Trastuzumab deruxtecan in breast cancer.

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) consisting of a humanised, anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody covalently linked to a topoisomerase I inhibitor cytotoxic payload (DXd). The high drug-to-antibody ratio (8:1) ensures a high DXd concentration is delivered to target tumour cells, following internalisation of T-DXd and subsequent cleavage of its tetrapeptide-based linker. DXd's membrane-permeable nature enables it to cross cell membranes and potentially exert antitumour activity on surrounding tumour cells regardless of HER2 expression. T-DXd's unique mechanism of action is reflected in its efficacy in clinical trials in patients with HER2-positive advanced breast cancer (in heavily pretreated populations and in those previously treated with a taxane and trastuzumab), as well as HER2-low metastatic breast cancer. Thus, ADCs such as T-DXd have the potential to change the treatment paradigm of targeting HER2 in metastatic breast cancer, including eventually within the adjuvant/neoadjuvant setting.

Do we really know if they are in pain? A cross-sectional study in hospitalised adult patients in Spain.

AIMS: To describe the prevalence and characteristics of pain in adult hospitalised patients, as well as to analyse the concordance between patient-reported and recorded pain and its impact on analgesic management. DESIGN: A cross sectional study. METHODS: The study was performed on a sample of 611 patients, from October to December 2017. Data were obtained from patient interviews, review of medical and nursing records and review of electronic prescribing. RESULTS: The prevalence of pain at the time of the interview was 36.7%. The median VAS score was 4. 90% of the patients had their pain assessed within the last 24 h; however, concordance between patient-reported pain and recorded pain in the nursing record was slight. CONCLUSION: Pain is still often documented inadequately. Despite the wide use of analgesics, half of the patients with moderate to severe pain do not have adequate pain management. A systematic assessment and recording of pain promotes appropriate analgesic prescription. IMPLICATIONS FOR THE PROFESSION AND PATIENT CARE: The findings of our study provide insight into the main gaps in the correct management of pain in hospitalised patients. A systematic assessment and recording of the pain suffered by the patient facilitates its control and allows a better management of the analgesic prescription by the physician. This information could help hospital managers to develop training programmes on pain assessment and on the importance of doctor-nurse collaboration to improve pain management, increasing the quality of care and reducing hospital costs. REPORTING METHOD: The study has adhered to the relevant EQUATOR guidelines, according to The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.

Utilización de medicamentos off-label y unlicensed en una unidad de cuidados intensivos pediátricos de un hospital de alta complejidad español. Estudio descriptivo / Off-label and unlicensed drug use in a pediatric intensive care unit of a tertiary care Spanish hospital. A descriptive study

Introducción. En las unidades de cuidados intensivos pediátricos, se utiliza gran cantidad de medicamentos, muchos prescritos fuera de las condiciones establecidas en su ficha técnica (prescripciones off-label y unlicensed). El objetivo de este estudio fue describir el uso de medicamentos y estimar la prevalencia de fármacos off-label y unlicensed en una unidad de cuidados intensivos pediátricos de un hospital de tercer nivel español. Población y métodos. Estudio transversal, observacional, de una cohorte de niños ingresados en una unidad de cuidados intensivos pediátricos. El estudio se llevó a cabo en 2017. Se revisó cada fármaco prescrito, sus condiciones de uso y administración. Además, se analizaron las fichas técnicas de los fármacos implicados con la finalidad de identificar si el uso de los medicamentos se realizaba según sus condiciones de autorización, o bien se hacía fuera de prospecto (off-label) o como unlicensed. Resultados. La muestra fue de 97 pacientes. El 74,2 % (n = 72) de los pacientes recibieron algún fármaco off-label o unlicensed. El 23,8 % (n = 243) de las prescripciones fueron off-label y el 8,7 % (n = 89), unlicensed. El subanálisis realizado por grupos de edad mostró que el grupo de edad que recibió mayor número de prescripciones totales (n = 611) y el mayor porcentaje de fármacos prescritos en condiciones off-label y/o unlicensed (38,4 %) fue el de menores de 2 años. Conclusiones. La prescripción de fármacos off-label y/o unlicensed es una práctica habitual en la unidad de cuidados intensivos pediátricos. Este estudio permite documentar la complejidad de la terapéutica en niños.

