Daratumumab-based therapies in transplant-ineligible patients with untreated multiple myeloma and hepatic dysfunction: A systematic review of subgroup analyses.

INTRODUCTION: There is subgroup analysis suggesting a lack of benefit of daratumumab use in multiple myeloma (MM) and hepatic disease (HD). The objectives of this study were to conduct a systematic review and interpretation of daratumumab-based regimen efficacy in transplant-ineligible patients with untreated MM and HD. METHODS: A systematic search in Pubmed® database about randomized clinical trials (RCTs) with subgroup analysis regarding hepatic function for overall survival (OS) or progression-free survival (PFS) were developed. Two methodologies were applied. One of them considered statistical interaction, prespecification, biological support and consistency of subgroup results. Second methodology was two-part validated tool: preliminary questions to reject subset analysis without minimal relevance, and a checklist relating a recommendation for applicability in clinical practice. RESULTS: It was included three records. About first methodology, statistical interaction among subgroups was found for PFS in one RCT. Subsets were prespecified in all RCTs. Biological support of efficacy differences could be reasonable. Inconsistent results were found. Second methology directly rejected applicability of subset analysis in two records. Checklist recommended "null" application of results in the remaining RCT. CONCLUSIONS: No consistent heterogeneity for daratumumab-based regimen efficacy was observed among subgroups regarding hepatic function in transplant-ineligible patients with untreated MM. Patients with normal hepatic function and HD could benefit from these treatments.

Switching of monoclonal antibodies against calcitonin gene-related peptide in chronic migraine in clinical practice: a case series.

A multicentre case series of patients with chronic migraine (CM) treated with monoclonal antibodies directed against calcitonin gene-related peptide (CGRP-mAbs) switching were developed. The effectiveness and safety of CGRP-mAbs switching as a preventive treatment for CM in clinical practice were recorded. Effectiveness was measured by ≥50% reduction of monthly migraine days in respect to baseline and reduction in pain intensity. Safety was analysed through adverse events (AEs) and treatment discontinuations. Seven patients were included. The reason for switching was non-response in all cases. Two patients presented a response to the first CGRP-mAb, but the effect was lost after 3 months. The remaining five patients were non-responders. Response to the second CGRP-mAb was observed in three patients, one of them for >3 months. Less than half of the patients previously treated with a CGRP-mAb responded to switching with a second CGRP-mAb. AEs were rare, with no treatment discontinuations.

Patient benefit as a goal of humanization.

Patient empowerment is one of the main pillars of humanisation. Therefore, consideration of patients' preferences and expectations should be  taken into account during the practice of any healthcare professional.  Improving overall survival and quality of life are the main wishes of patients.  Indeed, the recent emergence of Patient Reported Outcomes has become an important focus for healthcare providers. The hospital pharmacist  specialised in drug evaluation is a professional who evaluates the efficacy,  safety, appropriateness and efficiency of treatments prescribed by physicians, and decision-making must be based on both technical factors and  the four principles of bioethics. The correct application of evidence-based  clinical practice allows to provide patients with increases in survival and/or quality of life, adapting the convenience and costs to the current  situation. With this in mind, it could be said that the evaluation of medicines  involves a strong commitment to humanisation. On the other hand,  rganisations that promote the rigorous evaluation and selection of medicines  stand as allies of patients, as they have a direct impact on them and an  indirect impact on society. Regulatory agencies in charge of approving and  financing medicines in healthcare systems play a key role in the process of humanising clinical decision-making and empowering patients. If  these agencies approve the use of new medicines based on data that do not measure quality of life or survival of patients when there are already other therapeutic alternatives for these pathologies, they are indirectly failing  to meet patients' expectations and are infringing bioethical principles. This can  have a considerable influence on the benefit-risk ratio of drugs, and  patients  may be treated with regimens that do not provide benefit, or may even harm  them. Therefore, where should the process of humanisation be oriented? It  seems reasonable that the benefit of the patient should be the fundamental  objective of the process of humanisation of healthcare, evidently.

El empoderamiento del paciente supone uno de los principales pilares de la  humanización. Por ello, la consideración de las preferencias y expectativas de  los pacientes debería ser tenida en cuenta durante el ejercicio de cualquiera de  los profesionales de la salud. Mejorar la supervivencia global y la calidad de  vida son los deseos principales de los pacientes. De hecho, la reciente  aparición de los llamados Patient Reported Outcomes ha supuesto un  importante foco para los agentes involucrados en la asistencia sanitaria. El  farmacéutico hospitalario especializado en la evaluación de medicamentos es  un profesional que evalúa la eficacia, seguridad, adecuación y eficiencia de los  tratamientos prescritos por facultativos, y debe basar la toma de decisiones  tanto en factores técnicos como en los cuatro principios bioéticos. La correcta  aplicación de la práctica clínica basada en la evidencia permite proveer a los  pacientes de incrementos de supervivencia y/o calidad de vida, adecuando la  conveniencia y costes a la situación actual. Teniendo en cuenta esto, podría  decirse que la evaluación de medicamentos supone un fuerte compromiso con  la humanización. Por otra parte, las organizaciones que promueven la  evaluación y selección de medicamentos rigurosamente se erigen como aliados  de los pacientes, ya que repercuten de forma directa en éstos y de  forma indirecta en la sociedad. Las agencias reguladoras encargadas de la  aprobación y financiación de medicamentos en los sistemas sanitarios  protagonizan un papel fundamental en el proceso de humanización de la toma  de decisiones clínicas y empoderamiento de pacientes, ya que si aprueban el  uso de nuevos medicamentos según datos que no miden la calidad de vida o  supervivencia de los pacientes cuando ya existen otras alternativas  terapéuticas para estas patologías, indirectamente no estarán dando respuesta a las expectativas de los pacientes y conculcarán los principios bioéticos. Esto puede tener una considerable influencia en la relación beneficio-riesgo de los  fármacos, pudiendo tratar a pacientes con esquemas que no aportan beneficio,  o incluso podrían perjudicarles. Por tanto, ¿hacia dónde debiera ir  orientado el proceso de humanización? Parece razonable que el beneficio del  paciente sea el objetivo fundamental del proceso de humanización de la  asistencia sanitaria, evidentemente.

