Composite endpoint for ALS clinical trials based on patient preference: Patient-Ranked Order of Function (PROOF)

BackgroundPatients with amyotrophic lateral sclerosis (ALS) show considerable variation in symptoms. Treatments targeting an overall improvement in symptomatology may not address what the majority of patients consider to be most important. Here, we propose a composite endpoint for ALS clinical trials that weighs the improvement in symptoms compared with what the patient population actually wants.MethodsAn online questionnaire was sent out to a population-based registry in The Netherlands. Patients with ALS were asked to score functional domains with a validated self-reported questionnaire, and rank the order of importance of each domain. This information was used to estimate variability in patient preferences and to develop the Patient-Ranked Order of Function (PROOF) endpoint.ResultsThere was extensive variability in patient preferences among the 433 responders. The majority of the patients (62.1%) preferred to prioritise certain symptoms over others when evaluating treatments. The PROOF endpoint was established by comparing each patient in the treatment arm to each patient in the placebo arm, based on their preferred order of functional domains. PROOF averages all pairwise comparisons, and reflects the probability that a patient receiving treatment has a better outcome on domains that are most important to them, compared with a patient receiving placebo. By means of simulation we illustrate how incorporating patient preference may upgrade or downgrade trial results.ConclusionsThe PROOF endpoint provides a balanced patient-focused analysis of the improvement in function and may help to refine the risk–benefit assessment of new treatments for ALS.

A Population-Based Registry Analysis on Hospitalized COVID-19 Patients with Previous Cardiovascular Disease: Clinical Profile, Treatment, and Predictors of Death

A high percentage of patients with COVID-19 (coronavirus disease 2019) have previous cardiovascular disease (CVD). The findings presented here came from an epidemiological population-based registry study (real-world data) that enrolled all in-hospital COVID-19 patients with previous CVD from 1 March to 31 May 2020. Death, other comorbidities, hospital stay variables, ventilation type, and main clinical outcomes were evaluated. In Castile and Leon, 35.83% of the 7307 in-hospital COVID-19 patients who participated in this study had previous CVD, particularly arrhythmias (48.97%), cerebrovascular disease (25.02%), ischemic heart disease (22.8%), and chronic heart failure (20.82%). Of the patients, 21.36% were men and more than 90% were over 65 years of age, and the mortality rate achieved 32.93%. The most used medicines were antibiotics (91.41%), antimalarials (73.3%), steroids (46.64%), and antivirals (43.16%). The main predictors of death were age over 65 years (OR: 5), ventilation needs (OR: 2.81), treatment with anti-SIRS (systemic inflammatory response syndrome) medicines (OR: 1.97), antivirals (OR: 1.74) or steroids (OR: 1.68), SIRS (OR: 5.75), SARS (severe acute respiratory syndrome) (OR: 2.44), or AKI (acute kidney injury) (OR: 1.63) occurrence. Chronic heart failure and cerebrovascular disease were associated with a worse clinical course of COVID-19, especially in men older than 65 years with diabetes who developed SIRS, SARS, or AKI.

Abstract 12069: Long-Term Trends in the Incidence and Outcome of Refractory and Non-Refractory Ventricular Fibrillation Cardiac Arrest