Introduction. In pediatric intensive care units, a large number of drugs are used, many of which are prescribed for condition beyond those established in their summary of product characteristics (off-label and unlicensed drug prescriptions). The objective of this study was to describe drug use and estimate the prevalence of off-label and unlicensed drugs in a pediatric intensive care unit of a tertiary care Spanish hospital. Population and methods. Cross-sectional, observational study with a single cohort of children admitted to a pediatric intensive care unit. The study was conducted in 2017. Each drug prescription, its conditions of use and administration were reviewed. In addition, the summary of product characteristics of drugs used were analyzed in order to identify whether they were used according to their conditions of authorization, or whether they were used in an off-label or unlicensed manner. Results. The sample included 97 patients. At least one off-label or unlicensed drug was administered to 74.2% (n = 72) of patients; 23.8% (n = 243) corresponded to off-label prescriptions and 8.7% (n = 89), unlicensed prescriptions. A sub-analysis by age group showed that the age group that received a higher number of total prescriptions (n = 611) and a higher percentage of off-label and/or unlicensed drug prescriptions (38.4%) was under 2 years of age. Conclusions. Off-label and/or unlicensed drug prescription is a common practice in the pediatric intensive care unit. This study allowed us to document the complexity of therapeutics in children.

Off-label and unlicensed drug use in a pediatric intensive care unit of a tertiary care Spanish hospital. A descriptive study. / Utilización de medicamentos off-label y unlicensed en una unidad de cuidados intensivos pediátricos de un hospital de alta complejidad español. Estudio descriptivo.

Introduction. In pediatric intensive care units, a large number of drugs are used, many of which are prescribed for condition beyond those established in their summary of product characteristics (off-label and unlicensed drug prescriptions). The objective of this study was to describe drug use and estimate the prevalence of off-label and unlicensed drugs in a pediatric intensive care unit of a tertiary care Spanish hospital. Population and methods. Cross-sectional, observational study with a single cohort of children admitted to a pediatric intensive care unit. The study was conducted in 2017. Each drug prescription, its conditions of use and administration were reviewed. In addition, the summary of product characteristics of drugs used were analyzed in order to identify whether they were used according to their conditions of authorization, or whether they were used in an off-label or unlicensed manner. Results. The sample included 97 patients. At least one off-label or unlicensed drug was administered to 74.2% (n = 72) of patients; 23.8% (n = 243) corresponded to off-label prescriptions and 8.7% (n = 89), unlicensed prescriptions. A sub-analysis by age group showed that the age group that received a higher number of total prescriptions (n = 611) and a higher percentage of off-label and/or unlicensed drug prescriptions (38.4%) was under 2 years of age. Conclusions. Off-label and/or unlicensed drug prescription is a common practice in the pediatric intensive care unit. This study allowed us to document the complexity of therapeutics in children.

Introducción. En las unidades de cuidados intensivos pediátricos, se utiliza gran cantidad de medicamentos, muchos prescritos fuera de las condiciones establecidas en su ficha técnica (prescripciones off-label y unlicensed). El objetivo de este estudio fue describir el uso de medicamentos y estimar la prevalencia de fármacos off-label y unlicensed en una unidad de cuidados intensivos pediátricos de un hospital de tercer nivel español. Población y métodos. Estudio transversal, observacional, de una cohorte de niños ingresados en una unidad de cuidados intensivos pediátricos. El estudio se llevó a cabo en 2017. Se revisó cada fármaco prescrito, sus condiciones de uso y administración. Además, se analizaron las fichas técnicas de los fármacos implicados con la finalidad de identificar si el uso de los medicamentos se realizaba según sus condiciones de autorización, o bien se hacía fuera de prospecto (off-label) o como unlicensed. Resultados. La muestra fue de 97 pacientes. El 74,2 % (n = 72) de los pacientes recibieron algún fármaco off-label o unlicensed. El 23,8 % (n = 243) de las prescripciones fueron off-label y el 8,7 % (n = 89), unlicensed. El subanálisis realizado por grupos de edad mostró que el grupo de edad que recibió mayor número de prescripciones totales (n = 611) y el mayor porcentaje de fármacos prescritos en condiciones off-label y/o unlicensed (38,4 %) fue el de menores de 2 años. Conclusiones. La prescripción de fármacos off-label y/o unlicensed es una práctica habitual en la unidad de cuidados intensivos pediátricos. Este estudio permite documentar la complejidad de la terapéutica en niños.

Immune response and reactogenicity after immunization with two-doses of an experimental COVID-19 vaccine (CVnCOV) followed by a third-fourth shot with a standard mRNA vaccine (BNT162b2): RescueVacs multicenter cohort study.

