Clinical research and drug regulation in the challenging times of individualized therapies: A pivotal role of clinical pharmacology.

Since the 1980s, medical specialists in Clinical Pharmacology have been playing a crucial role in the development of drug regulation in Spain. In this article we report on the activities carried out and the prospects for development in three very relevant areas from the regulatory perspective: 1) the development of stable public infrastructures to facilitate non-commercial clinical research with medicines, 2) the regulatory aspects of individual access to medicines in special situations, beyond their regular access after marketing approval and funding by the National Health System, and 3) the challenges of development and access to advanced therapies, with special reference to the figure of the hospital exemption.

When and How to Use Reversal Agents for Direct Oral Anticoagulants?

PURPOSE OF REVIEW: Our objective is to describe currently available reversal agents for direct oral anticoagulants (DOACs), their target population, the available clinical practice recommendations and future directions. RECENT FINDINGS: Specific (idarucizumab for dabigatran and andexanet alfa for direct factor Xa inhibitors) and non-specific (prothrombin complex concentrates) reversal agents are effective in neutralizing the anticoagulant effect of DOACs. New investigational antidotes such as ciraparantag and VMX-C001 offer an alternative to andexanet alfa in reversing the anticoagulant activity of direct oral factor Xa inhibitors, but more clinical data are needed before they could be licensed for use. Specific reversal agents are recommended for use in clinical situations within their licensed indications (i.e.: reversal of DOACs in patients with severe uncontrolled or life-threatening bleeding or in need of emergency surgery or other invasive procedures), while non-specific reversal agents may be used when specific antidotes are not available or indicated.

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.

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.

GEMA 5.3. Spanish Guideline on the Management of Asthma.

The Spanish Guideline on the Management of Asthma, better known by its acronym in Spanish GEMA, has been available for more than 20 years. Twenty-one scientific societies or related groups both from Spain and internationally have participated in the preparation and development of the updated edition of GEMA, which in fact has been currently positioned as the reference guide on asthma in the Spanish language worldwide. Its objective is to prevent and improve the clinical situation of people with asthma by increasing the knowledge of healthcare professionals involved in their care. Its purpose is to convert scientific evidence into simple and easy-to-follow practical recommendations. Therefore, it is not a monograph that brings together all the scientific knowledge about the disease, but rather a brief document with the essentials, designed to be applied quickly in routine clinical practice. The guidelines are necessarily multidisciplinary, developed to be useful and an indispensable tool for physicians of different specialties, as well as nurses and pharmacists. Probably the most outstanding aspects of the guide are the recommendations to: establish the diagnosis of asthma using a sequential algorithm based on objective diagnostic tests; the follow-up of patients, preferably based on the strategy of achieving and maintaining control of the disease; treatment according to the level of severity of asthma, using six steps from least to greatest need of pharmaceutical drugs, and the treatment algorithm for the indication of biologics in patients with severe uncontrolled asthma based on phenotypes. And now, in addition to that, there is a novelty for easy use and follow-up through a computer application based on the chatbot-type conversational artificial intelligence (ia-GEMA).

La Guía Española para el Manejo del Asma, mejor conocida por su acrónimo en español, GEMA, está a nuestra disposición desde hace más de veinte años. Veintiuna sociedades científicas o grupos relacionados, tanto de España como de otros países, han participado en la preparación y desarrollo de la edición actualizada de GEMA que, de hecho, se ha posicionado en la actualidad a nivel mundial como la guía de referencia sobre asma en lengua española.Su objetivo es prevenir y mejorar la situación clínica de las personas con asma, aumentando el conocimiento de los profesionales sanitarios involucrados en su cuidado. Su propósito es convertir la evidencia científica en recomendaciones prácticas sencillas y fáciles de seguir. Por lo tanto, no se trata de una monografía que reúna todo el conocimiento científico sobre la enfermedad, sino más bien de un documento conciso con lo esencial, diseñado para ser aplicado rápidamente en la práctica clínica de rutina. Las recomendaciones son necesariamente multidisciplinares, están desarrolladas para ser útiles y una herramienta indispensable para médicos de diferentes especialidades, así como para profesionales de enfermería y farmacia.Seguramente, los aspectos más destacados de la guía son las recomendaciones para: establecer el diagnóstico del asma utilizando un algoritmo secuencial basado en pruebas diagnósticas objetivas; el seguimiento de los pacientes, preferentemente basado en la estrategia de lograr y mantener el control de la enfermedad; el tratamiento según el nivel de gravedad del asma utilizando seis escalones, desde la menor hasta la mayor necesidad de medicamentos, y el algoritmo de tratamiento basado en fenotipos para la indicación de biológicos en pacientes con asma grave no controlada. A esto se suma ahora una novedad para su fácil uso y seguimiento a través de una aplicación informática basada en la inteligencia artificial conversacional de tipo chatbot (ia-GEMA).

