Changes in Health Services Use Among Commercially Insured US Populations During the COVID-19 Pandemic.

Importance: The coronavirus disease 2019 (COVID-19) pandemic has placed unprecedented strain on patients and health care professionals and institutions, but the association of the pandemic with use of preventive, elective, and nonelective care, as well as potential disparities in use of health care, remain unknown. Objective: To examine changes in health care use during the first 2 months of the COVID-19 pandemic in March and April of 2020 relative to March and April of 2019 and 2018, and to examine whether changes in use differ by patient's zip code-level race/ethnicity or income. Design, Setting, and Participants: This cross-sectional study analyzed health insurance claims for patients from all 50 US states who receive health insurance through their employers. Changes in use of preventive services, nonelective care, elective procedures, prescription drugs, in-person office visits, and telemedicine visits were examined during the first 2 months of the COVID-19 pandemic in 2020 relative to existing trends in 2019 and 2018. Disparities in the association of the pandemic with health care use based on patient's zip code-level race and income were also examined. Results: Data from 5.6, 6.4, and 6.8 million US individuals with employer-sponsored insurance in 2018, 2019, and 2020, respectively, were analyzed. Patient demographics were similar in all 3 years (mean [SD] age, 34.3 [18.6] years in 2018, 34.3 [18.5] years in 2019, and 34.5 [18.5] years in 2020); 50.0% women in 2018, 49.5% women in 2019, and 49.5% women in 2020). In March and April 2020, regression-adjusted use rate per 10 000 persons changed by -28.2 (95% CI, -30.5 to -25.9) and -64.5 (95% CI, -66.8 to -62.2) for colonoscopies; -149.1 (95% CI, -162.0 to -16.2) and -342.1 (95% CI, -355.0 to -329.2) for mammograms; -60.0 (95% CI, -63.3 to -54.7) and -118.1 (95% CI, -112.4 to -113.9) for hemoglobin A1c tests; -300.5 (95% CI, -346.5 to -254.5) and -369.0 (95% CI, -414.7 to -323.4) for child vaccines; -4.6 (95% CI, -5.3 to -3.9) and -10.9 (95% CI, -11.6 to -10.2) for musculoskeletal surgery; -1.1 (95% CI, -1.4 to -0.7) and -3.4 (95% CI, -3.8 to -3.0) for cataract surgery; -13.4 (95% CI, -14.6 to -12.2) and -31.4 (95% CI, -32.6 to -30.2) for magnetic resonance imaging; and -581.1 (95% CI, -612.9 to -549.3) and -1465 (95% CI, -1496 to -1433) for in-person office visits. Use of telemedicine services increased by 227.9 (95% CI, 221.7 to 234.1) per 10 000 persons and 641.6 (95% CI, 635.5 to 647.8) per 10 000 persons. Patients living in zip codes with lower-income or majority racial/ethnic minority populations experienced smaller reductions in in-person visits (≥80% racial/ethnic minority zip code: 200.0 per 10 000 [95% CI, 128.9-270.1]; 79%-21% racial/ethnic minority zip code: 54.2 per 10 000 [95% CI, 33.6-74.9]) but also had lower rates of adoption of telemedicine (≥80% racial/ethnic minority zip code: -71.6 per 10 000 [95% CI, -87.6 to -55.5]; 79%-21% racial/ethnic minority zip code: -15.1 per 10 000 [95% CI, -19.8 to -10.4]). Conclusions and Relevance: In this cross-sectional study of a large US population with employer-sponsored insurance, the first 2 months of the COVID-19 pandemic were associated with dramatic reductions in the use of preventive and elective care. Use of telemedicine increased rapidly but not enough to account for reductions in in-person primary care visits. Race and income disparities at the zip code level exist in use of telemedicine.

Patients with melanoma treated with an anti-PD-1 antibody beyond RECIST progression: a US Food and Drug Administration pooled analysis.