Long-lasting effect of belantamab mafodotin in heavily pretreated multiple myeloma.

Belantamab mafodotin (BLMF) is an interesting therapeutic alternative for multiple myeloma (MM) patients pretreated with immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies. Scientific evidence on BLMF provides immature data about progression-free survival and overall survival by short follow-up of patients with poor prognoses. Cases with long follow-ups could provide additional information about BLMF. This case reports a patient with MM treated with BLMF who had received nine previous lines of therapy with a follow-up of 11 months. No complete response was obtained. However, no disease progression was observed and the patient was still alive at the end of this work. BLMF showed manageable adverse effects. Our patient presented advanced disease, good functional status at the beginning of BLMF treatment, and elevated levels of lactate dehydrogenase during BLMF therapy. The influence of these last two factors was not evaluated in clinical trials. This relationship should be assessed more deeply in future studies.

El beneficio del paciente como objetivo de la humanización / Patient benefit as a goal of humanization

El empoderamiento del paciente supone uno de los principales pilares dela humanización. Por ello, la consideración de las preferencias y expectativas de los pacientes debería ser tenida en cuenta durante el ejerciciode cualquiera de los profesionales de la salud. Mejorar la supervivenciaglobal y la calidad de vida son los deseos principales de los pacientes. Dehecho, la reciente aparición de los llamados Patient Reported Outcomes hasupuesto un importante foco para los agentes involucrados en la asistenciasanitaria. El farmacéutico hospitalario especializado en la evaluación demedicamentos es un profesional que evalúa la eficacia, seguridad, adecuación y eficiencia de los tratamientos prescritos por facultativos, y debebasar la toma de decisiones tanto en factores técnicos como en los cuatroprincipios bioéticos. La correcta aplicación de la práctica clínica basadaen la evidencia permite proveer a los pacientes de incrementos de supervivencia y/o calidad de vida, adecuando la conveniencia y costes a lasituación actual. Teniendo en cuenta esto, podría decirse que la evaluaciónde medicamentos supone un fuerte compromiso con la humanización. Porotra parte, las organizaciones que promueven la evaluación y selecciónde medicamentos rigurosamente se erigen como aliados de los pacientes,ya que repercuten de forma directa en éstos y de forma indirecta en lasociedad. Las agencias reguladoras encargadas de la aprobación y financiación de medicamentos en los sistemas sanitarios protagonizan un papelfundamental en el proceso de humanización de la toma de decisiones clínicas y empoderamiento de pacientes, ya que si aprueban el uso de nuevos medicamentos según datos que no miden la calidad de vida o supervivencia de los pacientes cuando ya existen otras alternativas terapéuticaspara estas patologías, indirectamente no estarán dando respuesta a lasexpectativas de los pacientes y conculcarán los principios bioéticos. (AU)

Patient empowerment is one of the main pillars of humanisation. Therefore,consideration of patients’ preferences and expectations should be takeninto account during the practice of any healthcare professional. Improvingoverall survival and quality of life are the main wishes of patients. Indeed,the recent emergence of Patient Reported Outcomes has become animportant focus for healthcare providers. The hospital pharmacist specialised in drug evaluation is a professional who evaluates the efficacy, safety,appropriateness and efficiency of treatments prescribed by physicians,and decision-making must be based on both technical factors and thefour principles of bioethics. The correct application of evidence-based clinical practice allows to provide patients with increases in survival and/orquality of life, adapting the convenience and costs to the current situation.With this in mind, it could be said that the evaluation of medicines involvesa strong commitment to humanisation. On the other hand, organisationsthat promote the rigorous evaluation and selection of medicines standas allies of patients, as they have a direct impact on them and an indirect impact on society. Regulatory agencies in charge of approving andfinancing medicines in healthcare systems play a key role in the processof humanising clinical decision-making and empowering patients. If theseagencies approve the use of new medicines based on data that do notmeasure quality of life or survival of patients when there are already othertherapeutic alternatives for these pathologies, they are indirectly failing tomeet patients’ expectations and are infringing bioethical principles. (AU)

Concordance between expectations and preferences of patients and evaluation criteria of the European Medicines Agency.

OBJECTIVE: The European Medicines Agency's marketing authorisation criteria  for drugs are reflected in the European Public Assessment Reports. The  objective is to describe the expectations and preferences of our  oncohematological outpatients with respect to their oral treatments, and to  evaluate the concordance with the results of European Public Assessment Reports. METHOD: A survey of onco-hematological patients' expectations and preferences about overall survival and quality of life was developed, with three items: expectations on treatment, preferences of benefit and  willingness to receive novel treatments with non-definitive results. European  Public Assessment Reports of the indicated drugs were reviewed. Kappa index  (κ) was used to assess the agreement between patients' expectations  and preferences respect to the benefit in overall survival and quality of life  described in the corresponding European Public Assessment Report.  Concordance between willingness of patients to receive novel treatments and European Public Assessment Reports results was evaluated by absolute  agreement (Ao). RESULTS: There were 29 participants, and 19 different European Public Assessment Reports were consulted. Patients' expectations about their  treatment: 82.1% expected improvement in overall survival and quality of life; the κ value between expectations and results of European Public Assessment Reports was 0.091 (confidence interval 95%: -0.025 to 0.207). Patients' preferences about benefit of their treatment: 92.6%  preferred quality of life; the κ value was 0.016 (confidence interval 95%: - 0.127 to 0.160). Willingness to receive novel treatments: 82.1% participants demanded benefit in overall survival or quality of life; exigences were met in Ao = 53.6% of patients. CONCLUSIONS: Little agreement was observed between expectations and  preferences of our onco-hematological patients and European Public Assessment Reports, according to overall survival and quality of life.  Most patients preferred an improvement in quality of life, but also expected  an  increase in overall survival with their treatment. Almost half of  patients would not meet their requirements to receive their drug when it was  authorized.