Pharmacotherapy for stroke prevention in nonvalvular atrial fibrillation: current strategies and future directions.

INTRODUCTION: Cardioembolic stroke, associated to nonvalvular atrial fibrillation (NVAF), accounts for approximately one in every four strokes. Cardioembolic stroke has a bad prognosis and is associated with a significant rate of recurrence. AREAS COVERED: This article reviews current pharmacotherapeutic options for prevention of stroke in NVAF, paying special attention to their use in particular clinical settings (e.g. cardioversion, catheter ablation). We also aim to review new drug candidates that have entered clinical studies in this indication. EXPERT OPINION: Oral anticoagulant therapy (OAT) remains the mainstay for ischemic stroke prophylaxis in NVAF in patients at risk. Several oral (asundexian, milvexian) and parenteral (abelacimab, osocimab, xisomab, IONIS-FXIRX, fesomersen) factor XIa inhibitors are under development. These new compounds appear to be associated with a low bleeding tendency and have the potential to complement current existing alternatives for anticoagulation. However, it is also of paramount importance to implement interventions to improve adherence to available anticoagulants, which is currently suboptimal. Non-anticoagulant drugs, such as colchicine, metformin and dronedarone, also being investigated to reduce the burden of NVAF and cardioembolic stroke. Additional clinical data are needed to more clearly define the role of these drugs for stroke prevention in NVAF.

Spanish Asthma Management Guidelines (GEMA) VERSION 5.1. Highlights and Controversies. / Guía española para el manejo del asma (GEMA) versión 5.1. Aspectos destacados y controversias.

In this fifth phase of development, the contents of the Spanish Asthma Management Guidelines (GEMA), which include versions 5.0 and 5.1, have undergone a thorough review. The aim here is to set the main changes in context. These could be summarized as follows: DIAGNOSIS: new FENO cut-off and severity classification based on treatment needed to maintain control; INTERMITTENT ASTHMA: a more restrictive concept and treatment extended to include a glucocorticoid/adrenergic combination as needed; MILD ASTHMA: glucocorticoid/adrenergic therapy as needed as an alternative in case of low therapeutic adherence to conventional fixed-dose steroids; SEVERE ASTHMA: readjustment of phenotypes, incorporation of triple therapy in a single inhaler, and criteria for selection of a biologic in severe uncontrolled asthma; OTHERS: specific scoring in childhood asthma, incorporation of certain organizational aspects (care circuits, asthma units, telemedicine), new sections on COVID-19 and nasal polyposis.

[Translated article] Spanish Asthma Management Guidelines (GEMA) v.5.1. Highlights and Controversies.

In this fifth phase of development, the contents of the Spanish Asthma Management Guidelines (GEMA), which include versions 5.0 and 5.1, have undergone a thorough review. The aim here is to set the main changes in context. These could be summarized as follows: DIAGNOSIS: new FENO cut-off and severity classification based on treatment needed to maintain control; INTERMITTENT ASTHMA: a more restrictive concept and treatment extended to include a glucocorticoid/adrenergic combination as needed; MILD ASTHMA: glucocorticoid/adrenergic therapy as needed as an alternative in case of low therapeutic adherence to conventional fixed-dose steroids; SEVERE ASTHMA: readjustment of phenotypes, incorporation of triple therapy in a single inhaler, and criteria for selection of a biologic in severe uncontrolled asthma; OTHERS: specific scoring in childhood asthma, incorporation of certain organizational aspects (care circuits, asthma units, telemedicine), new sections on COVID-19 and nasal polyposis.

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.

New anticoagulants: focus on venous thromboembolism.

