Dissertations / Theses on the topic 'Apixaban'

Apixaban is a novel oral anticoagulant that prevents clotting by directly inhibiting Factor Xa in the coagulation cascade. Due to its different pharmacokinetics, previous standards for testing anticoagulant concentrations are ineffective at measuring apixaban. In this study, Hyphen Biomed Biophen Direct Xa Inhibitor and Biophen Heparin chromogenic kits from Aniara Diagnostica were used along with a NanoDrop™ One/OneC Microvolume UV-Vis Spectrophotometer to see if either of these kits provide acceptable precision and accuracy for the quantification of apixaban in plasma samples, as well as if there is a significant difference in these two kits at varying concentrations of apixaban. Apixaban is a novel oral anticoagulant that prevents clotting by directly inhibiting Factor Xa in the coagulation cascade. Due to its different pharmacokinetics, previous standards for testing anticoagulant concentrations are ineffective at measuring apixaban. In this study, Hyphen Biomed Biophen Direct Xa Inhibitor and Biophen Heparin chromogenic kits from Aniara Diagnostica were used along withused witha NanoDrop™ One/OneC Microvolume UV-Vis Spectrophotometer to see if either of these kits provide acceptable precision and accuracy for the quantification of apixaban in plasma samples,as well as and to evaluate if there is a significant difference in these two kits at varying concentrations of apixaban.

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas
Durante longos anos, os antagonistas da vitamina K e as heparinas foram os únicos anticoagulantes disponíveis. Apesar de eficazes na prevenção/tratamento das doenças tromboembólicas, apresentam numerosas limitações. No sentido de ultrapassar estas limitações, têm vindo a ser desenvolvidos novos fármacos, que ao contrário dos anteriores atuam num único fator da coagulação específico. Após vários estudos de eficácia e segurança, o dabigatrano etexilato (inibidor direto da trombina), o rivaroxabano e o apixabano (inibidores diretos do fator Xa) foram aprovados para prevenção de acidente vascular cerebral (AVC) e do tromboembolismo venoso em pacientes submetidos a artroplastia eletiva da anca ou joelho, para reduzir o risco de AVC e embolismo sistémico em pacientes com fibrilhação auricular não-valvular e também como tratamento em pacientes com trombembolismo venoso agudo. Estes novos anticoagulantes orais além de serem farmacologicamente previsíveis, não sofrem interações significativas com alimentos, nem com outros fármacos, não necessitam de monitorização laboratorial regular e são de administração oral. Os resultados dos estudos demonstraram que são pelo menos tão eficazes como a varfarina mas mais seguros, uma vez que apresentam um risco de hemorragias major inferior. No entanto, muito ainda está por explorar, sendo necessário prosseguir com as investigações nesta área, conhecendo melhor os efeitos a longo prazo e garantindo uma melhor eficácia e segurança para os pacientes.
For many years, vitamin K antagonists and heparins were the only available anticoagulants. Although effective in the prevention/treatment of thromboembolic diseases, they have numerous limitations. In order to overcome these drawbacks, new drugs that act on a single specific coagulation factor have been developed. After several studies on efficacy and safety, dabigatran etexilate (direct thrombin inhibitor), rivaroxaban and apixaban (factor Xa inhibitors) have been approved for prevention of stroke and venous thromboembolism in patients undergoing elective arthroplasty of hip or knee, to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation and in the treatment of patients with acute venous thromboembolism. These new oral anticoagulants are pharmacologically predictable, do not suffer from interaction with other drugs or with food, do not require regular laboratory monitoring and are orally active. The results of the studies showed that are at least as effective as warfarin but safer, since the risk of major bleeding is shorter. However, much remains to be explored, it is necessary to proceed with the investigations in this area, ensuring better efficacy and safety for patients.

Actualmente, de todos los Anticoagulantes de Acción Directa (ACODs) aprobados, sólo rivaroxaban ha mostrado unos resultados satisfactorios en el Síndrome Coronario Agudo (SCA); en cambio, apixaban no lo demostró. Una de las hipótesis de que apixaban no pudiera demostrar su eficacia, sin sacrificar la seguridad, incrementado los sangrados, sería que la dosis seleccionadas en este estudio fueron demasiado altas, y se deberían haber reducido respecto a las de Fibrilación Auricular (FA). Los mecanismos de acción de apixaban apoyan su potencial uso terapéutico en la prevención de complicaciones trombóticas en el sistema vascular arterial, sin embargo los efectos de estos agentes sobre la activación y agregación plaquetaria en un modelo celular de la coagulación rico en plaquetas no se han investigado en detalle. Esta tesis ha tratado de actualizar la información disponible sobre la farmacología y los datos clínicos de apixaban en la prevención del ictus y de la embolia sistémica en pacientes con FA, y la posterior evaluación y cuantificación de los efectos inhibidores de apixaban sobre diferentes aspectos de la formación de trombos en el territorio arterial (deposición de fibrina y agregación plaquetaria a índices de cizalladura arteriales; propiedades tromboelastométricas del coágulo en formación; y generación de trombina local en un modelo celular de la coagulación enriquecido en plaquetas). Para la confirmación de las hipótesis planteadas se han utilizado distintas aproximaciones experimentales en condiciones de flujo dinámico y estático con el fin de determinar si apixaban a dosis más bajas, que a las que están indicadas para la prevención y tratamiento de complicaciones tromboembólicas, podría ser un candidato para la prevención de eventos isquémicos en el territorio arterial. Las principales conclusiones son: 1. Apixaban mostró una acción inhibidora diferencial sobre los componentes de hemostasia primaria y secundaria dependiendo de las técnicas utilizadas para su estudio. 2. Los efectos de concentraciones crecientes (10, 40 y 160 ng/mL) de apixaban inhibieron distintamente la generación de trombina local, los parámetros tromboelastométricos durante la formación del coágulo, y la deposición de plaquetas y fibrina en los vasos dañados en los estudios con la sangre circulante. 3. En los estudios en condiciones de flujo, apixaban muestra una acción antiplaquetaria notable con las concentraciones más altas (40 y 160 ng/mL). 4. La concentración más elevada de apixaban inhibe casi completamente la formación de fibrina en los estudios en condiciones de flujo arterial. 5. Concentraciones de apixaban 4 a 16 veces inferiores a la Cmax, alcanzada con la dosis antitrombótica aprobada para FA, podrían ser adecuadas para reducir la generación de trombina, la formación de agregados de plaquetas grandes y, aun así, permitir la formación de fibrina, preservando así su contribución a la hemostasia en el contexto del SCA. 6. Los estudios en los ensayos modificados de generación de trombina mediados por plaquetas podrían ser útiles para investigar la acción antiplaquetaria de otros ACODs en la prevención de complicaciones aterotrombóticas en territorios arteriales. 7. Nuestros resultados indican que los estudios experimentales en condiciones de flujo en combinación con los ensayos de la generación de trombina modificados podrían facilitar la selección de la concentración de ACOD, la cual prevendría el reclutamiento de plaquetas relacionadas con la trombina en los trombos patológicos arteriales, reduciendo el riesgo de interferir con la formación de fibrina necesario para la consolidación de la hemostasia. Estos datos deben permitir el desarrollo de estudios posteriores en los que se pueda establecer el efecto antitrombótico de las asociaciones de apixaban a bajas dosis, que a las que están indicadas para la prevención y tratamiento de complicaciones tromboembólicas, con los agentes antiplaquetarios utilizados en la prevención secundaria de eventos aterotrombóticos.
Currently, of all approved Direct Oral Anticoagulants (DOACs), only rivaroxaban has shown satisfactory results in Acute Coronary Syndrome (ACS); On the other hand, apixaban did not demonstrate it. One of the hypotheses that apixaban was not successful could be that the selected doses in this study were too high, and should have been reduced compared to prevention of stroke in patients with atrial fibrillation (SPAF) dose. This thesis has updated the available apixaban data in SPAF, and has evaluated and quantified of its inhibitory effects on different aspects of thrombi formation in the arterial territory with different experimental approaches, in order to determine if they were applied at lower doses than those indicated for the prevention and treatment of thromboembolic complications. The main conclusions are: 1. Apixaban showed a differential inhibitory action on the components of primary and secondary hemostasis depending on the techniques used for its study. 2. The effects of increasing concentrations of apixaban (10, 40 and 160 ng/mL) differentially inhibited the local thrombin generation (TG), thromboelastometric parameters during clot formation, and deposition of platelets and fibrin in vessels damaged in the studies with circulating blood. 3. In studies under flow conditions, apixaban shows a remarkable antiplatelet action with the highest concentrations (40 and 160 ng/mL). 4. The highest concentration of apixaban almost completely inhibits fibrin formation in studies under arterial flow conditions. 5. Concentrations of apixaban 4 to 16 times lower than Cmax, achieved with the antithrombotic dose approved for AF, could be adequate to reduce the TG, the formation of large platelet aggregates and, nevertheless, allow the formation of fibrin, thus preserving its contribution to hemostasis in the ACS context. 6. Studies in modified platelet-mediated TG assays may be useful in investigating the antiplatelet action of other DOACs in the prevention of atherothrombotic complications in arterial territories. 7. Our results indicate that experimental studies under flow conditions in combination with modified TG assays could facilitate [DOAC] selection, which would prevent recruitment of thrombin-related platelets in pathological arterial thrombi, reducing the risk of interfering with the formation of fibrin necessary for the consolidation of hemostasis.