OBJETIVO: Los criterios de autorización de comercialización de medicamentos de la Agencia Europea del Medicamento se reflejan en los European Public Assessment Reports. El objetivo es describir las  expectativas y preferencias de nuestros pacientes externos oncohematológicos con respecto a sus tratamientos orales, y evaluar la  concordancia con los resultados de los European Public Assessment Reports. Método: Se elaboró una encuesta sobre las expectativas y preferencias de los  pacientes oncohematológicos respecto a la supervivencia global y calidad de  vida, con tres ítems: expectativas sobre el tratamiento, preferencias de  beneficio y disposición a recibir tratamientos novedosos con resultados  inmaduros. Se revisaron los European Public Assessment Reports de los  fármacos indicados. Se utilizó el índice kappa (κ) para evaluar la concordancia  entre las expectativas y preferencias de los pacientes respecto al beneficio en  supervivencia global y calidad de vida descrito en el European Public  Assessment Report correspondiente. La concordancia entre la disposición de  los pacientes a recibir nuevos tratamientos y los resultados de los European  Public Assessment Reports se evaluó mediante la concordancia absoluta (Ao). RESULTADOS: Se incluyeron 29 participantes y se consultaron 19 European Public Assessment Reports diferentes. Expectativas de los pacientes sobre su tratamiento: el 82,1% esperaba una mejora de la  supervivencia global y calidad de vida; el valor κ entre las expectativas y los  resultados de los European Public Assessment Reports fue de 0,091 (intervalo  de confianza 95%: ­0,025 a 0,207). Preferencias de los pacientes sobre el beneficio de su tratamiento: el 92,6% prefirió la calidad de vida; el valor κ fue de 0,016 (intervalo de confianza 95%: ­0,127 a 0,160). Disposición a  recibir tratamientos novedosos: el 82,1% de los participantes exigió un beneficio en la supervivencia global o en la calidad de vida; las exigencias se cumplieron en Ao = 53,6% de los pacientes. CONCLUSIONES: Se observó poca concordancia entre las expectativas y  preferencias de nuestros pacientes oncohematológicos y los European Public  Assessment Reports, según la supervivencia global y la calidad de vida. La  mayoría de los pacientes preferían una mejora de la calidad de vida, pero  también esperaban un aumento de la supervivencia global con su tratamiento.  Casi la mitad de los pacientes no cumpliría con sus requisitos para recibir su  medicación cuando ésta fuera autorizada.

Systematic review and meta-analysis of interleulin-6 inhibitors in reducing mortality for hospitalized patients with COVID-19.

OBJECTIVE: One year after the declaration of the SARS-CoV-2 pandemic, only  dexamethasone has clearly shown a reduction in mortality for COVID-19  hospitalized patients. For interleukin-6 inhibitors, results are variable and  nclear. The objective was to review and analyze the effect of tocilizumab and  sarilumab on survival in this setting. METHOD: The PRISMA statements were fulfilled for the systematic review. A  systematic search in Medline, Embase and medRxiv was conducted to identify  randomized controlled trials with tocilizumab or sarilumab in hospitalized  patients with COVID-19. Mortality data from non-critical and critical patients  were extracted. A random-effects (DerSimonian-Laird) meta-analysis was  performed for both subgroups and the whole population using MAVIS software  v. 1.1.3. Similarity and homogeneity among trials were assessed. RESULTS: Twenty-five and 23 articles were identified in Medline and Embase,  respectively, five were trials with tocilizumab and/or sarilumab; two more were  identified at medRxiv. Seven randomized clinical trials fulfilled the  inclusion criteria. Another trial was pre-published and included post-hoc. The  meta-analysis, with eight randomized clinical trials and 6,340 patients, showed  a benefit on mortality for interleukin-6  heterogeneity (I2 = 7%), but  a low similarity among studies. The results showed no differences among  critical and non-critical patients. A sensitivity analysis excluding non-similar or  heterogeneous studies showed different results, without benefit and with low  precision of the result in non-critical patients. CONCLUSIONS: A benefit in mortality for interleukine-6 inhibitors was found, but  with important differences among the scenarios analyzed in the clinical  trials. Positive results are mainly caused by two randomized clinical trials which  are similar in concomitant use of steroids and veryhigh mortality in  critical patents. Sarilumab was poorly represented in the meta-analysis.  Nevertheless, an association between the benefit and the critical/non-critical  condition was not found. More randomized clinical trials, mainly focused in  atients at high mortality risk, are needed to confirm the benefit of interleukine- 6 inhibitors for COVID-19. Sarilumab was underrepresented in the meta- analysis.