Background: There is no evidence to date on immunogenic response among individuals who participated in clinical trials of COVID-19 experimental vaccines redirected to standard national vaccination regimens. Methods: This multicentre, prospective controlled cohort study included subjects who received a COVID-19 experimental vaccine (CVnCoV)(test group, TG) - and unvaccinated subjects (control group, CG), selected among individuals to be vaccinated according to the Spanish vaccination program. All study subjects received BNT162b2 as a standard national vaccination schedule, except 8 (from CG) who received mRNA-1273 and were excluded from immunogenicity analyses. Anti-RBD antibodies level and neutralising titres (NT50) against G614, Beta, Mu, Delta and Omicron variants were analysed. Reactogenicity was also assessed. Findings: 130 participants (TG:92; CG:38) completed standard vaccination. In TG, median (IQR) of anti-RBD antibodies after first BNT162b2 dose were 10740·0 BAU/mL (4466·0-12500) compared to 29·8 BAU/mL (14·5-47·8) in CG (p <0·0001). Median NT50 (IQR) of G614 was 2674·0 (1865·0-3997·0) in TG and 63·0 (16·0-123·1) in CG (p <0·0001). After second BNT162b2 dose, anti-RBD levels increased to ≥12500 BAU/mL (11625·0-12500) in TG compared to 1859·0 BAU/mL (915·4-3820·0) in CG (p <0·0001). NT50 was 2626·5 (1756·0-5472·0) and 850·4 (525·1-1608·0), respectively (p <0·0001). Variant-specific (Beta, Mu, Omicron) response was also assessed. Most frequent adverse reactions were headache, myalgia, and local pain. No severe AEs were reported. Interpretation: Heterologous BNT162b2 as third and fourth doses in previously suboptimal immunized individuals elicit stronger immune response than that obtained with two doses of BNT162b2. This apparent benefit was also observed in variant-specific response. No safety concerns arose. Funding: Partly funded by the Institute of Health Carlos-III and COVID-19 Fund, co-financed by the European Regional Development Fund (FEDER) "A way to make Europe".

Meta-Analysis of Reversal Agents for Severe Bleeding Associated With Direct Oral Anticoagulants.

BACKGROUND: Direct oral anticoagulants (DOACs) have shown a positive benefit-risk balance in both clinical trials and real-world data, but approximately 2% to 3.5% of patients experience major bleeding annually. Many of these patients require hospitalization, and the administration of reversal agents may be required to control bleeding. OBJECTIVES: The aim of this study was to investigate clinical outcomes associated with the use of 4-factor prothrombin complex concentrates, idarucizumab, or andexanet for reversal of severe DOAC-associated bleeding. METHODS: The investigators systematically searched for studies of reversal agents for the treatment of severe bleeding associated with DOAC. Mortality rates, thromboembolic events, and hemostatic efficacy were meta-analyzed using a random effects model. RESULTS: The investigators evaluated 60 studies in 4,735 patients with severe DOAC-related bleeding who were treated with 4-factor prothrombin complex concentrates (n = 2,688), idarucizumab (n = 1,111), or andexanet (n = 936). The mortality rate was 17.7% (95% confidence interval [CI]: 15.1% to 20.4%), and it was higher in patients with intracranial bleedings (20.2%) than in patients with extracranial hemorrhages (15.4%). The thromboembolism rate was 4.6% (95% CI: 3.3% to 6.0%), being particularly high with andexanet (10.7%; 95% CI: 6.5% to 15.7%). The effective hemostasis rate was 78.5% (95% CI: 75.1% to 81.8%) and was similar regardless of the reversal agent considered. The rebleeding rate was 13.2% (95% CI: 5.5% to 23.1%) and 78% of rebleeds occurred after resumption of anticoagulation. The risk of death was markedly and significantly associated with failure to achieve effective hemostasis (relative risk: 3.63; 95% CI: 2.56 to 5.16). The results were robust regardless of the type of study or the hemostatic scale used. CONCLUSIONS: The risk of death after severe DOAC-related bleeding remains significant despite a high rate of effective hemostasis with reversal agents. Failure to achieve effective hemostasis strongly correlated with a fatal outcome. Thromboembolism rates are particularly high with andexanet. Comparative clinical trials are needed.

Benefits of the application of heat and pressure on peripheral venous cannulation in adults: A randomized controlled trial.

AIM: To evaluate the effectiveness of the application of topical heat, high pressure or a combination of both on antebrachial venous cannulation. DESIGN: A cross-over clinical trial blinded for haemolysis analysis. METHODS: This cross-over clinical trial with two periods was performed in the Clinical Trial Unit of Hospital Universitario de La Princesa (Madrid) during June-July of 2017 in 59 healthy adults who were randomly allocated to one of three interventions: (1) Using dry topical heat for 7 min produced by two hot seed bags (N = 21), (2) Applying controlled pressure from a sphygmomanometer inflated to 100 mmHg (N = 18) and (3) combining heat and pressure (N = 20) in one period out of two. All interventions were contrasted to standard clinical practice in the other period. The comparator involved a standard tourniquet around the upper arm to restrict venous blood flow. The primary outcome was effectiveness measured as vein cannulation at first attempt. Secondary outcomes were vein perception, pain, haemolysis in blood samples and adverse events. RESULTS: All the interventions were more effective than comparator. Vein perception was optimized in about all individuals. Moreover, pain relief was significantly higher when high pressure was applied. Haemolysis was not affected in any of the three interventions. In addition, no serious adverse events appeared. CONCLUSION: High pressure is determined to be the most effective in vein catheterization, pain relief, vein perception and quality of blood sample inalterability. Moreover, it is safe considering that only one adverse event appeared. IMPACT: Vein cannulation is a very common invasive technique, where repeated failures have been registered. Thus, we consider it relevant to develop interventions to achieve venous catheterization at first attempt to alleviate the pain and anxiety associated with this technique. We advocate using high pressure intervention for emergency, due to swiftest method and feasible in case of lacking resources, such as sphygmomanometers in the ambulance. Interventions can be extrapolated to healthy young adults, adults and patients who have healthy vein status perception. Pressure intervention could be an alternative to heat intervention when performing vein cannulation due to its lower risk of transient paresthesia for older people who often suffer from arterial hypertension.

