Vpliv dejavnikov na izid možganske kapi pri bolnikih zdravljenih z neposrednimi peroralnimi antikoagulacijskimi zdravili

Frol, Senta (author), Pretnar Oblak, Janja (mentor), Šabović, Mišo (comentor)

Izhodišče in namen. Ne-vitamin K oralni antikoagulanti (NOAK) so zdravila prvega izbora v primarni in sekundarni preventivi ishemične možganske kapi (IMK) pri bolnikih z nevalvularno atrijsko fibrilacijo (NVAF). Število bolnikov z NOAK, ki se uvedejo v klinični praksi, strmo narašča. Metaanalize in velike randomizirane kontrolirane raziskave (RKR) so nedvomno dokazale, da imajo NOAK primerljivo učinkovitost v preprečevanju ishemičnih dogodkov kot antagonisti vitamina K (AVK), ob čemer povzročijo manj velikih krvavitev. V RKR so bili večinoma vključeni bolniki, ki so prejemali NOAK v primarni preventivi. Podatkov o učinkovitosti in varnosti nižjih odmerkov NOAK v RKR, z izjemo dabigatrana, ni. Bolniki, ki so utrpeli ishemično možgansko kap (IMK) znotraj 14 dni pred vključitvijo v RKR, niso bili preučevani. Kljub visoki učinkovitosti in varnosti NOAK 1–2 % bolnikov doživi akutno IMK. Zlati standard zdravljenja bolnikov z akutno IMK je rekanalizacijska terapija, kamor sodita intravenska tromboliza (IVT) in mehanična rekanalizacija (MeR). Zdravljenje z IVT je za zdaj možno le pri bolnikih na dabigatranu z obratom antikoagulacije z antidotom oz. pri drugih NOAK, kadar s specifičnimi koagulacijskimi testi dokažemo odsotnost antikoagulacijskega učinka. Ob odsotnosti drugih možnosti večino bolnikov, ki utrpijo IMK med zdravljenjem z NOAK, zdravimo z MeR, ki pa je možna le v redkih centrih, in to le ob zapori velikih žil. Podatki o izhodu zdravljenja bolnikov na NOAK z akutno IMK so pomanjkljivi. Podobno pomanjkljivi so podatki o prognozi in pogojih za morebitno ponovno uvajanje NOAK pri bolnikih, ki so doživeli znotrajlobanjsko krvavitev (ZLK) ob zdravljenju z NOAK. Ti so po eni strani brez ponovne zaščite z NOAK zelo ogroženi za pojav IMK, po drugi pa jih ob uvedbi NOAK ogroža pojav ponovne ZLK. Namen pričujoče doktorske naloge je s pomočjo lastnih podatkov, pridobljenih iz kliničnih raziskav, in seznama bolnikov analizirati dejavnike, ki vplivajo na izhod možganske kapi pri bolnikih, zdravljenih z NOAK. Zasnova raziskav, metode. V prvi del naloge smo vključili vse bolnike, ki jim je bil NOAK uveden v sekundarni preventivi IMK na Kliničnem oddelku za vaskularno nevrologijo in intenzivno nevrološko terapijo (KOVNINT) od septembra 2012 do konca aprila 2018. Maja 2018 smo bolnikom poslali validiran vprašalnik, v katerem smo zajeli podatke o prejemanju terapije, zapletih in adherenci. Analizirali smo lastnosti bolnikov, učinkovitost in varnost NOAK v sklopu sekundarne preventive. Dobljene rezultate smo opisno primerjali z rezultati RKR in danskega registra. V drugi del naloge smo vključili vse bolnike, ki so prejemali dabigatran in so bili od leta 2016 do konca marca 2020 na KOVNINT zdravljeni z IVT. Z analizo podatkov o izhodu zdravljenja smo ocenjevali učinkovitost in varnost zdravljenja z IVT. Rezultate smo opisno primerjali z rezultati naših bolnikov, zdravljenih z IVT, ki niso prejemali antikoagulacijskega zdravljenja (AKZ), in rezultati podobne analize iz nemškega registra. Preučevanje tega vprašanja smo zaključili s sistematičnim pregledom ter