OBJETIVO: Un año después de la declaración de la pandemia por SARS­CoV-2,  solo dexametasona había mostrado claramente una reducción de la mortalidad  en pacientes hospitalizados por COVID-19. Los resultados de los inhibidores de  interleucina 6 son diversos y poco claros. El objetivo de este trabajo es  revisar y analizar el efecto de tocilizumab y sarilumab sobre la supervivencia  de los pacientes en este escenario.Método: La revisión sistemática siguió las recomendaciones de PRISMA. Se  realizó una búsqueda sistemática en Medline, Embase y medRxiv para identificar ensayos controlados aleatorizados con tocilizumab o sarilumab  en pacientes hospitalizados con COVID-19. Se recopilaron los datos de mortalidad de pacientes críticos y no críticos y se llevó a cabo un metaanálisis de efectos aleatorios (Der Simonian-Laird) para ambos  subgrupos y para toda la población, usando el software MAVIS v. 1.1.3. La similitud y homogeneidad entre los ensayos fue evaluada. RESULTADOS: Se identificaron 25 y 23 artículos en Medline y Embase, respectivamente; cinco eran ensayos con tocilizumab y/o sarilumab;  se identificaron dos más en medRxiv. En total, siete ensayos clínicos  aleatorizados cumplieron los criterios de inclusión. Posteriormente, se  prepublicó otro ensayo que cumplía los criterios de inclusión y se incorporó al  análisis. El metaanálisis, con ocho ensayos clínicos aleatorizados y 6.340  pacientes, mostró un beneficio sobre la mortalidad para los inhibidores de  interleucina-6 (hazard ratio 0,85; intervalo de confianza al 95% 0,74-0,99),  con baja heterogeneidad (I2 = 7%), pero reducida similitud entre los estudios.  Los resultados no mostraron diferencias entre pacientes críticos y no  críticos. Un análisis de sensibilidad excluyendo estudios heterogéneos o no  similares mostró resultados diferentes, sin beneficio y con baja precisión del  resultado en pacientes no críticos. CONCLUSIONES: Se encontró un beneficio en la mortalidad de los inhibidores de  la interleucina 6, pero con importantes diferencias entre los escenarios analizados en los ensayos clínicos. Los resultados positivos se  eben principalmente a dos ensayos que son similares en el uso concomitante  de esteroides y una mortalidad muy alta en pacientes críticos. Sarilumab estuvo escasamente representado en el metaanálisis. Sin embargo, el metaanálisis por subescenarios no encontró una relación entre  el beneficio y la condición de pacientes críticos/no críticos. Se necesitan más ensayos clínicos aleatorizados, principalmente enfocados en  pacientes con alto riesgo de mortalidad, para confirmar el beneficio de los  inhibidores de interleucina-6 en COVID-19.

Concordancia entre las expectativas y preferencias de los pacientes y los criterios de evaluación de la Agencia Europea del Medicamento / Concordance between expectations and preferences of patients and evaluation criteria of the European Medicines Agency

Objetivo: Los criterios de autorización de comercialización de medicamentosde la Agencia Europea del Medicamento se reflejan en losEuropean Public Assessment Reports. El objetivo es describir las expectativasy preferencias de nuestros pacientes externos oncohematológicoscon respecto a sus tratamientos orales, y evaluar la concordancia con losresultados de los European Public Assessment Reports.Método: Se elaboró una encuesta sobre las expectativas y preferenciasde los pacientes oncohematológicos respecto a la supervivencia globaly calidad de vida, con tres ítems: expectativas sobre el tratamiento, preferenciasde beneficio y disposición a recibir tratamientos novedosos conresultados inmaduros. Se revisaron los European Public Assessment Reportsde los fármacos indicados. Se utilizó el índice kappa (κ) para evaluar laconcordancia entre las expectativas y preferencias de los pacientes respectoal beneficio en supervivencia global y calidad de vida descrito enel European Public Assessment Report correspondiente. La concordanciaentre la disposición de los pacientes a recibir nuevos tratamientos y losresultados de los European Public Assessment Reports se evaluó mediantela concordancia absoluta (Ao). Resultados: Se incluyeron 29 participantes y se consultaron 19 EuropeanPublic Assessment Reports diferentes.

Objective: The European Medicines Agency’s marketing authorisationcriteria for drugs are reflected in the European Public Assessment Reports.The objective is to describe the expectations and preferences of our oncohematologicaloutpatients with respect to their oral treatments, and toevaluate the concordance with the results of European Public AssessmentReports.Method: A survey of onco-hematological patients’ expectations andpreferences about overall survival and quality of life was developed, withthree items: expectations on treatment, preferences of benefit and willingnessto receive novel treatments with non-definitive results. European PublicAssessment Reports of the indicated drugs were reviewed. Kappa index(κ) was used to assess the agreement between patients’ expectations andpreferences respect to the benefit in overall survival and quality of lifedescribed in the corresponding European Public Assessment Report. Concordancebetween willingness of patients to receive novel treatments andEuropean Public Assessment Reports results was evaluated by absoluteagreement (Ao). Results: There were 29 participants, and 19 different European PublicAssessment Reports were consulted. Patients’ expectations about theirtreatment: 82.1% expected improvement in overall survival and qualityof life; the κ value between expectations and results of European PublicAssessment Reports was 0.091 (confidence interval 95%: –0.025 to0.207). Patients’ preferences about benefit of their treatment: 92.6% preferredquality of life; the κ value was 0.016 (confidence interval 95%:–0.127 to 0.160). Willingness to receive novel treatments: 82.1% participantsdemanded benefit in overall survival or quality of life; exigenceswere met in Ao = 53.6% of patients.