Class of 2013 Abstract
Specific Aims:  To determine the efficacy of apixaban when compared to LMWH (enoxaparin) when used as thromboprophylaxis for patients undergoing total hip arthroplasty (THA), total knee arthroplasty (TKA), and medically ill patients  To determine the safety of apixaban when compared to LMWH (enoxaparin) when used as thromboprophylaxis for patients undergoing total hip arthroplasty (THA), total knee arthroplasty (TKA), and medically ill patients Methods: A systematic search of the literature for randomized controlled trials of apixaban thromboprophylaxis therapy versus enoxaparin was conducted using three databases: PubMed, EMBASE, and the Cochrane library. Data from five studies with 12,938 total patients were analyzed using Bayesian random effects meta-analysis. To evaluate efficacy, a composite of venous thromboembolism and death during follow-up was measured. To evaluate safety, major and total bleeding events were considered. Main Results: The odds ratio (OR) for the composite outcome of thromboembolism/death was 0.66 (95% CI: 0.33 to 1.29) for apixaban compared to enoxaparin, while there was a similar risk of major bleeding (OR=1.03, 95%CI: 0.36 to 3.73) and total bleeding (OR=0.92, 95%CI: 0.64 to 1.20). Conclusion: These results suggest a lack of clear superiority of apixaban relative to enoxaparin. Apixaban is an oral alternative with similar efficacy and safety to existing anticoagulant therapies.

La sécurité d’emploi et l’efficacité des anti-Xa oraux directs (AOD) en cas d’obésité ont été démontrés dans la littérature. En revanche les données pharmacocinétiques spécifiques de cette population sont rares, et les données après chirurgie bariatrique sont encore plus rares. Une revue systématique des modèles pharmacocinétiques de population de ces AOD a montré que plusieurs modèles de l’apixaban étaient applicables à la population des patient atteints d’obésité traités pour maladie veineuse thromboembolique (MVTE). En revanche, au moment de l’étude aucun des modèles publiés du rivaroxaban n’était applicable à cette population. Les extrapolations à partir de ces modèles, ou les résultats des simulations ne sont pas valables pour la population des patients atteints d’obésité et traités pour MVTE par rivaroxaban. L’étude de phase 1 ABSORB (NCT04180436) a évalué la pharmacocinétique et la sécurité d’emploi du rivaroxaban a pleine dose chez des sujets atteints d’obésité et après chirurgie bariatrique (gastrectomie longitudinale ou bypass gastrique). Les résultats de cette étude suggéraient que la chirurgie bariatrique n’avait pas d’impact cliniquement significatif sur la pharmacocinétique et la sécurité d’emploi du rivaroxaban. Une exposition inférieure au rivaroxaban était observée dans les groupes chirurgicaux, toutefois les différences étaient faibles et inférieures à la variabilité interindividuelle rapportée dans la population générale. Enfin, un logiciel libre et gratuit qui permet la personnalisation de ces traitements par approche Bayésienne a été développé, et ses performances ont été validées
The safety and efficacy of direct oral anti-Xa drugs (DOACs) in patients with obesity have been well established in the literature. However, pharmacokinetic data specific to this population are scarce, and data after bariatric surgery are even rarer. A systematic review of population pharmacokinetic models for these DOACs showed that several models for apixaban were applicable to the obese patient population treated for venous thromboembolic disease (VTE). None of the published models for rivaroxaban, however, were applicable to this population. Extrapolations from these models, the values of their pharmacokinetic parameters, or the results of simulations are not valid for the population of obese patients treated with rivaroxaban for VTE. The Phase 1 ABSORB study (NCT04180436) evaluated the pharmacokinetics and safety of full-dose rivaroxaban in patients with obesity and after bariatric surgery (gastric sleeve gastrectomy or gastric bypass). The results of this study indicated that bariatric surgery did not have a clinically significant effect on the pharmacokinetics and safety of rivaroxaban. Lower rivaroxaban exposure was observed in the surgical groups, but the differences were small and below the inter-individual variability reported in the general population. Finally, a free, open-source software package for personalizing these treatments using a Bayesian approach was developed and its performance was validated