BACKGROUND: Patients who receive immunotherapeutic drugs might develop an atypical response pattern, wherein they initially meet conventional response criteria for progressive disease but later have decreases in tumour burden. Such responses warrant further investigation into the potential benefits and risks for patients who continue immunotherapy beyond disease progression defined by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. METHODS: For this pooled analysis, we included all submissions of trial reports and data to the US Food and Drug Administration (FDA) in support of marketing applications for anti-programmed death receptor-1 (PD-1) antibodies (alone or in combination) for the treatment of patients with unresectable or metastatic melanoma that allowed for continuation of the antibody beyond RECIST-defined progression in the anti-PD-1 group and were approved by FDA before Jan 1, 2017. To investigate the effect of treatment beyond progression in patients with metastatic melanoma and to better characterise which of these patients would benefit from extended treatment, we pooled individual patient data from patients who received at least one dose of an anti-PD-1 antibody in the included trials. We included any patient receiving the anti-PD-1 antibody after their RECIST-defined progression date in the treatment beyond progression cohort and analysed them descriptively at baseline and at time of progression versus the cohort not receiving treatment beyond progression. We analysed the target lesion response after progression in patients in the treatment beyond progression cohort relative to progressive disease and baseline target lesion burden. We defined a treatment beyond progression response as a decrease in target lesion tumour burden (sum of the reference diameters) of at least 30% from the burden at the time of RECIST-defined progression that did not require confirmation at a subsequent assessment. We also compared individual timepoint responses, overall survival, and adverse events in the treatment beyond progression versus no treatment beyond progression cohorts. FINDINGS: Among the eight multicentre clinical trials meeting this study's inclusion criteria, we pooled the data from 2624 patients receiving immunotherapy. 1361 (52%) had progressive disease, of whom 692 (51%) received continued anti-PD-1 antibody treatment beyond RECIST-defined progression and 669 (49%) did not. 95 (19%) of 500 patients in the treatment beyond progresssion cohort with evaluable assessments had a 30% or more decrease in tumour burden, when considering burden at RECIST-defined progression as the reference point, representing 14% of the 692 patients treated beyond progression and 4% of all 2624 patients treated with immunotherapy. Median overall survival in patients with RECIST-defined progressive disease given anti-PD-1 antibody was longer in the treatment beyond progression cohort (24·4 months, 95% CI 21·2-26·3) than in the cohort of patients who did not receive treatment beyond progression (11·2 months, 10·1-12·9). 362 (54%) of 669 patients in the no treatment beyond progression cohort had a serious adverse event up to 90 days after treatment discontinuation compared with 295 (43%) of 692 patients in the treatment beyond progression cohort. Immune-related adverse events that occurred up to 90 days from discontinuation were similar between the treatment beyond progression cohort (78 [11%] of 692 patients) and the no treatment beyond progression cohort (106 [16%] of 669). INTERPRETATION: Continuation of treatment beyond progression in the product labelling of these immunotherapies has not been recommended because the clinical benefit remains to be proven. Treatment beyond progression with anti-PD-1 antibody therapy might be appropriate for selected patients with unresectable or metastatic melanoma, identified by specific criteria at the time of progression, based on the potential for late responses in the setting of the known toxicity profile. FUNDING: None.

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma.

On September 4, 2014, the FDA approved pembrolizumab (KEYTRUDA; Merck Sharp & Dohme Corp.) with a recommended dose of 2 mg/kg every 3 weeks by intravenous infusion for the treatment of patients with unresectable or metastatic melanoma who have progressed following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on demonstration of objective tumor responses with prolonged response durations in 89 patients enrolled in a randomized, multicenter, open-label, dose-finding, and activity-estimating phase 1 trial. The overall response rate (ORR) by blinded independent central review per RECIST v1.1 was 24% (95% confidence interval, 15-34); with 6 months of follow-up, 86% of responses were ongoing. The most common (≥20%) adverse reactions were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea. Immune-mediated adverse reactions included pneumonitis, colitis, hepatitis, hypophysitis, and thyroid disorders. The benefits of the observed ORR with prolonged duration of responses outweighed the risks of immune-mediated adverse reactions in this life-threatening disease and represented an improvement over available therapy. Important regulatory issues in this application were role of durability of response in the evaluation of ORR for accelerated approval, reliance on data from a first-in-human trial, and strategies for dose selection. Clin Cancer Res; 23(19); 5666-70. ©2017 AACR.

Rhabdomyolysis reports show interaction between simvastatin and CYP3A4 inhibitors.