Revisión sistemática y metaanálisis de inhibidores de interleucina-6 para reducir la mortalidad en pacientes hospitalizados con COVID-19 / Systematic review and meta-analysis of interleulin-6 inhibitors in reducing mortality for hospitalized patients with COVID-19

Objetivo: Un año después de la declaración de la pandemia porSARS‑CoV-2, solo dexametasona había mostrado claramente una reducciónde la mortalidad en pacientes hospitalizados por COVID-19. Losresultados de los inhibidores de interleucina 6 son diversos y poco claros.El objetivo de este trabajo es revisar y analizar el efecto de tocilizumaby sarilumab sobre la supervivencia de los pacientes en este escenario.Método: La revisión sistemática siguió las recomendaciones de PRISMA.Se realizó una búsqueda sistemática en Medline, Embase y medRxiv paraidentificar ensayos controlados aleatorizados con tocilizumab o sarilumaben pacientes hospitalizados con COVID-19. Se recopilaron los datosde mortalidad de pacientes críticos y no críticos y se llevó a cabo unmetaanálisis de efectos aleatorios (Der Simonian-Laird) para ambos subgruposy para toda la población, usando el software MAVIS v. 1.1.3. Lasimilitud y homogeneidad entre los ensayos fue evaluada.Resultados: Se identificaron 25 y 23 artículos en Medline y Embase,respectivamente; cinco eran ensayos con tocilizumab y/o sarilumab; seidentificaron dos más en medRxiv. En total, siete ensayos clínicos aleatorizadoscumplieron los criterios de inclusión. Posteriormente, se prepublicóotro ensayo que cumplía los criterios de inclusión y se incorporó absoalanálisis. El metaanálisis, con ocho ensayos clínicos aleatorizados y6.340 pacientes, mostró un beneficio sobre la mortalidad para los inhibidoresde interleucina-6 (hazard ratio 0,85; intervalo de confianza al 95%0,74-0,99), con baja heterogeneidad (I2 = 7%), pero reducida similitudentre los estudios. Los resultados no mostraron diferencias entre pacientescríticos y no críticos. Un análisis de sensibilidad excluyendo estudios heterogéneoso no similares mostró resultados diferentes, sin beneficio y conbaja precisión del resultado en pacientes no críticos.

Objective: One year after the declaration of the SARS-CoV-2 pandemic,only dexamethasone has clearly shown a reduction in mortality forCOVID-19 hospitalized patients. For interleukin-6 inhibitors, results arevariable and unclear. The objective was to review and analyze the effectof tocilizumab and sarilumab on survival in this setting.Method: The PRISMA statements were fulfilled for the systematic review.A systematic search in Medline, Embase and medRxiv was conductedto identify randomized controlled trials with tocilizumab or sarilumab inhospitalized patients with COVID-19. Mortality data from non-critical andcritical patients were extracted. A random-effects (DerSimonian-Laird)meta-analysis was performed for both subgroups and the whole populationusing MAVIS software v. 1.1.3. Similarity and homogeneity amongtrials were assessed.Results: Twenty-five and 23 articles were identified in Medline andEmbase, respectively, five were trials with tocilizumab and/or sarilumab;two more were identified at medRxiv. Seven randomized clinical trialsfulfilled the inclusion criteria. Another trial was pre-published and includedpost-hoc. The meta-analysis, with eight randomized clinical trialsand 6,340 patients, showed a benefit on mortality for interleukin-6 inhibitor (hazard ratio 0.85; confidence interval 95% 0.74-0.99), lowheterogeneity (I2 = 7%), but a low similarity among studies. The resultsshowed no differences among critical and non-critical patients. A sensitivityanalysis excluding non-similar or heterogeneous studies showeddifferent results, without benefit and with low precision of the result innon-critical patients.

Belantamab mafodotin for relapsed or refractory multiple myeloma.

Objective: Refractory multiple myeloma (MM) presents poor responses to therapies. New drugs for highly pretreated MM are a hope for this clinical context with limited treatment options. We developed a comparative commentary on the evidence about the use of belantamab mafodotin in heavily pretreated relapsed or refractory MM with respect to other therapies. Data sources: Regimen data were extracted from pivotal clinical trials. Data summary: Response rates were the main efficacy outcomes reported in trials. Overall response was achieved by approximately 30% of patients trated with belantamab mafodotin. Response rates of different regimens must be supported by more relevant data, such as overall survival or progression-free survival. Subgroups of patients with extramedullary disease and revised International Staging System III should be thoroughly evaluated in phase III comparative clinical trials with larger sample sizes. Belantamab mafodotin presented specific adverse events (visual disturbances and kerathopathies). Grade 3-4 adverse events involved high percentages of patients treated with the different schemes. The budgetary impact of different treatments for heavily pretreated refractory MM would be very high. Literature suggested increased efficiency of belantamab mafodotin versus chimeric antigen receptor T-cell therapies. Conclusions: Belantamab mafodotin and other regimens are promising drugs for MM, especially for triple-class refractory patients. Comparative studies are necessary to perform a reliable therapeutic positioning.

Clinical and pharmacoeconomic impact of subgroup analysis in onco-hematological patients.

Subgroup analysis evaluates a health intervention in subpopulations according to a characteristic or factor. It can be useful for generating new hypotheses or conducting new studies. However, subgroup analysis presents several limitations and it should be considered cautiously. The development of new onco-hematological drugs is accelerating in recent years and the impact of subgroup analysis on clinical decision-making is increasing. The interpretation of subgroup analyses can be controversial in some cases, negatively affecting patients and healthcare systems. This work is a review of the clinical and pharmacoeconomic impact of subgroup analysis in onco-hematological patients. The study describes some illustrative examples of inadequate interpretations about subset analysis: combination of pembrolizumab plus chemotherapy in lung cancer, inhibitors of cyclin-dependent kinases in breast cancer, daratumumab-based regimens in newly diagnosed multiple myeloma, combination of nivolumab with ipilimumab in melanoma and docetaxel in prostate cancer. Subgroup analysis can have a significant impact on the data selection for the development of studies; efficacy, safety, and convenience of treatments in onco-hematological patients; efficiency of therapies in health systems; and therapeutic positioning of antineoplastic drugs. There is a strong need to establish homogeneous criteria for the assessment of subgroup analysis and to develop new tools for its consideration.