Introduzione: gli anticoagulanti orali svolgono un importante ruolo nel ridurre complicanze e mortalità associate ai disturbi tromboembolici. Il Warfarin, un antagonista della vitamina K (AVK), ha rappresentato per 50 anni l’unico farmaco disponibile ed efficace per la profilassi di eventi tromboembolici, i cui limiti sono dati da un monitoraggio dell’INR, da interazioni alimentari e farmacologiche. Tali limiti sono stati superati con i nuovi anticoagulanti orali (NAO), che si somministrano in dosi fisse, non necessitano di monitoraggio continuo, hanno una rapida insorgenza d’azione, un buon profilo di sicurezza, una farmacodinamica ed una farmacocinetica prevedibile, poche interazioni con cibo e farmaci, e sono utilizzati nella terapia anticoagulante orale di quei pazienti con patologie come fibrillazione atriale, cardiopatie dilatative, valvulopatie, malattie tromboemboliche e protesi valvolari cardiache. Si tratta del Dabigatran, inibitore diretto della trombina (fattore IIa), e del Rivaroxaban e Apixaban, inibitori del fattore Xa. È stata riportata una variabilità inter-individuale nelle concentrazioni di farmaco ritrovate nel sangue; in particolare i geni ABCB1 e CES1 esercitano un effetto importante nel metabolismo degli anticoagulanti e varianti alleliche in questi due loci giocano un ruolo determinante sulla suscettibilità del farmaco. Obiettivi: analizzare i polimorfismi su geni coinvolti nel processo metabolico del Dabigatran, Rivaroxaban e Apixaban, in particolare sul gene ABCB1 che codifica per un trasportatore della glicoproteina P (pompa di efflusso ATP-dipendente) per tutti e tre i farmaci e sul gene CES1 che è un enzima metabolizzante carbossilesterasi 1, che interviene nella trasformazione del dabigatran etexilato in forma attiva. Inoltre, determinazione della concentrazione plasmatica dei 3 farmaci prima e dopo assunzione dello stesso. Materiali e Metodi: In una coorte di 92 pazienti in terapia con i dabigatran, 51 con rivaroxaban e71 con apixaban, abbiamo esaminato, attraverso sequenziamento diretto, le varianti geniche del gene ABCB1(rs4148738) per tutti i farmaci e le varianti geniche del gene CES1 (rs8192935 e rs2244613) per i pazienti in dabigatran e determinato la concentrazione plasmatica di valle e di picco dei farmaci stessi, attraverso la tecnica combinata HPLC-spettrometria di massa. Risultati e Conclusioni: Tra i 92 pazienti che assumono dabigatran (età media: 72.0 anni) analizzati, nessuna variabile clinico o genotipo è stata associata con una differenza significativa nelle concentrazioni di picco di dabigatran. Per quanto riguarda le concentrazioni di valle, oltre alla clearance della creatinina, e il sesso è stata rilevata una significativa associazione con i rs8192935 CES1 SNP (p = 0,023). I livelli plasmatici medi aggiustati erano più elevati tra i pazienti con il genotipo CC (86,3 ng / dl) rispetto a quelli che portano l’allele T (62,1 ng / dl). Nessun effetto significativo è stato rilevato per i rs4148738 ABCB1 SNP. Nel caso del Rivaroxaban per entrambe le dosi, non è stato trovato nessun effetto dello SNP ABCB1 sui livelli plasmatici. Per l’Apixaban, invece, è stata rilevata un’associazione con la dose di 10 mg, in particolare una significativa associazione con lo SPN di ABCB1 (p=0,048). Abstract in English Background: the oral anticoagulants play an important role in reducing complications and mortality associated with thromboembolic disorders. Warfarin, a vitamin K antagonist (VKA), represented for 50 years the only drug available and effective for the prophylaxis of thromboembolic events, but it presents the limits, in particular it needs a monitoring of INR, interaction of food and drug. These limits have been exceeded with the new oral anticoagulants (NAO), which are administered in fixed doses, do not require continuous monitoring, they have a rapid onset of action, a good safety profile, pharmacodynamics and pharmacokinetics predictable, few interactions with food and drugs, and are used in the oral anticoagulation therapy for patients with diseases such as atrial fibrillation, dilated heart disease, valvular disease, thromboembolic disease and heart valve prostheses. They are the Dabigatran, direct inhibitor of thrombin (factor IIa), and the rivaroxaban and apixaban, factor Xa inhibitors. It was found an inter-individual variability in drug concentrations found in the blood; especially the ABCB1 and CES1 genes exert an important effect in the metabolism of anticoagulants and allelic variants in these two loci play a decisive role on the susceptibility of the drug. Objectives: to analyze the polymorphisms of genes involved in the metabolic process of dabigatran, rivaroxaban and apixaban, in particular on the ABCB1 gene encoding a transporter P-glycoprotein (ATP-dependent efflux pump) for all three drugs and CES1 gene that is an enzyme carboxylesterase 1, which is involved in the transformation of dabigatran etexilate in active form. Furthermore, we have determined the plasma concentration of 3 drugs before and after intake of the same. Patients/Methods: In a cohort of 92 patients treated with dabigatran, 51 with rivaroxaban and 71 with apixaban, we have examined by direct sequencing, gene variants of the ABCB1 (rs4148738 gene) for all drugs and genetic variants of CES1 gene (rs8192935 and rs2244613) for patients on dabigatran and we have determined the plasma concentration of trough and peak of the drugs, by the combined technique HPLC-mass spectrometry . Results and Conclusion: Among the 92 patients treated with dabigatran (mean age: 72.0 years) analyzed, no clinical variable or genotype was associated with a significant difference in peak concentrations of dabigatran. As for trough concentrations, in addition to creatinine clearance and sex it is found a significant association with rs8192935 SNP CES1 (p=0.023) . The adjusted average plasma levels were higher among patients with the CC genotype (86.3 ng/dl) than those who carry the T allele (62.1 ng/dl). No significant effect was observed for the ABCB1 SNP rs4148738. In the case of rivaroxaban for both doses, it was not found any of the ABCB1 SNP effect on plasma levels. For the apixaban, instead, an association has been detected with the dose of 10 mg, in particular a significant association with the SPN of the ABCB1 (p = 0.048).