Introduction: Although many developed countries are reporting temporal improvements in out-of-hospital cardiac arrest (OHCA) outcomes from initial shockable rhythms, trends in the incidence and outcome of refractory ventricular fibrillation are not well understood. Methods: Between 2010 and 2019, we performed a retrospective observational study of OHCA from a population-based registry in Victoria, Australia. We included all adult, non-traumatic OHCA with an initial shockable rhythm. Temporal trends in incidence and survival to hospital discharge were compared across non-refractory and refractory OHCA, defined as cases receiving 3 or more consecutive shocks for a persistent shockable rhythm. Risk-adjusted logistic regression models were used to describe the year-on-year change in the likelihood of refractory OHCA and survival to hospital discharge. Results: Of the 7,267 initial shockable OHCA with an attempted resuscitation, 4168 (57.4%) and 3,099 (42.6%) were non-refractory and refractory OHCA, respectively. The proportion of cases with refractory OHCA declined over the study period from 48.4% in 2010 to 40.2% in 2019 (p trend <0.001). Unadjusted survival to hospital discharge was higher in non-refractory OHCA (46.3% vs. 25.8%, p<0.001), although both populations experienced increases in survival over time (p trend <0.05 for both). After adjustment for arrest confounders, the likelihood of refractory VF decreased by 4.4% every year (adjusted odds ratio [AOR]: 0.96, 95% CI: 0.94, 0.97; p<0.001). Factors reducing the likelihood of refractory OHCA were female sex, bystander CPR, arrest witnessed by emergency medical services, and public location. In the survival model, refractory OHCA was independently associated with a reduction in survival to hospital discharge (AOR 0.50, 95% CI: 0.45, 0.56; p<0.001). Temporal improvements in survival were observed year-on-year (AOR 1.03, 95% CI: 1.02, 1.05; p<0.001) and this did not differ between non-refractory and refractory OHCA (group interaction, p = 0.51). Conclusions: The incidence of refractory OHCA is declining in our region and survival outcomes are improving. Further research identifying factors contributing to the decline in refractory OHCA may help to improve outcomes further.

Abstract 12097: The Impact of a High-Performance Cardiopulmonary Resuscitation Protocol on Survival From Out-of-Hospital Cardiac Arrests Witnessed by Paramedics

Introduction: Some emergency medical services (EMS) have shown increases in survival from out-of-hospital cardiac arrest (OHCA) following the implementation of a high-performance cardiopulmonary resuscitation (CPR) protocol. Despite this, little is known about the effect of high-performance CPR on OHCA witnessed by EMS personnel. Methods: We performed a retrospective cohort study of adult, EMS-witnessed OHCA patients of medical etiology from a population-based registry in Victoria, Australia. Patients treated after the introduction of a high-performance CPR protocol and training program between February 2019 and January 2020 were compared to historical controls between January 2015 and January 2019. The effect of the intervention on survival to hospital discharge was examined using logistic regression models adjusted for temporal and arrest factors. Results: A total of 1,561 and 420 EMS-witnessed OHCA patients were treated in the control and intervention periods, respectively. Baseline characteristics were similar across control and intervention periods, including the median age of cases (69 vs. 69 years, p=0.97), male sex (65.2% vs. 60.5%, p=0.08) and initial shockable arrests (33.7% vs. 29.3%, p=0.09). Resuscitation interventions were similar across groups, except for the use of mechanical CPR which declined during the intervention period (17.0% vs. 10.7%, p<0.001). Unadjusted survival to hospital discharge was similar across control and intervention periods for the overall population (29.4% vs. 32.1%, p=0.27), but significantly higher during the intervention period for initial shockable arrests (66.6% vs. 76.9%, p=0.03). After adjustment for confounders, cases in the intervention period were associated with a 43% increase (adjusted odds ratio [AOR] 1.43; 95% CI: 1.05, 1.94; p=0.02) in the risk-adjusted odds of survival to hospital discharge or a 79% increase (AOR 1.79, 95% CI: 1.09, 2.95; p=0.02) for initial shockable arrests. Conclusions: The implementation of a high-performance CPR quality improvement intervention was associated with significant improvement in survival from EMS witnessed OHCA. Efforts to monitor and improve CPR performance could yield further improvements in patient outcomes.