Use of docetaxel in low- and high-burden metastatic hormone-sensitive prostate cancer: A systematic review and assessment of subgroup analyses.

BACKGROUND: Use of docetaxel in low- and high-burden metastatic hormone-sensitive prostate cancer presents considerable controversy. There is literature suggesting lack of benefit for low-volume of metastases. OBJECTIVE: The study aims to develop a systematic review and methodological assessment of subset analysis about use of docetaxel in metastatic hormone-sensitive prostate cancer regarding volume of metastatic disease. METHODS: A systematic review in the Pubmed® database was conducted up to 25 September 2020. A reference tracking was also developed. Randomised clinical trials with subgroup analysis according volume of metastatic disease for overall survival were selected. Two methodologies were used. One of them considered statistical interaction of subsets (p(i) < 0.1), pre-specification, biological plausibility and consistency among subset results of similar randomised clinical trials. The second methodology was a two-part validated tool: preliminary questions to discard subset analysis without minimal relevance and a checklist The checklist provides recommendations for applicability of subgroup analysis in clinical practice. RESULTS: A total of 31 results were found in systematic reviews in the Pubmed® database. One result was identified in the reference tracking. Of the total of 32 results, four randomised clinical trials were included in the study. About first methodology, statistical interaction among subgroups was obtained in one randomised clinical trial. Subgroup analysis was pre-specified in two randomised clinical trials. Biological plausibility was reasonable. No external consistency among results of subgroup analyses in randomised clinical trials was observed. Preliminary questions of second methodology rejected applicability of subgroup analysis in three randomised clinical trials. A 'null' recommendation for applicability of subset results was obtained in the remaining randomised clinical trial. CONCLUSIONS: Patients with low- and high-burden metastatic hormone-sensitive prostate cancer would benefit from docetaxel therapy. No consistent differences for overall survival were observed in subgroup analyses regarding volume of metastatic disease.

Remdesivir y reducción de mortalidad en pacientes con COVID-19: análisis sistematizado de subgrupos de los ensayos clínicos / Remdesivir and mortality reduction in COVID-19 patients: a systematized subgroup analysis of clinical trials

OBJETIVO: Remdesivir no ha mostrado beneficio en supervivencia para pacientes con COVID-19 grave. Sin embargo, el análisis por subgrupos del estudio ACTT-1 mostró aparente reducción de mortalidad en pacientes que requerían oxígeno -no de alto flujo-. La difusión de resultados del estudio SOLIDARITY se acompañó de un metaanálisis que combinó resultados de mortalidad por subgrupos de los ensayos clínicos aleatorizados. El objetivo del presente estudio es analizar metodológicamente la fiabilidad y aplicabilidad clínica de los hallazgos por subgrupos sobre el efecto de remdesivir en mortalidad en pacientes con COVID-19. MÉTODO: Se usó una herramienta validada para valorar los hallazgos de los análisis por subgrupos en ensayos clínicos aleatorizados, incluido el metaanálisis anexo al estudio SOLIDARITY. La herramienta utilizada está estructurada en cuestiones preliminares para descartar análisis por subgrupos sin condiciones mínimas relevantes, y un cuestionario específico. Este último considera determinados criterios: asociación estadística, incluyendo p de interacción, preespecificación de subgrupos, tamaño muestral, número de factores valorados y resultado global del estudio; plausibilidad biológica de las diferencias observadas; y consistencia entre resultados de estudios similares. Se asignó una puntuación a cada criterio y la herramienta relacionó el sumatorio global con una recomendación sobre la aplicabilidad de los resultados de los subgrupos en la toma de decisiones clínicas. RESULTADOS: Las cuestiones preliminares tuvieron respuestas positivas, aplicándose el cuestionario. La asociación estadística obtuvo valoración "nula" (-3 puntos), con p de interacción dudosa (p = 0,0650) y resultado de mortalidad no significativo en población global, restando fiabilidad al análisis de subgrupos. La plausibilidad biológica fue considerada "probable" (+3 puntos), ya que el antiviral pudiera tener mayor efecto antes del proceso inflamatorio y empeoramiento clínico. La consistencia se valoró "posible" (+2 puntos) por compatibilidad de resultados del estudio ACTT-1 y SOLIDARITY. La recomendación de aplicación del análisis por subgrupos según el riesgo de los pacientes fue "nula". CONCLUSIONES: Esta interpretación estructurada de análisis por subgrupos sugiere que la hipótesis de que remdesivir podría reducir la mortalidad en pacientes con COVID-19 grave que precisan oxígeno -no de alto flujo- presenta demasiada incertidumbre, y es probable que sea un hallazgo casual. Por tanto, es imprescindible la realización de un ensayo clínico aleatorizado sobre mortalidad en pacientes con oxígeno -no de alto flujo-