Objective: The primary objective of this study was to estimate the long-term cost-effectiveness of stroke prevention in patients with nonvalvular atrial fibrillation (NVAF) in the United States using new anticoagulant therapies - dabigatran 150 mg, apixaban 5 mg, and rivaroxaban 20 mg - as well as the standard treatment, warfarin. Methods: A Markov decision-analysis model was constructed using data from clinical trials that evaluated the new oral anticoagulants relative to warfarin (apixaban 5 mg & ARISTOTLE, dabigatran 150 mg & RE-LY, and rivaroxaban 20 mg & ROCKET-AF) to compare the lifetime cost and quality-adjusted life expectancy. The Markov model target population was a hypothetical cohort of 70-year old patients with nonvalvular atrial fibrillation, an increased risk for stroke (CHADS₂ ≥ 1, or equivalent), a renal creatinine clearance (CrCl) of 50 or above, and no contraindication to anticoagulant therapy. Using pair-wise comparisons of each therapy, analyses were conducted to evaluate incremental cost-effectiveness ratios (ICERs), net monetary benefits (NMBs), lifetime costs, life-years, and quality-adjusted life-years (QALYs). Results: In the base case, warfarin had the lowest cost of $71,857 (95% confidence interval [CI]: $68,730, $77,452), followed by rivaroxaban 20 mg ($74,023; 95% CI: $70,943, $77,307), dabigatran 150 mg ($78,584; 95% CI: $75,277, $81,968), and apixaban 5 mg ($81,180; 95% CI: $78,642, $83,756). Apixaban 5 mg also yielded the highest QALY estimate, 8.63 (95% CI: 8.52, 8.72), followed by dabigatran 150 mg (8.55; 95% CI: 8.43, 8.67), rivaroxaban 20 mg (8.42; 95% CI: 8.31, 8.54), and warfarin (8.17; 95% CI: 8.1, 8.24). In a Monte Carlo probabilistic sensitivity analysis, apixaban 5 mg, dabigatran 150 mg, rivaroxaban 20 mg, and warfarin were cost effective in 45%, 37%, 19%, 0%, respectively, of the simulations using a willingness-to pay threshold of $50,000 per QALY gained. From the one-way sensitivity analyses, new anticoagulant (apixaban 5 mg, dabigatran 150 mg, rivaroxaban 20 mg) costs and probabilities associated with intracranial hemorrhage and stroke for patients receiving rivaroxaban 20 mg were identified as significant influential variables impacting model results. Conclusion: In patients with NVAF and an increased risk of stroke prophylaxis, apixaban 5 mg, dabigatran 150 mg, and rivaroxaban 20 mg may all be cost-effective alternatives to warfarin depending on pricing in the United States and neurologic events for rivaroxaban 20 mg.

Apixaban och lågmolekylärt heparin (LMH) är antikoagulantia som förhindrar blodproppsbildning genom att hämma faktor Xa. Allt mer patienter använder apixaban och LMH, vilket gör att laboratoriemedicin på länssjukhuset Ryhov är i behov av att utvärdera analysmetoder för apixaban och LMH för att kunna implementera analyserna i klinisk rutin. Syftet med studien var att utvärdera analysmetoden för bestämning av anti-FXa aktivitet i plasma hos patienter behandlade med apixaban eller LMH med hjälp av kromogen substratmetod. Metodutvärderingen bestod av fyra steg: repeterbarhet, mellanliggande precision, överensstämmelse med validerad metod och analys av normalpopulation. Utvärderingen genomfördes med hjälp av Sysmex CS-2100 där det analyserades 20 respektive 40 patientprover för apixaban och LMH samt 10 normalprover. Aktivitet av faktor Xa bestämdes kvantitativt med användning av ljusabsorption vid 405 nm. Repeterbarhet och mellanliggande precision visade låg CV. Patientprover visade överensstämmande resultat med referensvärden från andra laboratorium där r2 för apixaban och LMH var 0,95. Avvikande resultat kan bero på mätfel eller förväxling mellan prover. Analys av normalpopulation visade att värden låg under det lägsta tillförlitliga värdet. Utvärdering av analysmetoden apixaban och LMH på Ryhovs laboratorium visade goda resultat vilket bekräftar att analysmetoden kan användas i klinisk rutin.
Introduction: Apixaban and low molecular weight heparin (LMWH), are anticoagulants that prevent clot formation by inhibiting factor Xa. Increasingly more patients use apixaban and LMWH, for this reason the laboratory medicine at the county hospital Ryhov needs to evaluate methods of analysis for apixaban and LMWH to be able to implement the analyzes in clinical routine. Aim: The purpose of the study was to evaluate the assay method for determining anti-FXa activity in plasma in patients treated with apixaban or LMWH using chromogenic substrate method. Method: The method evaluation consisted of four steps: repeatability, intermediate precision measures, compliance with validated method and analysis of normal population. The evaluation was performed using Sysmex CS-2100 where 20 respective 40 patient samples were analyzed for apixaban and LMWH as well as 10 normal population samples. Factor Xa activity was quantitatively determined using light absorption at 405 nm.Result and discussion: Repeatability and intermediate precision showed low CV. Patient samples showed consistent results with reference values from other laboratories where r2 for apixaban and LMWH were 0.95. Deviant results may be due to measurement errors or confusion between samples. Analysis of normal population showed that values were below the lowest reliable value. Conclusion: Evaluation of the analysis method apixaban and LMWH at Ryhov's laboratory showed good results, which confirms that the assay method can be used in clinical routine.