La isoapariencia farmacéutica un factor de riesgo de errores de medicación / Pharmaceutical "isoappearance": a risk factor for medication errors

OBJETIVO: conocer la opinión de los profesionales de Enfermería sobre la influencia de la isoapariencia farmacéutica en el desarrollo de errores de medicación. MÉTODO: se realizó un estudio descriptivo transversal entre abril y mayo de 2017. Los sujetos de estudio fueron profesionales de Enfermería procedentes de dos hospitales españoles de nivel terciario. Para la recolección de los datos se utilizó un cuestionario diseñado ad hoc para el estudio, que incluía 21 ítems con cinco posibles respuestas según escala Likert (1 = muy en desacuerdo a 5 = muy de acuerdo). Se realizó estadística descriptiva. Se usó del software estadístico SPSS V.22. RESULTADOS: participaron 123 profesionales de Enfermería. El 96% (n = 118) de los encuestados consideró la isoapariencia farmacéutica como un factor de riesgo para la incursión en un error de medicación. Un 15% (n = 19) de la muestra reconoció haber cometido un error por este motivo. CONCLUSIONES: la isoapariencia farmacéutica es percibida por los profesionales de Enfermería como un factor de riesgo de errores de medicación

OBJECTIVE: to understand the opinion of Nursing Professionals about the influence of pharmaceutical "isoappearance" on the occurrence of medication errors. METHOD: a descriptive cross-sectional study was conducted between April and May, 2017. The study subjects were Nursing Professionals from two Spanish tertiary hospitals. Data collection was conducted through a questionnaire designed ad hoc for the study, including 21 items with five possible answers according to the Likert Scale (1 = extremely disagree to 5 = extremely agree). Descriptive statistics analysis was conducted, using the SPSS statistical software version 22. RESULTS: the study included 124 Nursing professionals; 96% (n = 118) of the participants considered that pharmaceutical "isoappearance" was a risk factor for making medication errors, while 15% (n = 19) of the sample admitted that they had made a mistake for this reason. CONCLUSIONS: pharmaceutical "isoappearance" is perceived by Nursing professionals as a risk factor for medication errors

Causes of Death in Patients with Venous Thromboembolism Anticoagulated with Direct Oral Anticoagulants: A Systematic Review and Meta-Analysis.

Death is more frequent than nonfatal recurrent venous thromboembolism (VTE) and major bleeding after acute VTE. The analysis of the causes of death is fundamental to explore new strategies to reduce mortality rates in these patients. The authors performed a meta-analysis to analyze mortality and independently adjudicated causes of death in anticoagulated patients due to VTE, and to evaluate potential differences between different anticoagulant schemes. They searched MEDLINE and CENTRAL, from January 1, 2000, to January 31, 2017, and performed additional searches in Web sites of regulatory agencies, clinical trial registers, and conference proceedings. Two investigators independently selected studies and extracted the data. Study quality was assessed with the Cochrane Collaboration's tool for assessing the risk of bias in randomized studies. Seven prospective randomized trials in 29,844 patients (22,025 patient-year follow-up) were included, comparing dabigatran, rivaroxaban, apixaban, and edoxaban with the standard anticoagulant treatment of VTE. A total of 718 patients died during the follow-up (3.4% per year; 95% confidence interval [CI]: 2.3-4.8). The most frequent causes of death were cancer (42%), followed by VTE (20%), infections (13%), hemorrhage (6%), heart disease (4%), and stroke (2%). There were no differences in the overall survival and causes of death according to the anticoagulant type. Concomitant active cancer during the study was significantly associated with death (odds ratio: 15.2; 95% CI: 9.2-25.1). Cancer is the leading cause of death in contemporary VTE trials. Interventions beyond anticoagulation, particularly in patients with active cancer, are needed.

Causes of Death in Anticoagulated Patients With Atrial Fibrillation.