OBJECTIVE: Remdesivir has not shown survival benefit for patients with severe COVID-19. However, subgroup analysis of ACTT-1 Study Group showed an apparent reduction in mortality for patients who required non-high-flow oxygen. Presentation of SOLIDARITY study results were associated by a meta-analysis combining mortality results by subsets from randomized clinical trials. The aim is a methodological assessment of reliability and clinical applicability about findings by subgroups on the effect of remdesivir on mortality in patients with COVID-19. METHOD: A validated tool was used to evaluate the findings of subgroup analyses in randomized clinical trials, including meta-analysis attached to SOLIDARITY study. It is structured in preliminary questions to reject subset analyses without relevant minimum conditions, and a specific checklist. The latter considers certain criteria: statistical association, which encompassed p of interaction, prespecification of subgroups, sample size, number of factors analyzed, and overall study result; biological plausibility of observed differences; and consistency between results of similar studies. A score was assigned to each criterion and the tool related global summation to a recommendation on the applicability of subset results in clinical decision making. RESULTS: Preliminary questions had positive answers, so checklist was applied. Statistical association obtained "null" assessment (-3 points), including a "doubtful" p of interaction (p = 0.0650) among subgroups and mortality reached no statistical significance for global population. These findings reduced the reliability of subset analysis. Biological plausibility was considered "probable" (+3 points) because antiviral could have a greater effect before the inflammatory process and clinical worsening. Consistency between results of similar studies was evaluated as "possible" (+2 points) analysis for compatibility of ACTT-1 and SOLIDARITY study results. The recommendation about application of subset analysis results according to the risk of patients was "null". CONCLUSIONS: This structured interpretation of subgroup analysis suggested too much uncertainty in hypothesis about remdesivir could reduce mortality in patients with severe COVID-19 who required non-high-flow oxygen. It was probably a random finding. Therefore, a randomized clinical trial about effect of remdesivir in mortality in patients with COVID-19 and non-high-flow oxygen is essential

Remdesivir and mortality reduction in COVID-19 patients: a systematized subgroup analysis of clinical trials.

OBJECTIVE: Remdesivir has not shown survival benefit for patients with severe COVID-19. However, subgroup analysis of ACTT-1 Study Group showed an apparent reduction in mortality for patients who required non­high-flow oxygen. Presentation of SOLIDARITY study results were associated by a meta-analysis combining mortality results by subsets rom randomized clinical trials. The aim is a methodological assessment of reliability and clinical applicability about findings by subgroups on the effect of remdesivir on mortality in patients with COVID-19. METHOD: A validated tool was used to evaluate the findings of subgroup analyses in randomized clinical trials, including meta-analysis atached to SOLIDARITY study. It is structured in preliminary questions to  reject subset analyses without relevant minimum conditions, and a specific checklist. The latter considers certain criteria: statistical association, which encompassed p of interaction, prespecification of subgroups, sample size,  number of factors analyzed, and overall study result; biological plausibility of observed differences; and consistency between results of  similar studies. A score was assigned to each criterion and the tool related  global summation to a recommendation on the applicability of subset  results in clinical decision making. RESULTS: Preliminary questions had positive answers, so checklist was applied. Statistical association obtained "null" assessment (-3 points), including a "doubtful" p of interaction (p = 0.0650) among  subgroups and mortality reached no statistical significance for global  population. These findings reduced the reliability of subset analysis.  Biological plausibility was considered "probable" (+3 points) because  antiviral could have a greater effect before the inflammatory process and  clinical worsening. Consistency between results of similar studies was  evaluated as "possible" (+2 points) analysis for compatibility of ACTT-1  and SOLIDARITY study results. The recommendation about application of  subset analysis results according to the risk of patients was "null". CONCLUSIONS: This structured interpretation of subgroup analysis  suggested too much uncertainty in hypothesis about remdesivir could  reduce mortality in patients with severe COVID-19 who required non-high- flow oxygen. It was probably a random finding. Therefore, a randomized  clinical trial about effect of remdesivir in mortality in patients with  COVID­19 and non-high-flow oxygen is essential.

Objetivo: Remdesivir no ha mostrado beneficio en supervivencia para pacientes con COVID-19 grave. Sin embargo, el análisis por  subgrupos del estudio ACTT-1 mostró aparente reducción de mortalidad en pacientes que requerían oxígeno ­no de alto flujo­. La difusión de  resultados del estudio SOLIDARITY se acompañó de un metaanálisis que  combinó resultados de mortalidad por subgrupos de los ensayos clínicos  aleatorizados. El objetivo del presente estudio es analizar  metodológicamente la fiabilidad y aplicabilidad clínica de los hallazgos por  subgrupos sobre el efecto de remdesivir en mortalidad en pacientes con  COVID-19.Método: Se usó una herramienta validada para valorar los hallazgos de  los análisis por subgrupos en ensayos clínicos aleatorizados, incluido el  metaanálisis anexo al estudio SOLIDARITY. La herramienta utilizada está estructurada en cuestiones preliminares para descartar análisis por  subgrupos sin condiciones mínimas relevantes, y un cuestionario  específico. Este último considera determinados criterios: asociación  estadística, incluyendo p de interacción, preespecificación de subgrupos,  tamaño muestral, número de factores valorados y resultado global del  estudio; plausibilidad biológica de las diferencias observadas; y  consistencia entre resultados de estudios similares. Se asignó una  puntuación a cada criterio y la herramienta relacionó el sumatorio global  con una recomendación sobre la aplicabilidad de los resultados de los  subgrupos en la toma de decisiones clínicas.Resultados: Las cuestiones preliminares tuvieron respuestas positivas, aplicándose el cuestionario. La asociación estadística obtuvo  valoración "nula" (­3 puntos), con p de interacción dudosa (p = 0,0650) y  resultado de mortalidad no significativo en población global, restando  fiabilidad al análisis de subgrupos. La plausibilidad biológica fue  considerada "probable" (+3 puntos), ya que el antiviral pudiera tener  mayor efecto antes del proceso inflamatorio y empeoramiento clínico. La  consistencia se valoró "posible" (+2 puntos) por compatibilidad de  resultados del estudio ACTT-1 y SOLIDARITY. La recomendación de  aplicación del análisis por subgrupos según el riesgo de los pacientes fue  "nula".Conclusiones: Esta interpretación estructurada de análisis por subgrupos sugiere que la hipótesis de que remdesivir podría reducir la  mortalidad en pacientes con COVID-19 grave que precisan oxígeno ­no de  alto flujo­ presenta demasiada incertidumbre, y es probable que sea un  hallazgo casual. Por tanto, es imprescindible la realización de un ensayo  clínico aleatorizado sobre mortalidad en pacientes con oxígeno ­no de alto  flujo­.