Anticoagulation is recommended for prophylaxis and treatment of venous thromboembolism (VTE) (deep vein thrombosis and pulmonary embolism) and/or arterial thromboembolism. The therapeutic arsenal of anticoagulants available to clinicians is mainly composed by unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), fondaparinux and oral vitamin K antagonists (VKA) (i.e. warfarin and acenocumarol). These anticoagulants are effective, but they require parenteral administration (UFH, LMWH, fondaparinux) and/or frequent anticoagulant monitoring (intravenous UFH, oral VKA). Novel anticoagulants in clinical testing include orally active direct factor II inhibitors [dabigatran etexilate (BIBR 1048), AZD0837)], parenteral direct factor II inhibitors (flovagatran sodium), orally active direct factor X inhibitors [rivaroxaban (BAY 59-7939), apixaban, betrixaban, YM150, DU-176b, LY-517717, GW813893, TAK-442, PD 0348292] and new parenteral FXa inhibitors [idraparinux, idrabiotaparinux (biotinilated idraparinux; SSR 126517), ultra-low-molecular-weight heparins (ULMWH: AVE5026, RO-14)]. These new compounds have the potential to complement heparins and fondaparinux for short-term anticoagulation and/or to replace VKA for long-term anticoagulation in most patients. Dabigatran and rivaroxaban have been the firsts of the new oral anticoagulants to be licensed for the prevention of VTE after hip and knee replacement surgery. In the present review, we discuss the pharmacology of new anticoagulants, the key points necessary for interpreting the results of studies on VTE prophylaxis and treatment, the results of clinical trials testing these new compounds and their potential advantages and drawbacks over existing therapies.

Evaluation of the effectiveness and safety of bemiparin in a large population of orthopedic patients in a normal clinical practice.

The authors conducted a prospective, open, multicenter, observational study to audit the utilization patterns of bemiparin in orthopedic patients in daily clinical practice. They analyzed rates of documented symptomatic venous thromboembolism (VTE) (deep vein thrombosis and pulmonary embolism) confirmed by objective methods, major bleeding, death, thrombocytopenia, and other adverse events. It was also intended to analyze the influence of concomitant factors (bemiparin dose, concomitant medications, age, and obesity) on VTE and bleeding rates. A total of 7959 patients were included and received bemiparin for 28 days (median). Bemiparin 3500 IU/d was used in 84.9% of patients, whereas bemiparin 2500 IU/d was administered to 15.1% of patients. Reason for prophylaxis (number of cases [%]) included cast immobilization of the leg (2052 [25.8%]), knee replacement (1082 [13.6%]), hip replacement (876 [11.0%]), hip fracture surgery (437 [5.5%]), other lower limb surgery (1569 [19.7%]), knee arthroscopy (769 [9.7%]), and spine surgery (231 [2.9%]). A total of 943 patients with insufficient data on reason for prophylaxis and 560 patients with no outcome assessment were excluded from the analysis of clinical outcomes. Among 6456 assessable patients, the authors found a low rate of documented symptomatic VTE (0.91%), major bleeding (0.17%), deaths (0.37%), and mild to moderate thrombocytopenia (0.51%). None of the major bleedings was fatal or occurred in a critical organ. There were 3 deaths in which fatal pulmonary embolism (PE) could not be ruled out. There were no cases of severe type-II thrombocytopenia. VTE rates were not increased in obese patients, and major bleeding rates were not increased in elderly patients or in patients taking nonsteroidal anti-inflammatory drugs. In conclusion, bemiparin prophylaxis, given for 3 to 4 weeks in cast immobilization of the leg and other orthopedic procedures, was associated with low rates of VTE, bleeding, and other adverse events in normal clinical practice.

When are the cardiovascular and stroke risks too high? Pharmacotherapy for stroke prophylaxis.

INTRODUCTION: Stroke is a significant source of morbidity and mortality in developed countries. Cardioembolic strokes represent approximately 15-30% of all ischemic strokes. They are frequently related to atrial fibrillation (AF) and have a worse prognosis and high recurrence rates when compared to other causes (e.g. atherosclerosis). AREAS COVERED: This review includes a summary of general and specific scores to assess cardiovascular and stroke risks, with a focus on specific scores available in AF. Recommendations for antithrombotic therapy are also reviewed. EXPERT OPINION: Several scores are available for the evaluation of stroke risk. They are useful to identify the risk factors that trigger the need for medical interventions. Integrated risk scores with visual interfaces showing the risk of events, with and without the proposed interventions, can aid decision-making. The risk of stroke can definitely be considered too high in those patients with a history of stroke/transient ischemic attack, who need antiplatelet therapy (after a non-cardioembolic stroke) or anticoagulant therapy (after a cardioembolic stroke). For primary prevention of stroke, antiplatelet therapy is not usually recommended, while anticoagulation should be considered if the patient has concomitant AF and at least one additional risk factor unrelated to sex.

Discovery methods of coagulation-inhibiting drugs.