BACKGROUND: Oral anticoagulation reduces the risk of mortality in atrial fibrillation (AF), but examination of the causes of death is essential to design new strategies to further reduce the high mortality rates observed in this population. OBJECTIVES: The authors sought to analyze and compare causes of death in patients receiving direct oral anticoagulants (DOAC) or warfarin for prevention of stroke and systemic embolism (SE) in AF. METHODS: The authors systematically searched for randomized trials of DOAC versus warfarin for prevention of stroke/SE in AF. The main outcome was mortality and independently adjudicated specific causes of death. The authors used the random effects model of meta-analysis to combine the studies. RESULTS: 71,683 patients from 4 trials were included (134,046 patient-years of follow-up). A total of 6,206 patients (9%) died during follow-up. Adjusted mortality rate was 4.72%/year (95% confidence interval [CI]: 4.19 to 5.28). Cardiac deaths accounted for 46% of all deaths, whereas nonhemorrhagic stroke/SE and hemorrhage-related deaths represented 5.7% and 5.6% of the total mortality, respectively. Compared with patients who were alive, those who died had more frequent history of heart failure (odds ratio [OR]: 1.75; 95% CI: 1.25 to 2.44), permanent/persistent AF (OR: 1.38; 95% CI: 1.25 to 1.52) and diabetes (OR: 1.37; 95% CI: 1.11 to 1.68); were more frequently male (OR: 1.24; 95% CI: 1.13 to 1.37) and older (mean difference 3.2 years; 95% CI: 1.6 to 4.8); and had a lower creatinine clearance (-9.9 ml/min; 95% CI: -11.3 to -8.4). There was a small, but significant, reduction in all-cause mortality with the DOAC versus warfarin (difference -0.42%/year; 95% CI: -0.66 to -0.18), mainly driven by a reduction in fatal bleedings. CONCLUSIONS: In contemporary AF trials, most deaths were cardiac-related, whereas stroke and bleeding represented only a small subset of deaths. Interventions beyond anticoagulation are needed to further reduce mortality in AF.

Direct oral anticoagulants for stroke prevention in patients with atrial fibrillation: meta-analysis by geographic region with a focus on European patients.

AIMS: To analyse clinical outcomes with direct oral anticoagulants in patients with atrial fibrillation according to geographic region. METHODS: We systematically searched MEDLINE, CENTRAL, websites of regulatory agencies, clinical trials registers and conference proceedings for randomized controlled trials of direct oral anticoagulants (DOAC: dabigatran, rivaroxaban, apixaban or edoxaban) against warfarin for prophylaxis of stroke and systemic embolic events (SEE) in patients with atrial fibrillation (AF). Two investigators independently extracted data. Relative risks of stroke and SEE as well as major bleeding depending on geographic region were estimated using a random effect meta-analysis. RESULTS: Five trials in 72 963 patients were analysed; 32 089 (44%) patients were recruited in Europe (Western Europe: 13 676; Eastern Europe: 18 413). We found significant subgroup differences for stroke/SEE depending on the geographic region (interaction P = 0.003; I(2) 88.5%), with a neutral effect of the DOAC vs. warfarin in Europe [relative risk (RR) 0.97, 95% confidence interval (CI) 0.85-1.11, I(2) 0%] and a significant reduction of stroke/SEE in other regions including North America, Latin America and Asia-Pacific/other (RR 0.72, 95% CI 0.63-0.83, I(2) 33%). There was a similar reduction in risk of major bleeding in Europe (RR 0.82, 95% CI 0.73-0.92, I(2) 0%) and in other regions (RR 0.86, 95% CI 0.72-1.02, I(2) 78%). CONCLUSION: The DOAC did not provide additional benefit in reducing the risk of stroke/SEE compared with warfarin in European patients with AF, but were generally associated with a lower bleeding tendency than warfarin regardless of geographic region.

Direct-acting oral anticoagulants: pharmacology, indications, management, and future perspectives.

In recent years, several direct-acting oral anticoagulants (DOAC) have become available for use in Europe and other regions in indications related to prophylaxis and treatment of venous and arterial thromboembolism. They include the oral direct thrombin inhibitor dabigatran etexilate (Pradaxa, Boehringer Ingelheim) and the oral direct FXa inhibitors rivaroxaban (Xarelto, Bayer HealthCare), apixaban (Eliquis, Bristol-Myers Squibb), and edoxaban (Lixiana/Savaysa, Daiichi-Sankyo). The new compounds have a predictable dose response and few drug-drug interactions (unlike vitamin k antagonists), and they do not require parenteral administration (unlike heparins). However, they accumulate in patients with renal impairment, lack widely available monitoring tests for measuring its anticoagulant activity, and no specific antidotes for neutralization in case of overdose and/or severe bleeding are currently available. In this review, we describe the pharmacology of the DOAC, the efficacy, and safety data from pivotal studies that support their currently approved indications and discuss the postmarketing experience available. We also summarize practical recommendations to ensure an appropriate use of the DOAC according to existing data. Finally, we discuss relevant ongoing studies and future perspectives.

