/leto, z rivaroksabanom 1,3 %/leto in z apiksabanom 1,0 %/leto. Bolniki, ki so prejeli majhen odmerek NOAK, so bili v primerjavi z ostalimi starejši, imeli so slabše ocenjeno ledvično delovanje in večji CHADS2. Razlike v pojavnosti zapletov ob zdravljenju z velikim in majhnim odmerkom NOAK niso bile statistično značilne. Kljub prilagoditvi odmerka NOAK smo pri bolnikih starih 85 in več let (N = 394) ugotovili večjo pojavnost vseh velikih krvavitev (4,6 vs. 1,8 %/leto, p = 0,003), intrakranialnih krvavitev (1,3 vs. 0,4 %/leto, p = 0,032) in velikih gastrointestinalnih krvavitev (2,6 %/leto vs. 1,0 %/leto, p = 0,035) v primerjavi z bolniki mlajšimi od 85 let. Pojavnost trombemboličnih dogodkov se med starejšimi in mlajšimi ni značilno razlikovala (2,9 vs. 1,8 %/leto, p = 0,463). Najboljšo korelacijo med posredno ocenjeno koncentracijo dabigatrana in tisto določeno z LC-MS/MS smo ugotovili za prilagojeni trombinski čas po hišnem protokolu (hišni pTČ) in ekarinski kromogeni test. Pri bolnikih na velikem (N = 23) in majhnem odmerku dabigatrana (N = 21) smo izmerili podobne vrednosti največjih in najmanjših koncentracij dabigatrana. Variabilnost najmanjših koncentracij dabigatrana je bila pomembno manjša od variabilnosti največjih koncentracij dabigatrana (17,0 ± 13,6 vs. 26,6 vs. 19,2 %, p = 0,02). Tekom enoletnega spremljanja je 10 bolnikov utrpelo majhno krvavitev, velikih krvavitev ali trombembolij ni bilo. Bolniki z majhno krvavitvijo so imeli pomembno večje vrednosti najmanjših koncentracij dabigatrana v primerjavi z bolniki, ki krvavitve niso utrpeli (93 ± 36 vs. 72 ± 62 μg/L, p = 0,02). Sklepi: Ocenjujemo, da je uporaba NOAK za zdravljenje bolnikov z AF v naši klinični praksi dovolj varna in učinkovita. Kot najbolj ogroženi za krvavitev so se izkazali bolniki stari 85 in več let, zato mora biti pri njih odločitev za uvedbo NOAK vedno skrbno pretehtana. Ugotovili smo, da hišni pTČ, ki je dostopen v klinični praksi, dobro odraža dejansko koncentracijo dabigatrana v plazmi in je primerna preiskava ob zapletih. Za spremljanje zdravljenja pa je najbolj smiselna enkratna določitev vrednosti najmanjše koncentracije dabigatrana, saj je njena intraindividualna variabilnost bistveno manjša od največje koncentracije. Pokazali smo, da se ob velikih vrednostih najmanjših koncentracij dabigatrana tveganje za krvavitev poveča.

Language:Slovenian
Keywords:dabigatran, rivaroksaban, apiksaban, atrijska fibrilacija, koagulacijske preiskave, koncentracija zdravila
Work type:Doctoral dissertation (mb31)
Organization:MF - Faculty of Medicine
Year:2018
Views:946
Downloads:492
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Secondary language

Language:English
Title:SAFETY AND EFFICACY OF NEW ORAL ANTICOAGULANTS IN PATIENTS WITH ATRIAL FIBRILLATION – A PROSPECTIVE CLINICAL STUDY
Abstract:
Background: In randomized clinical trials direct oral anticoagulants (DOAC) were shown to be safe and effective in atrial fibrillation (AF) patients and were rapidly taken up in clinical use. First quality analyses from daily-care are emerging, but there is only scarce data on DOAC safety in elderly patients and the necessity of laboratory monitoring in case of an adverse event. Methods: In our prospective non-interventional study we included AF patients who were treated at the Anticoagulation clinic of the Department of vascular diseases, University Medical Centre Ljubljana, from year 2012 until march 2017. Patients treated with dabigatran (N = 1308), rivaroxaban (N = 1102) or apixaban (N = 850) were enrolled and their data has been managed with computer software Trombo. We evaluated rates of major bleeding and thromboembolic events. In the second part of the study we included 44 AF patients who started treatment with dabigatran 150 and 110 mg twice daily. Each patient contributed 2 trough and 2 peak blood samples that were collected during dabigatran treatment in steady-state approximately one month apart. Plasma concentration was measured by liquid chromatography with tandem mass spectrometry (LC-MS/MS) and indirectly estimated by selected coagulation tests. Patients were followed for 12 months and relationship between plasma dabigatran concentrations and adverse events was assessed. Results: Patients were followed for a mean of 621 ± 464 days. Rates of major bleeding were 1,5, 2,6 and 2,5 %/year and rates of combined endpoint of stroke and systemic embolism were 0,9, 1,3 and 1,0 %/year on treatment with dabigatran, rivaroxaban and apixaban, respectively. Patients who were prescribed DOAC in a low dose were older, had worse renal function and higher CHADS2 score than patients who were prescribed DOAC in a high dose. Differences in the rates of major bleeding and thromboembolism were not significantly different between patients on high and low dose of DOAC. Despite dose adjustment, patients aged &#8805; 85 years had significantly higher rates of major bleeding (4,6 vs. 1,8 %/year, p = 0,003), intracranial bleeding (1,3 vs. 0,4 %/year, p = 0,032) and major gastrointestinal bleeding (2,6 vs. 1,0 %/year, p = 0,035) than patients aged < 85 years. Rates of thromboembolic events did not significantly differ between the two groups (2,9 vs. 1,8 %/year, p = 0,463). The best correlations between LC-MS/MS and coagulation tests for determining dabigatran concentration were expressed by in-house diluted thrombin time (in-house dTT) and ecarin chromogenic assay. Patients receiving dabigatran in high (N = 23) and low dose (N = 21) had similar dabigatran concentrations in both trough and peak samples. Dabigatran concentration varied less in trough than in peak samples (17,0 ± 13,6 vs. 26,6 ± 19,2 %, p = 0,02). During the 12-month follow-up, 10 patients suffered minor bleeding. There was no major bleeding or thromboembolic event. Patients with bleeding had significantly higher average trough dabigatran concentrations than patients without bleeding (93 ± 36 vs. 72 ± 62 &#956;g/L, p = 0,02). Conclusions: Results from our clinical practice have shown sufficient efficacy and safety of DOAC in AF patients. AF patients aged &#8805; 85 years were at highest risk of major bleeding, therefore the risks and benefits of anticoagulation treatment should be carefully assessed before prescribing them DOAC. In-house dTT, which is available in clinical practice, reliably estimates dabigatran plasma concentration and is an appropriate method to use in case of adverse events. For laboratory monitoring of dabigatran treatment one measurement of dabigatran trough concentration is more reliable than measurement of dabigatran peak concentration due to its lower intraindividual variability. High trough concentrations may predispose patients to higher risk of bleeding.

Keywords:dabigatran, rivaroxaban, apixaban, atrial fibrillation, blood coagulation tests, drug concentration

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