analizo učinkovitosti in varnosti zdravljenja z IVT pri vseh primerih bolnikov, ki so prejemali dabigatran, objavljenih v literaturi do konca oktobra 2020. Dodatno smo nato preučevali izhod zdravljenja pri bolnikih z ZLK na dabigatranu, ki so na KOVNINT prejeli idarucizumab v obdobju od 2016 do konca marca 2020. Rezultate smo opisno primerjali z rezultati podobne analize iz nemškega registra. V tretji del naloge smo vključili vse bolnike z akutno IMK, ki so prejemali NOAK in so bili zdravljeni z MeR na KOVNINT od januarja 2013 do konca avgusta 2019. Zbrane podatke o učinkovitosti in varnosti zdravljenja z MeR smo ocenjevali z opisno primerjavo z rezultati raziskav pri bolnikih brez AKZ. V zadnji del naloge smo vključili vse bolnike, na KOVNINT obravnavane od septembra 2012 do konca decembra 2018, ki so med prejemanjem NOAK doživeli ZLK (izključili smo bolnike s strukturno spremembo in hemoragično transformacijo (HT) IMK). Z analizo podatkov smo oblikovali predlog protokola s kriteriji za varno ponovno uvedbo NOAK. Preučevali smo varnost in učinkovitost ponovne uvedbe NOAK po ZLK ter ugotavljali dejavnike, ki imajo prognostični napovedni dejavnik za ponovno hemoragično kap. Rezultati. V prvi raziskavi smo potrdili, da so NOAK v sekundarni preventivi učinkovita in varna zdravila, tako v standardnih kot nižjih odmerkih. V letih od 2012 do 2018 je bil NOAK v sekundarni preventivi predpisan 566 bolnikom. Podatki so bili zbrani za 510 bolnikov, ki smo jih povprečno spremljali 2,6 leta. Njihova povprečna starost je bila 78 let. Dabigatran je bil predpisan 66 % bolnikov, apiksaban 21 % in rivaroksaban 13 %. Pri 58 % bolnikov je bil uveden nižji odmerek NOAK. Letne incidence ponovnih IMK, velikih krvavitev in ZLK so bile 1,7 %, 1,6 % in 0,2 %. Ugotovili smo, da je bila letna pojavnost ponovnih IMK, velikih krvavitev in ZLK v naši raziskavi nizka in primerljiva z opisanimi v RKR in danskem registru, tako za standardne kot nižje odmerke NOAK. Uvajanje NOAK v zgodnjem obdobju po IMK je ob upoštevanju vseh običajnih dejavnikov, ki kažejo na možnost krvavitve oz. HT, učinkovito in varno. Dabigatran je bil najbolj predpisovano zdravilo, zato so podatki zanj zanesljivi, za druge NOAK manj. Dodatno smo ugotovili visoko adherenco prejemanja NOAK v sekundarni preventivi, saj je le 7,3 % bolnikov poročalo o prenehanju jemanja NOAK. Naši podatki kažejo, da je adherenca v okviru sekundarne preventive večja v primerjavi s podatki iz literature za primarno preventivo. V drugi raziskavi smo potrdili, da je IVT pri bolnikih z akutno IMK ob zdravljenju z dabigatranom po obratu antikoagulacijske aktivnosti z idarucizumabom učinkovita in varna. Dvaindvajset bolnikov povprečne starosti 75 let, ki so prejemali dabigatran, je bilo zdravljenih z IVT po obratu antikoagulacijske aktivnosti. Mediano izboljšanje po lestvici Nacionalnega inštituta za zdravje za oceno nevrološke prizadetosti po možganski kapi (NIHSS) ob odpustu je bilo 7 točk. Dober funkcionalni izhod (modificirana Rankinova lestvica (mRS) ? 