INTRODUCTION: In the last decade, several direct oral anticoagulants (DOAC) targeting thrombin (dabigatran) or activated factor X (FXa) (rivaroxaban, apixaban and edoxaban) have been marketed for a number of indications related to prophylaxis and treatment of thrombotic diseases. All these drugs are effective in preventing thrombosis, but are associated with an increased bleeding risk. Areas covered: This review includes a summary of new targets for anticoagulation (e.g.: FXIa, FXIIa, protein disulfide isomerase, polyphosphates, etc.), the discovery process and pharmacological features of new anticoagulant compounds and the available results from non-clinical and clinical studies. A significant number of new anticoagulant compounds are currently in development. These compounds were developed using different technologies like SELEX (aptamers), antisense technology (ASOs), hybridoma (MAB) and structure based drug design. Compounds like ichorcumab (a parenteral thrombin inhibitor), BMS-986177 (oral FXIa inhibitor), BAY-1213790 and xisomab (parenteral FXIa inhibitors) are currently in the clinical development stage. Expert opinion: It's important to be cautious when interpreting preliminary findings of new compounds showing a good antithrombotic effect without altering haemostasis. That being said, the anticoagulants in development have the potential to provide a safer alternative to the currently available anticoagulants in patients at high risk of bleeding, but further investigation is warranted.

Causes of death in atrial fibrillation: Challenges and opportunities.

Atrial fibrillation (AF) is an age-related arrhythmia associated with several co-morbidities and significant mortality. Most AF patients are in need of anticoagulation due to increased risk of stroke. Despite anticoagulation, AF patients still have a significant risk of death (about 5%/y). Approximately half of deaths in AF are due to heart-related causes (i.e., sudden death, heart failure, and myocardial infarction), one-third of deaths are due to non-vascular causes (i.e., cancer, respiratory diseases, and infections) and the remaining AF patients die from stroke or hemorrhage (about 6% each), or other causes. This review describes current situations related to causes of death in AF, the challenges in the management of AF (e.g., frequent presence of cardiovascular risk factors and co-morbidities, physicians adherence to clinical guidelines and patients adherence to cardiovascular medications in AF) as well as the opportunities for intervention.

Cost effectiveness of bemiparin sodium versus unfractionated heparin and oral anticoagulants in the acute and long-term treatment of deep vein thrombosis.

INTRODUCTION: Low-molecular-weight heparins (LMWHs) are at least as effective and well tolerated as unfractionated heparin (UFH) in the treatment of deep vein thrombosis (DVT), offering easier administration and obviating the need for anticoagulant monitoring, but have a higher acquisition cost than UFH. OBJECTIVE: To quantify the potential economic impact of two regimens of subcutaneous bemiparin 115 IU/kg/day for 7-10 days (plus oral anticoagulants [OAC] or followed by long-term bemiparin 3500IU) versus dose-adjusted intravenous UFH for 7 days plus OAC for 3 months in the acute and long-term treatment of DVT. The representative patient was a 62-year-old, 77 kg male with proximal DVT of the lower limbs. METHODS: A cost-effectiveness analysis was performed using a decision-tree modelling approach. The results were expressed in terms of costs (euro, 2002 values) and incremental cost effectiveness. The treatment costs (hospital stay, physician services, drug administration) and costs incurred due to complications (pulmonary embolism, recurrent DVT, bleeding events, thrombocytopenia and deaths) during the 3-month study period were considered for the primary analysis. Life expectancy and QALYs were considered for the secondary analysis. The study was performed in the setting of the Spanish National Health System. RESULTS: Bemiparin plus OAC or long-term bemiparin for 3 months provided net cost savings of euro 769 and euro 908 per patient, respectively, compared with UFH plus OAC (UFH plus OAC euro 4128 vs bemiparin plus OAC euro 3359 vs long-term bemiparin euro 3220). Bemiparin plus OAC and long-term bemiparin for 3 months were calculated to avoid 27 and 7 additional VTE events, respectively, per 1000 patients treated. Bemiparin plus OAC or long-term bemiparin increased quality-adjusted life expectancy by approximately 1.72 and 0.74 years, respectively, compared with UFH plus OAC. The univariate sensitivity analysis supported the cost effectiveness of bemiparin in all the ranges tested for complications and costs. CONCLUSIONS: Our model suggests that bemiparin plus OAC or long-term bemiparin for 3 months may be dominant strategies over UFH plus OAC in the treatment of DVT from the Spanish National Health System perspective, offering better outcomes and cost savings. Long-term bemiparin may be a cost-neutral alternative to bemiparin plus OAC.