Apixabana é um novo fármaco da classe dos anticoagulantes orais utilizado na prevenção e no tratamento de eventos de tromboembolismo venoso em pacientes submetidos à cirurgia de quadril e joelho, além de reduzir os riscos de acidente vascular cerebral e fibrilação arterial. Uma vez que impurezas e contaminantes podem estar presentes no produto farmacêutico final, as agências regulatórias preveem leis para monitorar essas substâncias. O conceito de Quality by Design (QbD), uma abordagem sistemática que inicia com objetivos pré-definidos e análise de risco, está sendo amplamente utilizado no âmbito farmacêutico para desenvolver formulações e metodologias analíticas. Sendo assim, este trabalho almejou desenvolver e validar um método indicativo de estabilidade simples, rápido e sensível utilizando cromatografia líquida de alta eficiência (CLAE) para determinação simultânea da apixabana e três impurezas sintéticas aplicando a abordagem QbD. O desenho experimental foi feito através do software MODDE® 11 (Umetrics, Suíça) e executado utilizando um cromatógrafo Shimadzu® LC-20A Prominence CLAE-DAD com detecção a 220 nm. O método cromatográfico foi estabelecido utilizando uma coluna Inertsil® CN-3 (150 × 4,6 mm, 5,0 μm) com temperatura do forno de 30°C e volume de injeção de 10 μL. A constituição da fase móvel foi metanol e água (50,2:49,8) com fluxo de 1,015 mL/min sem ajuste de pH. O método foi validado seguindo as guias do ICH e da ANVISA, sendo considerado específico, sensível, linear (r > 0,999), preciso (DPRs < 10% para as impurezas) e exato. Para especificidade, foi realizada busca de produtos de degradação submetendo os comprimidos de apixabana a condições de estresse (radiação UVC, temperatura, oxidação e hidrólise). As substâncias envolvidas no presente trabalho também foram caracterizadas quimicamente e avaliadas quanto ao seu perfil toxicológico in vitro através dos ensaios de MTT e vermelho neutro. A mistura da APX e suas impurezas demonstrou toxicidade aguda, porém este resultado não se manteve durante a exposição prolongada, sugerindo um mecanismo de compensação mitocondrial. Já a impureza 3 apresentou danos significativos em 96 horas de exposição, de modo que mais estudos devem efetuados para avaliar sua toxicidade.
Apixaban is a novel anticoagulant agent used to prevent and treat venous thromboembolic events in adults who have undergone total hip or knee replacement surgery and to lower the risk of stroke in patients with atrial fibrillation. As impurities and contaminants may be present in the pharmaceutical product, current regulatory guidelines recommend monitoring such substances. The concept of Quality by Design (QbD), a systematic approach that begins with predefined objectives and risk management, is being widely used in the pharmaceutical field to develop new formulations and analytical methods. Thus, the aim of this work was to develop and validate a simple, fast and sensitive stability indicating method by high-performance liquid chromatography (HPLC) for the simultaneous determination of apixaban and three synthesis impurities using QbD approach. Experiments were designed and assessed on MODDE® 11 (Umetrics, Sweden) software and carried out in a Shimadzu® LC-20A Prominence HPLC-DAD at 220 nm. The HPLC method was established using an Inertsil® CN-3column (150 × 4.6 mm, 5.0 μm) at the temperature of 30°C and injection volume of 10 μL. The mobile phase consisted of methanol and water (50.2:49.8) at a flow rate of 1.015 mL/min with no pH adjustment. Validation of the method was conducted according to ICH and ANVISA Guidelines, which was considered specific, sensitive, linear (r > 0,999), precise (RSD < 10% for impurities) and accurate. For specificity, a degradation study was performed by exposing apixaban tablets to stress conditions (UVC radiation, temperature, oxidation and hydrolysis). The related substances in the present study were also chemically characterized and toxicological profile was evaluated by in vitro tests MTT and neutral red. The mixture of APX and its impurities showed acute toxicity, but this result did not persist during prolonged exposure, suggesting a mitochondrial compensation mechanism. Yet, impurity 3 presented significant damages in 96 hours of exposure and further studies should be considered to evaluate its toxicity.

Background: The risk of ischaemic stroke in patients with atrial fibrillation (AF) and mechanical heart valve (MHV) prostheses can be reduced by oral anticoagulation (OAC), which increases the risk of serious bleeding. The aims of this thesis were [1] to find out how effective and safe warfarin is where treatment quality is high, i.e. Sweden, with proportion of time that patients spend within the therapeutic range (TTR) >70%, [2] whether there is evidence for administering low-molecular-weight heparin (LMWH) during temporary interruptions of OAC (bridging therapy), and whether non-vitamin K-dependent oral anticoagulants (NOACs) as a group, [3] or individually, [4] are more effective and safer than warfarin when used for stroke prevention in patients with AF. Materials and methods: All four studies were retrospective, based on the Swedish anticoagulation register Auricula, and done with merging of data from some or all of the National Patient Register, the Prescribed Drug Register, the Swedish Stroke Register (Riksstroke), and the Cause of Death Register. In studies 2–4, propensity score matching was performed to obtain treatment groups with similar risk profiles. Outcomes were defined as haemorrhages or thromboses requiring specialist care, or death. Haemorrhages were intracranial, gastrointestinal, or other. Thromboses were ischaemic stroke, systemic embolism, myocardial infarction, or venous thromboembolism (VTE). Study 1 described all patients on warfarin during 2006–2011, which was before the introduction of NOACs. Study 2 was a cohort study of all patients who had a planned interruption of warfarin during the same period. Study 3 included all 49,011 patients starting OAC for stroke prevention due to AF between 1 July 2011 and 31 December 2014, and study 4 all 64,382 patients with the same indication between 1 January 2013 and 31 December 2015. Results: Study 1 showed that for the 77,423 patients on warfarin with 217,804 treatment years, TTR was 77.4% for patients with AF, 74.5% with MHV, and 75.9% with VTE. Annual rates of intracranial bleeding were 0.38%, 0.51%, and 0.30%. In study 2, with 14,556 warfarin interruptions, the 30-day risk of a bleeding requiring specialist care was 0.64% for LMWH treated and 0.46% for controls. For patients with VTE as indication for OAC, bleeding rate with LMWH was significantly higher at 0.85% vs. 0.16% (hazard ratio 5.24, 95% confidence interval 1.39–19.77), but with no difference for patients with MHV or AF. The incidence of ischaemic complications was higher in the LMWH bridging group overall and for patients with MHV and AF, but not for patients with VTE. In study 3, for the 12,694 patients starting NOAC (10,392 treatment years) or matched warfarin patients (9,835 treatment years, TTR 70%) due to AF, annual incidence of ischaemic stroke and systemic embolism did not differ between the groups (1.35% vs. 1.58%), but risks of major bleedings and intracranial bleedings were significantly lower: 2.76% vs. 3.61% and 0.40% vs. 0.69%. In study 4, patients on individual NOACs (6,574 dabigatran, 8,323 rivaroxaban, 12,311 apixaban) were compared to 37,174 patients starting warfarin (in total 81,176 treatment years). No NOAC showed any difference in risk of ischaemic stroke or systemic embolism, but there were fewer intracranial bleedings, serious bleedings overall, and deaths for dabigatran and apixaban compared to warfarin. For patients starting rivaroxaban the risk of gastrointestinal bleeding was higher than for matched warfarin counterparts, with no significant differences in other bleeding risks, or mortality. Conclusions: Swedish warfarin treatment shows TTR levels that are high by international standards, correlating to low incidences of ischaemic and haemorrhagic events. LMWH bridging has not been proven beneficial, even for patients with MHV, meaning that bridging in general cannot be recommended. NOACs as a group were safer than high-quality warfarin treatment. Efficacy did not differ, even when comparing individual NOACs to warfarin, but there were fewer bleedings on dabigatran and apixaban. Although not more efficient than warfarin with a high TTR, NOACs should be the recommended first choice for OAC in AF, on the merit of lower bleeding risks.