Case Fatality Rates of Recurrent Thromboembolism and Bleeding in Patients Receiving Direct Oral Anticoagulants for the Initial and Extended Treatment of Venous Thromboembolism: A Systematic Review.

BACKGROUND: In patients with venous thromboembolism (VTE), the study of the case fatality rate (CFR) of VTE recurrences and bleeding complications may be of help to balance the risks and benefits of anticoagulant therapy. OBJECTIVE: To investigate the CFR with the direct oral anticoagulants (DOACs; dabigatran, rivaroxaban, apixaban, and edoxaban) in patients with VTE. METHODS: We conducted a systematic review and meta-analysis of randomized clinical trials testing the DOACs versus standard initial treatment of VTE (parenteral anticoagulant for ≥5 days plus vitamin K antagonists [VKAs] for ≥3 months) and DOACs versus placebo or VKA for extended treatment. Two investigators independently extracted the data. A random effects meta-analysis was conducted using StatsDirect software. RESULTS: Overall, 10 trials in 35 029 patients were included. During initial treatment, the rate of recurrent VTE per 100 patient-years (%/yr) and CFR (%) was similar in patients receiving DOACs or standard therapy (4.1%/yr vs 4.4%/yr; P = .21 and 16% vs 13%; P = .61, respectively). However, major bleeding (1.8%/yr vs 3.1%/yr; P = .003), fatal bleeding (0.1%/yr vs 0.3%/yr; P = .02), and CFR (6% vs 10%; P = .18) were lower with DOACs than with standard therapy. During extended treatment, both all-cause mortality and recurrent VTE per 100 patient-years were lower with DOACs than with placebo (0.6%/yr vs 1.1%/yr; P = .01 and 1.9%/yr vs 10.9%/yr; P < .0001, respectively), but there were no statistical differences between treatments on CFR of VTE recurrences (P = .17). No fatal bleeding events were reported during extended treatment. CONCLUSION: The use of DOACs was associated with fewer major and fatal bleedings and corresponding CFR than standard initial treatment of VTE, and fewer recurrent VTEs and mortality than placebo during extended therapy, although the CFR of recurrent VTE was not reduced.

Specific antidotes in development for reversal of novel anticoagulants: a review.

In the last decade, several direct oral anticoagulants (DOAC; dabigatran, rivaroxaban, apixaban, edoxaban) have been marketed for prophylaxis and/or treatment of thromboembolism without having specific antidotes available for their reversal. Current management of bleeding associated to DOAC includes the removal of all antithrombotic medications and supportive care. Non-specific procoagulant agents (prothrombin complex concentrates and activated factor VIIa) have been used in case of serious bleeding. Currently, some specific antidotes for the DOAC are under development. Idarucizumab (BI 655075; Boehringer Ingelheim) is a fragment of an antibody (Fab), which is a specific antidote to the oral direct thrombin inhibitor dabigatran. Andexanet alfa (r-Antidote, PRT064445; Portola Pharmaceuticals) is a truncated form of enzymatically inactive factor Xa, which binds and reverses the anticoagulant action of the factor Xa inhibitors (e.g.: rivaroxaban, apixaban and edoxaban). Aripazine (PER-977, ciraparantag; Perosphere Inc.) is a synthetic small molecule (~500 Da) that reverses oral dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH in vivo. These antidotes could provide an alternative for management of life-threatening bleeding events occurring with the above-mentioned anticoagulants. In addition, the specific antidote anivamersen (RB007; Regado Biosciences Inc.) is an RNA aptamer in clinical development to reverse the anticoagulant effect of the parenteral factor IXa inhibitor pegnivacogin, which is also in development. This anticoagulant-antidote pair may provide an alternative in situations in which a fast onset and offset of anticoagulation is needed, like in patients undergoing cardiac surgery with extracorporeal circulation, as an alternative to the heparin/protamine pair. This patent review includes a description of the pharmacological characteristics of the novel specific antidotes, the available results from completed non-clinical and clinical studies and the description of ongoing clinical trials with the new compounds.

Direct oral anticoagulants in the treatment of venous thromboembolism, with a focus on patients with pulmonary embolism: an evidence-based review.

