Clinical Effectiveness of Antifibrotic Medications for Idiopathic Pulmonary Fibrosis.

Rationale: Since their approval, there has been no real-world or randomized trial evidence evaluating the effect of the antifibrotic medications pirfenidone and nintedanib on clinically important outcomes such as mortality and hospitalizations. Objectives: To evaluate the clinical effectiveness of the antifibrotic medications pirfenidone and nintedanib in patients with idiopathic pulmonary fibrosis. Methods: Using a large U.S. insurance database, we identified 8,098 patients with idiopathic pulmonary fibrosis between October 1, 2014 and March 1, 2018. A one-to-one propensity score-matched cohort was created to compare patients treated with antifibrotic medications (n = 1,255) with those not on treatment (n = 1,255). The primary outcome was all-cause mortality. The secondary outcome was acute hospitalizations. Subgroup analyses were performed to evaluate mortality differences by drug. Measurements and Main Results: The use of antifibrotic medications was associated with a decreased risk of all-cause mortality (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.62-0.98; P value = 0.034). However, this association was present only through the first 2 years of treatment. There was also a decrease in acute hospitalizations in the treated cohort (HR, 0.70; 95% CI, 0.61-0.80; P value <0.001). There was no significant difference in all-cause mortality between patients receiving pirfenidone and those on nintedanib (HR, 1.14; 95% CI, 0.79-1.65; P = 0.471). Conclusions: Among patients with idiopathic pulmonary fibrosis, antifibrotic agents may be associated with a lower risk of all-cause mortality and hospitalization compared with no treatment. Future research should test the hypothesis that these treatments reduce early, but not long-term, mortality as demonstrated in our study.

Is it time to consider a "time-out" before primary prevention implantable cardioverter-defibrillator placement in currently or recently hospitalized older patients with heart failure?

BACKGROUND: Trajectories of mortality after primary prevention implantable cardioverter-defibrillator (ICD) placement for older patients with heart failure during or soon after acute hospitalization have not been assessed. OBJECTIVE: The purpose of this study was to compare trajectories of mortality after primary prevention ICD placement during or soon after acute cardiac or non-cardiac hospitalization. METHODS: We identified older patients with heart failure undergoing primary prevention ICD placement using 20% Medicare data (2008-2018). Placement settings were as follows: (1) Current-H-during current hospitalization, (2) Recent-H-within 90 days of hospitalization, or (3) Chronic stable. Hospitalization was categorized as cardiac vs non-cardiac. Interval mortality rates and hazard ratios (HRs) using Cox regression were estimated at 0-30, 31-90, and 91-365 days after ICD placement. RESULTS: Of the 61,710 patients (mean age 76 years; 35% female; 85% white), 19% (11,947), 25% (15,147), and 56% (34,616) had ICDs in Current-H, Recent-H, and Chronic stable settings. Mortality rates (per 100 person-years) were highest during 0-30 days, with 38 (34-42) and 22 (19-24) for Current-H and Recent-H, which declined to 21 (20-22) and 16 (15-17) during 91-365 days, respectively. Compared to Chronic stable, HRs were highest during 0-30 days post-ICD placement (5.5 [4.5-6.8] for Current-H and 3.4 [2.8-4.2] for Recent-H) and decreased during 91-365 days (2.0 [1.8-2.1] for Current-H and 1.6 [1.5-1.7] for Recent-H). HR pattens were similar for cardiac and non-cardiac hospitalizations. CONCLUSION: Primary prevention ICD placement during or soon after hospitalization for any reason was associated with worse mortality with diminishing risks after 90 days. Hospitalization likely identifies a sicker population in whom early mortality with or without ICD may be higher. Our results support careful consideration regarding ICD placement during the 90 days after hospitalization.

An assessment of completeness and medical coding of Medicare Advantage hospitalizations in two national data sets.

OBJECTIVE: To compare the Encounter Data System (EDS) and Medicare Provider Analysis and Review (MedPAR) completeness and medical coding of Medicare Advantage hospitalizations. DATA SOURCES: FY 2016-FY 2019 data limited to hospitals paid under Medicare's Inpatient Prospective Payment System. STUDY DESIGN: Secondary data analysis. DATA COLLECTION/EXTRACTION METHODS: Completeness of EDS and MedPAR data was estimated using the total number of unique hospitalizations in both data sources as denominator. Deriving this denominator involved matching cases in the EDS and MedPAR by MA enrollee, discharge date, and hospital. The higher the match rate, the more informative the comparison of EDS and MedPAR medical coding of the same hospitalization. EDS and MedPAR codes were assessed for similarity on six measures of Medicare Severity Diagnosis-Related Group (MS-DRG) assignment and identical diagnosis and procedure codes. PRINCIPAL FINDINGS: EDS hospitalizations' completeness increased steadily each year from 90% to 93%, driven by the 23 largest Medicare Advantage Organizations, which account for 83% of total cases. MedPAR completeness was relatively stable (89%) and benefited from 91% completeness among the largest hospitals, which are often teaching hospitals and account for 63% of MedPAR cases. By 2019, 97% of medical cases were assigned the same MS-DRG, indicating the high consistency of the severity level coding, since 98% were assigned the same base MS-DRGs, which include all severity levels for the same condition. Without chart reviews, medical cases with identical diagnosis codes increased from 87% to 92%. CONCLUSIONS: The EDS has a completeness advantage over MedPAR for studies of non-teaching disproportionate share (DSH) hospitals and individual hospitals generally. MedPAR is only slightly less complete for hospitalizations of teaching DSH hospitals and large hospitals in general. A highly consistent EDS and MedPAR medical coding of matched cases is an important finding since the matched cases are 88% of EDS and 90% of MedPAR cases.