2) po 3 mesecih je doseglo 86 % bolnikov. Pet odstotkov bolnikov je razvilo simptomatsko znotrajlobanjsko krvavitev (SICH) in 14 % jih je umrlo. Izhod zdravljenja bolnikov v naši raziskavi je bil primerljiv z izhodom zdravljenja bolnikov v nemški kohorti. Dober izhod je bil statistično značilno pogosteje dosežen pri bolnikih z akutno IMK, ki so bili zdravljeni z idarucizumabom in IVT, kot v skupini bolnikov z akutno IMK, ki niso prejemali AKZ (n = 182) (86 % vs. 57 %; p < 0,05). Učinkovitost in varnost zdravljenja z IVT pri bolnikih na dabigatranu smo podprli tudi z rezultati sistematičnega pregleda vseh primerov, objavljenih v literaturi. Z analizo izhoda zdravljenja bolnikov, ki so na terapiji z dabigatranom utrpeli ZLK in so bili zdravljeni z idarucizumabom (n=13), smo ugotavljali, da idarucizumab lahko izboljša izhod zdravljenja, saj je bila umrljivost nižja (15 %), kot je opisovano v literaturi glede umrljivosti bolnikov z ZLK na NOAK brez zdravljenja s specifičnimi antidoti (18–27 %). Naši rezultati so bili primerljivi z rezultati iz nemške kohorte. V tretji raziskavi smo potrdili, da je MeR pri bolnikih z akutno IMK na terapiji z NOAK učinkovita in varna. Z MeR je bilo zdravljenih 32 bolnikov z zaporo velike arterije, povprečne starosti 75 let. Signifikantno izboljšanje kliničnega stanja 24 ur po revaskularizaciji (izboljšanje NIHSS za ? 8 točk) je doseglo 25 % bolnikov. Dober izhod zdravljenja (mRS ? 2) po 3 mesecih je doseglo 44 % bolnikov. SICH je utrpelo 6 % bolnikov in 9 % jih je umrlo. Izhod zdravljenja bolnikov v naši raziskavi je bil primerljiv z rezultati metaanalize kliničnih raziskav pri bolnikih brez AKZ. Dodatno smo uspešnost in varnost zdravljenja z MeR na terapiji z NOAK v naši kohorti podprli s primerjavo objavljenih rezultatov našega centra iz leta 2015, v katerih so bili zajeti bolniki, zdravljeni z MeR od leta 2009 do 2012. Rezultati študije iz leta 2015 so pokazali visok delež uspešnosti rekanalizacije (84 % bolnikov je imelo uspešnost rekanalizacijskega zdravljenja (TICI) 2b/3), 16-% umrljivost in izboljšan klinični status (mRS ? 2) pri 40 % bolnikov. V zadnji raziskavi smo potrdili, da je pri skrbno izbranih bolnikih po ZLK ponovna uvedba NOAK lahko varna in učinkovita. Krvavitev v osrednji živčni sistem (OŽS) je utrpelo 54 bolnikov, povprečne starosti 80 let, 18 jih je umrlo mesec dni po krvavitvi. Povprečen čas opazovanja je bil 590 dni. Z analizo podatkov smo oblikovali predlog protokola s kriteriji za varno ponovno uvedbo NOAK po ZLK. NOAK je bil ponovno uveden pri 36 % bolnikov in nihče od njih ni utrpel ponovne ZLK. Ugotavljali smo, da sta bila pri bolnikih, pri katerih je bil vzrok krvavitve odpravljen (6 bolnikov), nazaj uvedena ista vrsta in odmerek NOAK. Pri bolnikih z ZMK (7 bolnikov) je bil v primeru skrbno urejenih dejavnikov tveganja in z magnetno resonančno tomografijo (MRT) glave izključene diagnoze cerebralne amiloidne angiopatije (CAA) uveden NOAK v nižjem odmerku, najpogosteje dabigatran. Sklepi. NOAK so v sekundarni preventivi IMK učinkovita in varna zdravila v standardnih in nižjih odmerkih. Učinkovitost in varnost sta primerljivi kot v raziskavah v sklopu primarne preventive. Zgodnje uvajanje NOAK po IMK je učinkovito in varno. Pri bolnikih z akutno IMK na dabigatranu je po obratu antikoagulacijske aktivnosti z idarucizumabom IVT učinkovita in varna. Zdravljenje z idarucizumabom pri bolnikih z ZLK na dabigatranu najverjetneje izboljša funkcionalni izhod zdravljenja. Pri skrbno izbranih bolnikih po ZLK je ponovna uvedba NOAK lahko varna in učinkovita.