Pulmonary embolism (PE) is a relatively common cardiovascular emergency. PE and deep vein thrombosis (DVT) are considered expressions of the same disease, termed as venous thromboembolism (VTE). In the present review, we describe and meta-analyze the efficacy and safety data available with the direct oral anticoagulants (DOAC; dabigatran, rivaroxaban, apixaban, edoxaban) in clinical trials testing these new compounds in the acute/long-term and extended therapy of VTE, providing subgroup analyses in patients with index PE. We analyzed ten studies in 35,019 randomized patients. A total of 14,364 patients (41%) had index PE. In the acute/long-term treatment of VTE, the DOAC showed comparable efficacy in preventing recurrent VTE to standard treatment in patients with index PE (risk ratio [RR]: 0.88; 95% confidence interval [CI]: 0.70-1.11) and index DVT (RR: 0.93; 95% CI: 0.75-1.16) (P for subgroup differences =0.76). VTE recurrence depending on PE anatomical extension and presence/absence of right ventricular dysfunction was only reported in two trials, with results being consistent with those obtained in the overall study populations. In the single trial comparing extended therapy of VTE with DOAC versus warfarin, the point estimate for recurrent VTE tended to disfavor the DOAC in patients with index PE (RR: 2.05; 95% CI: 0.83-5.03) and in patients with index DVT (RR: 1.11; 95% CI: 0.49-2.50) (P for subgroup differences =0.32). In trials that compared DOAC versus placebo for extended therapy, the reduction in recurrent VTE was consistent in patients with PE (RR: 0.15; 95% CI: 0.01-1.82) and in patients with DVT (RR: 0.25; 95% CI: 0.10-0.61) (P for subgroup differences =0.71). The DOAC were associated with a consistently lower risk of clinically relevant bleeding (CRB) than standard treatment of acute VTE and higher risk of CRB than placebo for extended therapy of VTE regardless of index event. In summary, the DOAC were as effective as, and safer than, standard treatment of (hemodynamically stable) PE. Their efficacy in preventing recurrent VTE seemed consistent regardless of anatomical extension of PE (extensive, intermediate, or limit) or presence/absence of right ventricular dysfunction although the data are limited. For extended therapy, the DOAC were more effective than placebo in preventing recurrent VTE but were associated with an increase in CRB regardless of index event.

Direct oral anticoagulants in the treatment of acute venous thromboembolism: a systematic review and meta-analysis.

INTRODUCTION: Acute venous thromboembolism (VTE) is a common disease associated to significant morbidity and mortality. MATERIALS AND METHODS: We systematically reviewed and meta-analysed clinical outcomes with direct oral anticoagulants (DOAC: dabigatran, rivaroxaban, apixaban or edoxaban) for treatment of acute VTE. We used MEDLINE and CENTRAL, clinical trials registers, conference proceedings, and websites of regulatory agencies to identify randomised clinical trials of DOAC compared with conventional treatment [parenteral anticoagulant followed by a vitamin K antagonist (VKA)] for acute VTE. Two investigators independently extracted data. Relative risk of recurrent VTE, bleeding events, deaths and a net clinical endpoint (composite of recurrent VTE, major bleeding, and death) were estimated using a random effect meta-analysis (RevMan software). RESULTS: Six trials including 27,127 patients were selected. The risk of recurrent VTE was similar with the DOAC and standard treatment (relative risk 0.91, 95% confidence interval 0.79 to 1.06). The DOAC reduced the risk of major bleeding in comparison with standard treatment (0.62, 0.45 to 0.85) (absolute risk difference, -0.6%; 95% confidence interval -1.0% to -0.3%), but there was heterogeneity across trials in the relative risk of bleeding. No between treatment differences were found in the relative risk of all-cause mortality (0.98, 0.84 to 1.14). The DOAC and conventional treatment differed on the net clinical endpoint (0.85, 0.75 to 0.97). Subgroup analyses in relevant subgroups (index pulmonary embolism, heparin lead-in, age, gender, renal function, presence of cancer), as well as sensitivity analyses, were consistent with the main analysis. CONCLUSIONS: The DOAC seem as effective as, and probably safer than standard treatment of acute VTE. The relative efficacy and safety of the DOAC was consistent across a wide range of patients.

Pharmacoeconomic evaluation of dabigatran, rivaroxaban and apixaban versus enoxaparin for the prevention of venous thromboembolism after total hip or knee replacement in Spain.