Acute and Post-Acute COVID-19 Severity and Mortality in Patients with Hematologic Malignancies: A Population-Based Registry Study

Introduction: The severity of acute clinical outcomes and mortality in hematologic malignancy (HM) patients infected by SARS-CoV-2 was exhaustively documented in the first weeks of the pandemic. A consistent increased mortality compared to non-cancer patients was observed across studies. In this study we aimed to estimate survival in COVID-19 HM patients by type of malignancy, to describe acute and post-acute clinical outcomes, and to compare outcomes in early and later pandemic periods. Methods: In this population-based registry study sponsored by the Madrid Society of Hematology (Asociación Madrileña de Hematología y Hemoterapia), we collected de-identified data on clinical characteristics, treatment and acute and post-acute outcomes in adult patients with hematologic malignancies and confirmed SARS-CoV-2 infection within the Madrid region of Spain. Our case series included all eligible patients admitted to 26 regional health service hospitals and 5 private healthcare centers between February 28, 2020 and February 18, 2021 with a coverage of 98% on a population of 6.6 million inhabitants. The study outcomes were all-cause mortality, severity of disease (WHO), oxygen support, ICU admission, and follow-up symptoms and signs and complications. Survival probabilities were estimated with the actuarial method and reported overall and stratified by type of malignancy and for two study periods (early cohort,-COVID-19 diagnosis from February 28 to 31 May, 2020, and later cohort, up to February 18, 2021). Results: Of the 1408 patients reported to the HEMATO-MADRID COVID-19 registry, 1166 were included in the present analyses; 839 (72%) had a lymphoid malignancy, including 325 (28%) with non-Hodgkin lymphoma, 50 (4%) with Hodgkin lymphoma and 263 (23%) with multiple myeloma; and 327 (28%) had a myeloid malignancy, including 115 (10%) with myelodysplastic syndrome, 92 (8%) with acute myeloid leukemia (AML) and 87 (7%) with Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms. Overall COVID-19 clinical severity was classified as critical in 19% of patients, severe in 36%, moderate in 22%, and mild in 22%; 10% were admitted to an ICU; 8% were on mechanical ventilation and 19% on noninvasive ventilation. Mild disease increased between early and later period from 15% to 38% of patients; severe disease decreased from 42% to 24%, p&lt;0.001. COVID-19 treatment with steroids increased from 38% to 59%, p&lt;0.001. At follow-up, 22% reported persistent symptoms related to COVID-19 at 2 months, 16% at 4 months and 14% at 6 months. 381 of 1166 (33%) patients died. Overall 30-day survival was 68%; 2 and 3-month overall survival probabilities were 56% and 53%, respectively. Survival was more favorable for patients with myeloproliferative neoplasms (82%, 69% and 65% at 30-days, 2 and 3 months, respectively) than for those with lymphoid malignancies (68%, 56% and 54%) or myelodysplastic syndrome/acute myeloid leukemia (61%, 51%, 46%), p=001. 285 (37%) patients died in the early period vs 96 (24%) in the later, p&lt;0.001, but median (interquartile range) follow-up time was much higher in the early vs later, 45 (20-116) days vs. 26 (11-86), respectively. Overall survival was not different between periods, p=0.5 (hazard ratio [95%C], 0.93 [0.73-1.17]). In the later cohort, 30 and 60-day survival probabilities were 71% and 56% vs. 67% and 56% in the early cohort Conclusions. A population-based registry in Spain provided strong evidence that although COVID-19 severity decreased over year 1 of the pandemic, mortality remained high, and survival was stable over time in the group of patients with hematological malignancy infected by SARS-Coc-2. A relevant proportion of the infected patients (1 in 6) referred persistent symptoms attributable to COVID-19. The improved clinical management of severe COVID-19 in non-cancer patients that followed the dissemination of evidence-based recommendations did not translate in more favorable survival in patients with hematological malignancies. Research is needed to address the specific characteristics and improve the clinical management of this vulnerable population. Disclosures Martinez-Lopez: Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Incyte: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau. Jiménez-Yuste: Pfizer: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; NovoNordisk: Consultancy, Honoraria, Research Funding; BioMarin: Consultancy; Sobi: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding. Kwon: Gilead: Honoraria.