• Language: Slovenian
• Keywords: neposredna peroralna antikoagulacijska zdravila, možganska kap
• Work type: Doctoral dissertation
• Organization: MF - Faculty of Medicine
• Year: 2021
• PID: 20.500.12556/RUL-133658
• COBISS.SI-ID: 90681347
• Publication date in RUL: 08.12.2021

Secondary language

• Language: English
• Title: Influence of factors affecting the occurence and outcome of stroke in patients treated with direct oral anticoagulant drugs

Abstract

Background and aim. Direct oral anticoagulants (DOACs) are first line therapy in primary and secondary stroke prevention in patients with nonvalvular atrial fibrillation (NVAF). Number of patients with DOAC initiation in clinical practice is rising rapidly. Meta-analysis and large randomized controlled trials (RCT) have undoubtedly shown that DOACs were comparably effective to vitamin K antagonists (VKA) in preventing stroke causing less amount of major bleeding. RCTs mainly included patients receiving DOACs for the primary prevention. There are no data on the efficacy and safety of reduced DOAC doses in RCTs, with the exception of dabigatran. Patients who suffered ischemic stroke (IS) 14 days prior to their inclusion in RCTs were not studied. Despite the high efficacy and safety of DOACs, 1-2% of patients suffer acute IS. The gold standard treatment for patients with acute IS is recanalization therapy, which includes intravenous thrombolysis (IVT) and mechanical recanalization (MeR). Treatment with IVT is currently possible only in dabigatran-treated patients after reversal of anticoagulation with antidote, or in other DOAC-treated patients when specific coagulation tests prove the absence of anticoagulation effect. In the absence of other options, most patients who suffer acute IS on DOAC therapy are treated with MeR, which is only possible in rare centers, and only when large vessel is occluded. Data on recanalization outcomes in DOAC-treated patients with acute IS are limited. Similarly, data on prognosis and conditions for possible DOAC reinitiation in patients who suffered intracranial hemorrhage (ICH) on DOAC therapy, are also lacking. These patients are at high risk from developing IS without DOAC therapy, but on the other hand they are more prone to recurrent ICH on DOAC therapy. The purpose of this doctoral thesis is to analyze factors which influence the outcome of stroke in patients treated with DOACs by our own clinical research and results. Research design, methods. In the first study all consecutive patients with DOAC prescription in secondary prevention from September 2012 till end of April 2018 at Clinical department of vascular neurology and neurological intensive care (KOVNINT) were included. In May 2018, a validated questionnaire on change of therapy, complications and adherence, was sent to the patient. We analyzed patient’s characteristics, efficacy and safety of DOACs in secondary stroke prevention. Our results were descriptively compared to results of RCTs and Danish registry. In the second study all consecutive patients receiving dabigatran, who were treated with IVT from 2016 until end of March 2020 at KOVNINT, were included. By analysing treatment outcome, effectiveness and safety of IVT was evaluated. Results were descriptively compared to results of our similar patients treated with IVT without anticoagulation therapy (ACT) and with results of similar analysis from German registry. The study of this issue was concluded with a systematic review and analysis of the efficacy and safety of IVT treatment of all cases of dabigatran-treated patients, published in the literature by the end of October 2020. In addition, the outcome of dabigatran-treated patients with intracranial haemorrhage (ICH) who received idarucizumab from 2016 till end of March 2020 at KOVNINT, was studied. Results were desciptively compared to results of similar analysis from German registry. In the third study all consecutive patients with acute IS on DOAC therapy, who were treated with MeR at KOVNINT from January 2013 till August 2019, were included. The collected data on efficacy and safety of MeR treatment were evaluated by a descriptive comparison with the results of studies in patients without ACT. In the last study all consecutive DOAC-treated patients with ICH at KOVNINT from September 2012 till end of December 2018, were included (patients with an underlying structural cause and hemorrhagic transformation (HT) of IS were excluded). By analysing the data, predefined diagnostic protocol with criteria for safe DOAC reinitiation, was proposed. Safety and effectiveness of DOAC re-initiation after ICH in DOAC-treated patients was explored and prognostic factors for recurrent ICH were identified. Results. In the first study we confirmed that DOACs are effective and safe in secondary stroke prevention in standard and reduced doses. Five-hundred sixty-six patients were prescribed