BACKGROUND: Patients undergoing total hip replacement (THR) or total knee replacement (TKR) surgery are at high risk of developing venous thromboembolism (VTE). Thromboprophylaxis with low-molecular-weight heparin, such as enoxaparin, is standard of care in these patients. Recently, three direct oral anticoagulants (DOACs; dabigatran, rivaroxaban and apixaban), have been approved for this indication, but their cost effectiveness is still unclear as it has usually been extrapolated from surrogate venographic outcomes in clinical trials. OBJECTIVE: To conduct a pharmacoeconomic evaluation of the DOACs versus subcutaneous (SC) enoxaparin for the prevention of VTE after THR or TKR surgery. METHODS: A decision-tree model was developed using TreeAge Pro 2011 to compare the cost utility and cost effectiveness of the DOACs with SC enoxaparin, with separate models for THR and TKR over a 3-month postoperative time horizon from the perspective of the Spanish National Health System. The probabilities of events (symptomatic VTE, clinically relevant bleedings, heparin-induced thrombocytopenia and deaths) were derived from a systematic review and meta-analysis. We used local cost estimates (€2013) and utility values were obtained from the literature. We reported costs, quality-adjusted life-years (QALYs) and symptomatic VTE events. We conducted sensitivity analyses to evaluate parameter uncertainty. RESULTS: The average costs per 1,000 patients treated with enoxaparin were higher than costs incurred by dabigatran, rivaroxaban and apixaban in THR (€435,208 vs. €283,574, €257,900 and €212,472, respectively) and TKR (€336,550 vs. €219,856, €251,734 and €201,946, respectively), with cost savings ranging from €151,634 to €222,766 in THR, and from €84,816 to €134,604 in TKR. Cost differences were largely driven by differences in costs associated with drug administration. The average QALYs per 1,000 patients treated were very similar for enoxaparin, dabigatran, rivaroxaban and apixaban in THR (199.34, 198.83, 199.08 and 199.68, respectively) and TKR (198.95, 199.41, 198.75 and 199.97, respectively). Rivaroxaban (in TKR and THR) and apixaban (in THR) avoided additional symptomatic VTE events compared with enoxaparin. Sensitivity analyses generally supported the robustness of the analysis to changes in model parameters. CONCLUSIONS: Our model suggests, based on its underlying assumptions and data, that the DOACs are cost-saving alternatives to SC enoxaparin for the prevention of VTE after THR or TKR, in the Spanish healthcare setting.

Potential role of new anticoagulants for prevention and treatment of venous thromboembolism in cancer patients.

Venous thromboembolism (VTE), encompassing deep vein thrombosis and pulmonary embolism, represents a major cause of morbidity and mortality in patients with cancer. Low molecular weight heparins are the preferred option for anticoagulation in cancer patients according to current clinical practice guidelines. Fondaparinux may also have a place in prevention of VTE in hospitalized cancer patients with additional risk factors and for initial treatment of VTE. Although low molecular weight heparins and fondaparinux are effective and safe, they require daily subcutaneous administration, which may be problematic for many patients, particularly if long-term treatment is needed. Studying anticoagulant therapy in oncology patients is challenging because this patient group has an increased risk of VTE and bleeding during anticoagulant therapy compared with the population without cancer. Risk factors for increased VTE and bleeding risk in these patients include concomitant treatments (surgery, chemotherapy, placement of central venous catheters, radiotherapy, hormonal therapy, angiogenesis inhibitors, antiplatelet drugs), supportive therapies (ie, steroids, blood transfusion, white blood cell growth factors, and erythropoiesis-stimulating agents), and tumor-related factors (local vessel damage and invasion, abnormalities in platelet function, and number). New anticoagulants in development for prophylaxis and treatment of VTE include parenteral compounds for once-daily administration (ie, semuloparin) or once-weekly dosing (ie, idraparinux and idrabiotaparinux), as well as orally active compounds (ie, dabigatran, rivaroxaban, apixaban, edoxaban, betrixaban). In the present review, we discuss the pharmacology of the new anticoagulants, the results of clinical trials testing these new compounds in VTE, with special emphasis on studies that included cancer patients, and their potential advantages and drawbacks compared with existing therapies.

Dabigatran, Rivaroxaban, or Apixaban versus Warfarin in Patients with Nonvalvular Atrial Fibrillation: A Systematic Review and Meta-Analysis of Subgroups.

Background. New oral anticoagulants (NOAC; rivaroxaban, dabigatran, apixaban) have become available as an alternative to warfarin anticoagulation in non-valvular atrial fibrillation (NVAF). Methods. MEDLINE and CENTRAL, regulatory agencies websites, clinical trials registers and conference proceedings were searched to identify randomised controlled trials of NOAC versus warfarin in NVAF. Two investigators reviewed all studies and extracted data on patient and study characteristics along with cardiovascular outcomes. Relative risks (RR) and 95% confidence intervals (CI) were estimated using a random effect meta-analysis. Results. Three clinical trials in 50,578 patients were included. The risk of non-hemorrhagic stroke and systemic embolic events (SEE) was similar with the NOAC and warfarin (RR = 0.93; 95% CI = 0.83-1.04), while the risk of intracranial bleeding (ICB) with the NOAC was lower than with warfarin (RR = 0.46; 95% CI = 0.33-0.65). We found differences in the effect size on all strokes and SEE depending on geographic region as well as on non-hemorrhagic stroke, SEE, bleeding and mortality depending on time in therapeutic range. Conclusion. The NOAC seem no more effective than warfarin for prevention of nonhemorrhagic stroke and SEE in the overall NVAF population, but are generally associated with a lower risk of ICB than warfarin.