Finansiär: Forskning och Utveckling, Region Västernorrland

Trois essais cliniques ARISTOTLE, RE-LY et ROCKET-AF, sont réalisés sur les quatre nouveaux anticoagulants oraux qui sont l’Apixaban, le Dabigatran 110mg, Dabigatran 150mg et le Rivaroxaban, afin d’améliorer la prise en charge de la fibrillation auriculaire (FA). Ils ne permettent pas de déterminer la meilleure option thérapeutique. L’objectif de cette thèse est de développer une approche d’aide multicritère à la décision pour la problématique du choix thérapeutique appliquée au cas de la FA afin d’évaluer ces quatre options thérapeutiques médicamenteuses. La méthodologie d’aide multicritère développée, PROMETHEE-GAIA appliquée à la FA permet de comparer ces quatre nouveaux anticoagulants (l’Apixaban, le Dabigatran 110mg, Dabigatran 150mg et le Rivaroxaban) en se basant sur les cinq critères essentiels élaborés selon un processus de concertation cadrée, qui sont l’efficacité, la sécurité, la fonction rénale, l’observance et le prix. Les résultats de l’évaluation de ces quatre nouveaux anticoagulants est un classement de ces options thérapeutiques par leur ordre de performance dans la prise en charge des patients de la FA selon ces cinq critères en considération.

BACKGROUND:Anticoagulation with vitamin K antagonists such as warfarin has historically been used for the long term management of patients with thromboembolic disease. However, these agents have a slow onset of action which requires bridging therapy with heparin and its analogues, which are available only in parenteral route. To overcome these limitations, new oral anticoagulants such as factor Xa inhibitors and direct thrombin inhibitors have been developed. The aim of this article is to systematically review the phase 3 clinical trials of new oral anticoagulants in common medical conditions.METHODS:We searched PubMed (Medline) from January 2007 to February 2013 using "Oral anticoagulants", "New oral anticoagulants", "Randomized controlled trial", "Novel anticoagulants", "Apixaban", "Rivaroxaban", "Edoxaban", "Dabigatran etexilate", "Dabigatran" and a combination of the above terms. The available evidence from the phase 3 RCTs was summarized on the basis of individual drug and the medical conditions categorized into "atrial fibrillation", "acute coronary syndrome", "orthopedic surgery", "venous thromboembolism" and "medically ill patients".RESULTS:Apixaban, rivaroxaban and dabigatran have been found to be either non-inferior or superior to enoxaparin in prophylaxis of venous thromboembolism in knee and hip replacement with similar bleeding risk, superior to warfarin for stroke prevention in atrial fibrillation with significant reduction in the risk of major bleeding, non-inferior to aspirin for reducing cardiovascular death and stroke in acute coronary syndrome with significant increase in the risk of major bleed. Rivaroxaban and dabigatran are also superior to the conventional agents in the management of symptomatic venous thromboembolism. However, compared to enoxaparin, apixaban and rivaroxaban use lead to significantly increased bleeding risk in medically ill patients. Additional studies evaluating the specific reversal agents of these new drugs for the management of life-threatening bleeding or other adverse effects are necessary.CONCLUSION:Considering their pharmacological properties, their efficacy and bleeding complications, the new oral agents offer a net favourable clinical profile in orthopedic surgery, atrial fibrillation, acute coronary syndrome and increase the risk of bleeding in critically ill patients. Further studies are necessary to determine the long term safety and to identify the specific reversal agents of these new drugs.

Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Bc. Ladislava Cablíková Supervisors: Ass. Prof. Mojca Božič-Mijovski, Ph.D., prof. PharmDr. Petr Pávek, Ph.D., RNDr. Jana Nekvindová, Ph.D. Thesis title: The Impact of Apixaban on Overall Hemostatic Potential Disorders at certain levels of the complicated haemostatic system can lead to either bleeding or excessive blood coagulation. These pathological conditions are treated with anticoagulants, which aim to correct excessive coagulation. However, traditional anticoagulant therapy has many limitations, which initiated efforts to develop oral anticoagulants with a better profile. These new-generation anticoagulants are called DOAC - Direct Oral AntiCoagulans. Apixaban, as one of xabans, has predictable pharmacokinetics and pharmacodynamics and therefore does not require a routine laboratory monitoring of the treatment effect. Nevertheless, it still requires evaluation in urgent clinical situations. Standard coagulation screening assays, e.g., PT (prothrombin test) and APTT (activated partial thromboplastin test), do not fully reflect the actual status of the drug. Therefore, researchers aim is to find a relatively simple and fast hemostatic assay that would correlate with the actual condition...

Relatório de Estágio do Mestrado Integrado em Ciências Farmacêuticas apresentado à Faculdade de Farmácia
Os novos anticoagulantes orais vieram revolucionar a terapêutica anticoagulante oral, que até então era baseada nos antagonistas da vitamina K. As limitações apresentadas por este último grupo de fármacos foi o fator que desencadeou o desenvolvimento dos inibidores diretos dos fatores da coagulação. Contrariamente aos antagonistas da vitamina K, estas novas moléculas têm como alvo terapêutico um fator específico da cascata da coagulação. Em Portugal, estão já aprovados e comercializados quatro fármacos: o apixabano, o edoxabano, o rivaroxabano e o dabigatrano etexilato. Estes novos anticoagulantes, para além de apresentarem uma margem terapêutica mais alargada e, consequentemente um perfil de segurança mais favorável, apresentam um perfil farmacocinético e farmacodinâmico mais previsível. Por conseguinte, estes fármacos carecem de monitorização regular, contrariamente ao que sucede com os antagonistas da vitamina K. No entanto, é de ressalvar que em determinadas situações clínicas é fundamental a monitorização da atividade anticoagulante destes fármacos, como é o caso de hemorragias potencialmente fatais e de intervenções cirúrgicas de urgência. Apesar de os testes da coagulação mais comummente usados estarem prolongados com a administração destes fármacos, não traduzem os seus efeitos farmacodinâmicos. Estão a ser levados a cabo estudos com o intuito de definir testes de coagulação que permitam uma monitorização adequada. Também nas situações referidas poderá haver necessidade de administrar um agente de reversão. Atualmente, já se encontra comercializado o primeiro agente de reversão específico para o dabigatrano, o idarucizumab. O andexanet alfa aguarda aprovação e o ciparantag encontra-se em ensaios clínicos.O Relatório de Estágio Curricular diz respeito ao estágio realizado em Farmácia Comunitária, tomando a forma de uma análise SWOT.
The new oral anticoagulants came to revolutionize oral anticoagulant therapy, which until now was based on vitamin K antagonists. The limitations presented by this last group of drugs was the factor that triggered the development of direct inhibitors of coagulation factors. Unlike vitamin K antagonists, these novel molecules target a specific coagulation cascade factor.In Portugal, four drugs have already been approved and marketed: apixaban, edoxaban, rivaroxaban and dabigatran etexilate. These new anticoagulants, in addition to having a wide therapeutic window and consequently a more favorable safety profile, present a more predictable pharmacokinetic and pharmacodynamic profile. Therefore, these drugs lack regular monitoring, contrary to what happens with the vitamin K antagonists. However, it is important to note that in certain clinical situations, monitoring of the anticoagulant activity of these drugs is essential, as is the case of potentially fatal bleeding and emergency surgery. Although the most commonly used coagulation tests are prolonged with the administration of these drugs, they do not translate their pharmacodynamic effects. Studies are being carried out to establish coagulation tests that allow adequate monitoring. Also in such situations it may be necessary to administer a reversal agent. Currently, the first specific reversal agent for dabigatran, idarucizumab, has been approved. Andexanet alfa is awaiting approval and ciparantag is in clinical trials.The Internship Report refers to the community pharmacy internship, taking the form of a SWOT analysis.