Mortality and Respiratory-Related Hospitalizations in Idiopathic Pulmonary Fibrosis Not Treated With Antifibrotics.

Background: Real-world data regarding outcomes of idiopathic pulmonary fibrosis (IPF) are scarce, outside of registries. The claims data from the French National Health System (SNDS) were used to describe outcomes in patients diagnosed with IPF in 2015-2016 but who did not receive antifibrotic therapies. Method: Patients aged <50 years were excluded, as were patients with pulmonary fibrosis other than IPF, patients who had previously received a lung transplant, and those who had received antifibrotic therapies at any time between 2010 and 2016. Patients were followed-up until their last health record, lung transplantation, initiation of antifibrotic therapies, death, or the end of the study period (31 December 2017), whichever occurred first. Results: A total of 5,360 patients (43.2%) not treated with antifibrotic therapies were included. The mean age was 75.5 years, and 57.9% were males. In the year before inclusion, 47.3% of patients had a Charlson score ≥5. During follow-up, 41.2% of patients died. The unadjusted incidence rate was 29.9 per 100 person-years (95%CI = [28.7-31.2]), and the cumulative incidence of death at 3 years was 50.2% (95% CI = [48.3-52.1%]). In the study population, 35.3% of patients experienced an acute respiratory-related hospitalization. The unadjusted incidence rate was 32.1 per 100 person-years (95%CI = [30.6-33.5]) and the cumulative incidence of the event at 3 years was 41.5% (95% CI = [39.7-43.2%]). Interpretation: This observational study showed that, if untreated with antifibrotics, IPF is associated with a 50% all-cause mortality at 3 years. These figures can serve as a historical control of the natural course of the disease.

Seven days treatment with the angiotensin II type 2 receptor agonist C21 in hospitalized COVID-19 patients; a placebo-controlled randomised multi-centre double-blind phase 2 trial.

BACKGROUND: COVID-19 morbidity and mortality remains high and the need for safe and effective drugs continues despite vaccines. METHODS: Double-blind, placebo-controlled, multi-centre, randomised, parallel group phase 2 trial to evaluate safety and efficacy of oral angiotensin II type 2 receptor agonist C21 in hospitalized patients with COVID-19 and CRP ≥ 50-150 mg/L conducted at eight sites in India (NCT04452435). Patients were randomly assigned 100 mg C21 bid or placebo for 7 days in addition to standard of care. Primary endpoint: reduction in CRP. The study period was 21 July to 13 October 2020. FINDINGS: 106 patients were randomised and included in the analysis (51 C21, 55 placebo). There was no significant group difference in reduction of CRP, 81% and 78% in the C21 and placebo groups, respectively, with a treatment effect ratio of 0.85 [90% CI 0.57, 1.26]. In a secondary analysis in patients requiring supplemental oxygen at randomisation, CRP was reduced in the C21 group compared to placebo. At the end of the 7-day treatment, 37 (72.5%) and 30 (54.5%) of the patients did not require supplemental oxygen in the C21 and placebo group, respectively (OR 2.20 [90% CI 1.12, 4.41]). A post hoc analysis showed that at day 14, the proportion of patients not requiring supplemental oxygen was 98% and 80% in the C21 group compared to placebo (OR 12.5 [90% CI 2.9, 126]). Fewer patients required mechanical ventilation (one C21 patient; four placebo patients), and C21 was associated with a numerical reduction in the mortality rate (one vs three in the C21 and placebo group, respectively). Treatment with C21 was safe and well tolerated. INTERPRETATION: Among hospitalised patients with COVID-19 receiving C21 for 7 days there was no reduction in CRP compared to placebo. However, a post-hoc analysis indicated a marked reduction of requirement for oxygen at day 14. The day 14 results from this study justify further evaluation in a Phase 3 study and such a trial is currently underway. FUNDING: Vicore Pharma AB and LifeArc, UK.