DOAC for secondary stroke prevention from 2012 to 2018. Data was gathered for 510 patients with an average observational time 2,6 years. The mean age of patients was 78 years. Dabigatran was prescribed in 66%, apixaban in 21% and rivaroxaban in 13% of patients. Fifty-eight % of patients were prescribed reduced DOAC dose. Yearly incidences of recurrent IS, major bleeding and ICH were 1,7%, 1,6% and 0,2%. We found that yearly incidences of recurrent IS, major bleeding and ICH were low and comparable to results of RCTs and Danish registry for standard and reduced doses. DOAC initiation in the early phase of stroke is effective and safe, considering all the usual factors suggesting the possibility of bleeding or HT. Dabigatran was the most prescribed DOAC, therefore the results are reliable for dabigatran and less so far for other DOACs. Additionally, very high adherence rate of DOAC therapy in secondary stroke prevention was observed, with only 7,3% of patients reporting discontinuation of DOAC therapy. Our data show that adherence in secondary stroke prevention is higher compared to primary prevention. In the second study we confirmed that IVT in dabigatran-treated patients with acute IS after anticoagulation reversal with idarucizumab is effective and safe. Twenty-two dabigatran-treated patients with mean age 75 years received IVT after reversal. Median improvement of National Institues of Health Stroke Scale (NIHSS) at discharge was 7. Favourable functional outcome (mRS ⡤ 2) after 3 months was achieved in 86% of patients. Symptomatic intracranial haemorrhage (SICH) occurred in 5% and 14% of patients died. Outcome of treatment was comparable to outcome reported in the German study. Good functional outcome was achieved statistically significantly more often in patients with acute IS treated with IVT after reversal compared to patients without ACT (n=182) (86 % vs. 57 %; p < 0,05). Effectiveness and safety of IVT in patients on dabigatran was additionally supported with results of systematic review of all published cases in literature. By analyzing the outcome of dabigatran treated patients with ICH receiving idarucizumab (n=13), we found that idarucizumab could improve treatment outcome of those patients, as mortality rate was lower (15 %) as described mortality rate in DOAC-treated patients with ICH without specific antidote treatment (18-27 %) in the literature. Our results were comparable to results from German cohort. In the third study we confirmed that MeR in DOAC-treated patients with acute IS is effective and safe. Thirty-two patients with large artery occlusion, aged 75 years were treated with MeR. Significanant clinical improvement, 24 hours after revacularization (NIHSS improvement of ⡥ 8 points), occurred in 25 % of patients. A favourable treatment outcome (mRS ⡤ 2) after 3 months was achieved in 44% of patients. SICH occurred in 6% of patients and 9% died. Outcome of MeR treatment in our study was comparable to results of meta-analysis in clinical trials in patients without ACT. Effectiveness and safety of MeR in our DOAC-treated patients was additionally confirmed with the results of our center published in year 2015, which included patients treated with MeR from 2009 to 2012. The study from 2015 showed high recanalization rate (84% of patients achieved Thrombolysis in Cerebral Infarction Scale (TICI) 2b/3), 16 % mortality and improved clinical status (mRS ⡤ 2) in 40 % of patients. In the last research we confirmed that in carefully selected DOAC-treated patients with ICH re-initiation of DOAC could be safe and effective. Fifty-four patients aged 80 suffered cebtral nervous system (CNS) hemorrhage, 18 patients died within a month. The average observational time was 590 days. By analising the data, a predefined protocol with criteria for safe DOAC reinitiation after ICH was formulated. DOACs were reinitiated in 36% of patients and none of them suffered a reccurrent ICH. We found that in patients in whom the cause of bleeding was excluded (6 patients), the same type and dose of DOAC was reinitiated. In patients with intracerebral hemorrhage (7 patients) in case of well controlled risk factors and with head magnetic resonance tomography (MRT) excluded cerebral amyloid angiopathy (CAA), a reduced DOAC dose was reiniatied, most commonly dabigatran. Conclusions. DOACs are effective and safe therapy in secondary stroke prevention in standard and reduced doses. Efficacy and safety is comparable to primary prevention studies. Prescription of DOACs in the early phase after acute IS is effective and safe. In dabigatran-treated patients with acute IS IVT after idarucizumab reversal is effective and safe. In dabigatran-treated patients with ICH idarucizumab improves patient’s functional outcome. In carefully selected patients after ICH DOAC reinitiation might be safe and effective.

• Keywords: direct oral anticoagulant drugs, stroke