Relatório de Estágio do Mestrado Integrado em Ciências Farmacêuticas apresentado à Faculdade de Farmácia
Os Anticoagulantes orais diretos (DOACs) são os medicamentos de primeira linha usados no tratamento do tromboembolismo venoso e na prevenção de acidentes vasculares cerebrais em doentes com fibrilação auricular, sobretudo porque os DOACs não requerem a monitorização bioquímica tipicamente obrigatória para a varfarina e porque apresentam tempos de meia-vida mais curtos e início de ação mais rápido. Uma vez que estudos recentes na população real evidenciaram uma maior prevalência de efeitos secundários comparativamente aos que estavam previstos nos Ensaios clínicos iniciais, a monitorização plasmática dos DOACs está a começar a ser cada vez mais utilizada de modo a permitir uma personalização da farmacoterapia de acordo com as características individuais do doente e de modo a avaliar a adesão à terapêutica. Para satisfazer as necessidades clínicas mencionadas previamente, estão disponíveis ensaios de coagulação específicos que determinam indiretamente a concentração de DOACs, no entanto estes não são suficientemente precisos e sensíveis. Na verdade, as técnicas de cromatografia líquida, sobretudo associadas à deteção de espetrometria massa, são atualmente consideradas os métodos mais adequados para determinar as concentrações plasmáticas dos DOACs com precisão adequada. Deste modo, esta monografia tem como objetivo fornecer pela primeira vez uma revisão dos métodos analíticos desenvolvidos e validados até à presente data, para a determinação quantitativa do apixabano, dabigatrano, edoxabano, rivaroxabano bem como os seus metabolitos principais em amostras biológicas. Será dado um maior enfase aos métodos cromatográficos e às principais dificuldades sentidas durante a otimização e validação das várias etapas. Para além disso, as caraterísticas físico-químicas, a farmacocinética e a farmacodinâmica dos vários fármacos serão relacionadas com as condições cromatográficas aplicadas, assim como a sua influência nos procedimentos de pré-tratamento da amostra e nas condições de armazenamento dos DOACs, sugerindo estratégias de otimização dos métodos de quantificação dos DOACs.
Direct oral anticoagulant drugs (DOACs) are the first-line drugs used on the treatment of venous thromboembolism and prevention of stroke in patients with atrial fibrillation particularly because DOACs do not require the regular biochemical monitoring that is mandatory for warfarin, and they exhibit shorter half-lives and a faster onset of action. Since recent real-world studies evidence higher prevalence of adverse side effects than it was anticipated in clinical trials, monitoring plasma concentrations of DOACs is starting to be used for personalizing their pharmacotherapy in accordance to individual characteristics and to assess therapy adherence. To attain the aforementioned clinical unmet need, there are specific coagulation assays available that indirectly assess the plasma concentrations of DOACs, however they are not sufficiently accurate or sensitive. Indeed, liquid chromatography techniques, mainly coupled with mass spectrometry detection, are considered the gold standard methods to accurately assess DOACs plasma concentrations. Therefore, the present paper aims at providing, for the first time, a comprehensive review of the current analytical methods that were developed and validated for the quantitative determination of apixaban, dabigatran, rivaroxaban and/or edoxaban and their main metabolites in biological samples. The chromatographic methods will be particularly highlighted and an emphasis will be placed on the major difficulties faced during optimization and development steps. In addition, physicochemical characteristics, pharmacokinetics and pharmacodynamics of each drug will be herein critically related with the employed chromatographic conditions as well as their influence on pre-treatment procedures and storage conditions of DOACs, suggesting strategies that should be employed to accurately quantify DOACs in biological samples.

Orientação: Ana Mirco
Os novos anticoagulantes orais são opções emergentes para a prevenção e tratamento das doenças tromboembólicas. São cada vez mais usados na prática clínica pela facilidade do seu uso e pelos seus benefícios clínicos mas a sua utilização mais generalizada carece de demonstração de custo efetividade. O objectivo consistiu na realização de uma revisão sistemática dos estudos de custo-efetividade dos novos anticoagulantes orais, dabigatrano, rivaroxabano e apixabano, em todas as suas indicações clínicas e descrever os resultados principais. Foi realizada uma revisão sistemática da literatura nas bases de dados Pubmed, Embase, Scopus, Cochrane e Web of Knowledge, para identificar todos os estudos de custo-efetividade dos novos anticoagulantes orais em todas as suas indicações clínicas. A pesquisa selecionou 42 estudos, 15 relacionados com a tromboprofilaxia na artroplastia total da anca ou na artroplastia total do joelho e 27 na prevenção do acidente vascular cerebral na fibrilhação auricular. Não foram identificados estudos para as indicações de tratamento e prevenção secundária do tromboembolismo venoso ou para a prevenção secundária após síndromes coronários agudos. Os resultados principais incluíram os rácios custo-efetividade incremental por anos de vida ajustados pela qualidade, comparações com o limite pré-fixado à disponibilidade a pagar e análises de sensibilidade que revelaram custo-efetividade ou dominância dos novos anticoagulantes orais. A presente revisão sistemática demonstra que os novos anticoagulantes orais são custo-efetivos para a tromboprofilaxia em cirurgia ortopédica major e para a prevenção do acidente vascular cerebral na fibrilhação auricular.
Novel oral anticoagulants are emerging options for the prevention and treatment of thromboembolic diseases. They are increasingly used in clinical practice due to simplicity of use and clinical benefits but an important step is to evaluate their cost-effectiveness. We aimed to perform a systematic review of cost-effectiveness studies of novel oral anticoagulants, dabigatran, rivaroxaban and apixaban, in all their clinical indications and describe key findings. A systematic review of the literature was conducted searching Pubmed, Embase, Scopus, Cochrane and Web of Knowledge databases to identify all cost-effectiveness studies of novel oral anticoagulants in all their clinical indications. The research selected 42 studies, 15 related to thromboprophylaxis in total hip arthroplasty or total knee arthroplasty and 27 to stroke prevention in non-valvular atrial fibrillation. No studies were identified for the indications of treatment and secondary prevention of venous thromboembolism or for the secondary prevention after acute coronary syndromes. Key findings included incremental cost-effectiveness ratios per quality-adjusted life-years, comparisons with appropriate willingness-to-pay thresholds and sensitivity analysis that revealed cost-effectiveness or dominance for the novel oral anticoagulants. This present systematic review demonstrates that novel oral anticoagulants are cost-effective for the thromboprophylaxis in major orthopedic surgery and for stroke prevention in atrial fibrillation.