Comparación indirecta ajustada de anticuerpos monoclonales contra el péptido relacionado con el gen de la calcitonina en migraña crónica / Monoclonal antibodies against calcitonin gene-related peptide in chronic migraine: an adjusted indirect treatment comparison

OBJETIVO: Recientemente se han desarrollado anticuerpos monoclonales contra la vía del péptido relacionado con el gen de la calcitonina para la prevención de la migraña. El objetivo de este estudio es comparar la eficacia de los fármacos anticuerpos monoclonales contra la vía del péptido relacionado con el gen de la calcitonina en migraña crónica a través de una comparación indirecta ajustada, y establecer si pueden considerarse alternativas terapéuticas equivalentes en esta patología. MÉTODO: Se realizó una búsqueda bibliográfica de ensayos clínicos aleatorizados en la base de datos PubMed el 26 de diciembre de 2019. Los criterios de inclusión fueron: ensayos clínicos aleatorizados fase II/III de anticuerpos monoclonales contra la vía del péptido relacionado con el gen de la calcitonina con similar población, duración de seguimiento y comparador. Se seleccionó la reducción de al menos un 50% de días de migraña/mes como variable de eficacia. Se definió migraña crónica como ≥ 15 días de dolor de cabeza/mes, de los cuales ≥ 8 fueron días de migraña (duración del evento ≥ 4 horas). Se excluyeron los ensayos clínicos aleatorizados con diferentes contextos clínicos de migraña crónica y definición de enfermedad. Se desarrolló una compa-ración indirecta ajustada utilizando el método de Bucher. Para la evaluación de la posible equivalencia terapéutica se siguieron las directrices de la guía de alternativas terapéuticas equivalentes de posicionamiento. El valor delta (Δ, máxima diferencia como criterio clínico de equivalencia) se calculó como la mitad de la reducción absoluta del riesgo obtenida en un metaanálisis de los ensayos clínicos aleatorizados incluidos en la comparación indirecta ajustada. RESULTADOS: Se encontraron 30 ensayos clínicos aleatorizados: erenumab (n = 12), fremanezumab (n = 7), galcanezumab (n = 10) y eptinezumab (n = 1). Se seleccionaron tres estudios: uno de erenumab, uno de fremanezumab y otro de eptinezumab. El resto no se incluyó en la comparación indi-recta ajustada por incumplimiento de los criterios de inclusión. Los resultados de la comparación indirecta ajustada entre las diferentes posologías de los fármacos estudiados no mostraron diferencias estadísticamente signifi-cativas, y la mayor parte del intervalo de confianza del 95% se encontró dentro de los márgenes delta calculados (Δ = 9,5%). No se encontraron diferencias de seguridad relevantes entre los tres medicamentos. CONCLUSIONES: La comparación indirecta ajustada no mostró diferencias estadísticamente significativas en la reducción de ≥ 50% de días de migraña/mes entre erenumab, fremanezumab y eptinezumab. Se encontró una probable equivalencia clínica entre estos fármacos en términos de eficacia y seguridad, por lo que podrían considerarse alternativas terapéuticas equivalentes en migraña crónica

OBJECTIVE: New monoclonal antibodies against the calcitonin gene-related peptide pathway have recently been developed for the prevention of migraine. The aim of this study is to compare the efficacy of monoclonal antibodies against the calcitonin generelated peptide pathway drugs in chronic migraine through an adjusted indirect treatment comparison, and to establish whether they can be considered equivalent therapeutic alter-natives in this pathology. METHOD: A bibliographic search of randomized clinical trials was performed in PubMed database on December 26, 2019. The inclusion criteria were phase II/III randomized clinical trials of monoclonal anti-bodies against the calcitonin generelated peptide pathway with similar population, length of follow-up and treatment comparator. The reduction of at least 50% migraine-days/month was selected as efficacy endpoint. Chronic migraine was defined as ≥ 15 headache days/month, of which ≥ 8 were migraine-days (event duration ≥ 4 hours). Randomized clinical trials with different clinical chronic migraine context and definition of disease were excluded. An indirect treatment comparison was developed using Bucher's method. The equivalent therapeutic alternatives positioning guide was used for the evaluation of potentially equivalent alternatives. Delta value (Δ, maximum difference as clinical criterion of equivalence) was calculated as half of absolute risk reduction obtained in a meta-analysis of randomized clinical trials included in indirect treatment comparison. RESULTS: Thirty randomized clinical trials were found: erenumab (n = 12), fremanezumab (n = 7), galcanezumab (n = 10) and eptinezumab (n = 1). Three studies were selected: one of erenumab, one of fremanezumab and another of eptinezumab. The rest were not included in indirect treatment comparison for non-compliance of inclusion criteria. Results of indirect treatment comparison among different regimens of studied drugs showed no statistically significant differences, and the most part of 95% confidence interval was within calculated delta margins (Δ = 9.5%). No relevant safety differences among the three drugs were found. CONCLUSIONS: Indirect treatment comparison showed no statistically sig-nificant differences in reduction of ≥ 50% migraine days/month between erenumab, fremanezumab and eptinezumab. Probable clinical equiva-lence was found between these drugs in terms of efficacy and safety, therefore they could be considered equivalent therapeutic alternatives in chronic migraine