Sendo o farmacêutico um profissional de saúde muito próximo da população e que integra equipas multidisciplinares, o Mestrado Integrado em Ciências Farmacêuticas está organizado de forma a permitir o contacto dos futuros farmacêuticos com as principais vertentes da profissão. Assim, o presente trabalho divide-se em três capítulos: Capítulo I – projeto de investigação desenvolvido; Capítulo II e III – relatórios dos estágios em farmácia hospitalar e comunitária, respetivamente. No Capítulo I foi feita uma abordagem sobre os novos anticoagulantes orais, de forma a expor as vantagens dos inibidores da trombina (dabigatrano) e do fator Xa (rivaroxabano, apixabano e edoxabano). Estes são administrados por via oral, em doses fixas, sem haver necessidade de monitorização regular e apresentam poucas interações medicamentosas. Por estes motivos começaram a ser considerados uma alternativa viável à varfarina – anticoagulante mais prescrito. Os ensaios clínicos publicados compararam cada um dos fármacos às terapêuticas convencionais. Os resultados revelam uma eficácia equivalente na prevenção de acidentes vasculares cerebrais e tromboembolismos e um perfil de segurança bastante favorável, notando-se que, em alguns casos, os novos anticoagulantes causam menos hemorragias. Foi objetivo deste trabalho, também, o estudo das prescrições dos novos fármacos em doentes internados no Centro Hospitalar Universitário Cova da Beira, sendo possível afirmar que a sua utilização é crescente e ultrapassou o consumo de varfarina, no período de estudo. O Capítulo II relata as diferentes funções do farmacêutico em meio hospitalar, desempenhadas no estágio no Centro Hospitalar de Trás-os-Montes e Alto Douro, desde dia 22 de janeiro a 16 de março. Como futura profissional, o contacto com o ambiente hospitalar foi importante para aprofundar conhecimentos acerca de terapias farmacológicas específicas e exclusivas de hospitais. No Capítulo III são descritas as ações desenvolvidas enquanto estagiária na Farmácia Barreira, durante o período de 19 de março a 1 de junho. Estas permitiram-me percecionar a relevância da interação farmacêutico-utente e do acompanhamento das terapêuticas, tendo sempre presente o espírito de missão e humanidade que a profissão acarreta.
Being the pharmacist a health professional in close contact with the population and integrated in multidisciplinary teams, the Integrated Master’s Degree in Pharmaceutical Sciences is organized to allow the contact of future professionals with the main dimensions of the profession. Therefore, this work is divided in three chapters: Chapter I – investigation project carried out; Chapters II and III – internship reports in hospital and community pharmacy, respectively. In Chapter I, an approach to novel oral anticoagulants has been made, in order to show the advantages of the thrombin inhibitors (dabigatran) and factor Xa (rivaroxaban, apixaban and edoxaban). These are administered orally, in fixed doses, without the need for regular monitoring and they present few drug interactions. For these reasons, they started to be considered a viable alternative to warfarin – the most prescribed anticoagulant. The published clinical trials compare each of the drugs to conventional therapeutics. The results reveal an equivalent efficiency in the prevention of stroke and thromboembolisms and a quite favourable security profile showing that, in some cases, the novel anticoagulants cause fewer bleedings. The study of the prescription of these new medicines in the Centro Hospitalar Universitário da Cova da Beira was also a goal of this work and it is possible to say that its use is increasing and has exceeded the consumption of warfarin, in the period studied. Chapter II describes the different duties of the pharmacist in hospital setting, carried out during the internship in the Centro Hospitalar de Trás-os-Montes e Alto Douro, from January 22nd to March 25th. As a future professional, the contact with hospital environment was important to deepen knowledge about specific pharmaceutical therapies exclusive to hospitals. In Chapter III are described the activities undertaken as a trainee at Farmácia Barreira during the period between March 19th and June 1st. These activities allowed me to realize the relevance of the interaction pharmacist-user and therapy follow up, always bearing in mind the sense of commitment and humanity that the profession entails.

Os novos anticoagulantes orais representam uma inovação terapêutica anticoagulante, tendo obtido recentemente aprovação para várias indicações clínicas. A varfarina foi um dos primeiros anticoagulantes orais a ser desenvolvido, no entanto acarreta inúmeras inconveniências tais como, interações medicamentosas e alimentares, margem terapêutica reduzida, monitorização frequente e variações de resposta entre indivíduos, que comprometem a eficácia do tratamento. Consequentemente, foi necessário investigar outras alternativas surgindo assim os novos anticoagulantes orais, dabigatrano, apixabano e rivaroxabano que detêm menos limitações e a mesma eficácia que os AVK. Estes anticoagulantes são eficientes na profilaxia e tratamento tromboembolismo venoso e na prevenção de AVC em pacientes com fibrilação auricular, contudo também apresentam as suas desvantagens como custo elevado e ausência de antídoto específico. Nesta revisão bibliográfica serão abordadas as propriedades farmacológicas, mecanismos de ação, vantagens e desvantagens, custos terapêuticos dos anticoagulantes clássicos e novos anticoagulantes, sendo feita uma comparação entre estes de modo a perceber qual será a melhor opção terapêutica.
The new oral anticoagulants represent an innovation in anticoagulant therapy, which has been recently approved for various clinical indications. Warfarin was the first oral anticoagulants to be developed, however entails numerous drawbacks such as drug and food interactions, narrow therapeutic index, frequent monitoring and interindividual response variations that compromise the effectiveness of treatment. Consequently, it was necessary to investigate other alternatives that lead to the discover of new oral anticoagulants, dabigatran, rivaroxaban and apixaban who hold fewer limitations and the same efficacy as the AVK. These anticoagulants are effective in the treatment and prevention of venous thromboembolism and for the prevention of stroke in patients with atrial fibrillation, but also have their disadvantages such as high cost and lack of specific antidote. In this literature review the pharmacological properties will be addressed as well as mechanisms of action, advantages and disadvantages, therapeutic costs of classic and new anticoagulants and a comparison between them in order to understand what the best treatment option is.