PURPOSE: To assess spontaneous reports of rhabdomyolysis associated with simvastatin (SV) and pravastatin (PV) for evidence of CYP3A4 interaction. Clinical trial results advocate cholesterol lowering in high-risk patients including diabetics and the elderly. Given the association between advancing age, metabolic, and cardiovascular disease, many patients are treated with concomitant medications upon statin initiation. Although statins are generally safe, minor and severe adverse reactions arise, especially when given to patients taking concomitant medications that inhibit the statin clearance and lead to increased statin plasma concentration. METHODS: We conducted a comparative case series of rhabdomyolysis reports associated with SV and PV. Domestic spontaneous reports were obtained from the FDA's Adverse Event Reporting System (AERS). Drug utilization data were obtained from IMS HEALTH and the National Ambulatory Medical Care Survey (NAMCS). Adverse event reporting rates (AER) and ratios (AERR) of rhabdomyolysis associated with SV and PV-with and without stratification by CYP3A4 inhibitor concomitancy were determined. RESULTS: Stratification by CYP3A4 inhibitor concomitancy did not change the rhabdomyolysis AER for PV with or without a CYP3A4 inhibitor (2.4 cases and 3.1 cases per 10 million Rx, respectively). However, stratification of SV reports with or without a concomitant CYP3A4 inhibitor resulted in a rhabdomyolysis AER (38.4 and 6.0 cases per 10 million Rx, respectively). The corresponding AERR with or without a CYP3A4 inhibitor were 0.77 for PV and 6.43 for SV. CONCLUSIONS: Spontaneous adverse event reports provide evidence of increased risk for rhabdomyolysis based on interaction between SV and selected CYP3A4 inhibitors.

Maximizing the retention of antigen specific lymphocyte function after cryopreservation.

The ability to cryopreserve lymphocytes in peripheral blood mononuclear cells (PBMC) to retain their function after thawing is critical to the analysis of cancer immunotherapy studies. We evaluated a variety of cryopreservation strategies with the aim of developing an optimized protocol for freezing and thawing PBMC to retain viability and function. We determined several factors which do not affect cell viability after cryopreservation such as shipping frozen samples on dry ice, the length of time and speed at which samples are washed and centrifuged after thawing, and the number of cells frozen per container. Different media additives, however, did impact the viability of the cells after thawing. There was a significant reduction in the viability of the cells after freezing when using human AB serum compared to all other additives tested (p<0.000). A second critical parameter was the temperature of the media used to wash the cells after removal from the cryotubes. When the media was cooled to 4 degrees C prior to washing, the mean viability was 69.7+/-12.5%, at 25 degrees C 92.55+/-3.1%, and at 37 degrees C 95.11+/-2.5%. Finally, we used an optimized cryopreservation protocol with different media additives to determine if functional T cell responses to tetanus toxoid could be preserved. There was a statistically significant correlation between the tetanus specific stimulation index (S.I.) of the non-cryopreserved PBMC and SI obtained from cells frozen with media containing human serum albumin as compared to other additives such as dextran or fetal bovine serum.

Impact of cryopreservation on tetramer, cytokine flow cytometry, and ELISPOT.

BACKGROUND: Cryopreservation of PBMC and/or overnight shipping of samples are required for many clinical trials, despite their potentially adverse effects upon immune monitoring assays such as MHC-peptide tetramer staining, cytokine flow cytometry (CFC), and ELISPOT. In this study, we compared the performance of these assays on leukapheresed PBMC shipped overnight in medium versus cryopreserved PBMC from matched donors. RESULTS: Using CMV pp65 peptide pool stimulation or pp65 HLA-A2 tetramer staining, there was significant correlation between shipped and cryopreserved samples for each assay (p

Rhabdomyolysis with HMG-CoA reductase inhibitors and gemfibrozil combination therapy.

CONTEXT: Elevated total cholesterol (total-C) and low-density lipoprotein cholesterol (LDL-C) levels are established risk factors for cardiovascular disease (CVD). HMG-CoA reductase inhibitors (statins) are effective cholesterol-lowering drugs that are commonly prescribed to treat this condition. These drugs are often combined with another class of drugs, fibric acid derivatives, to lower both cholesterol and triglyceride levels. Rhabdomyolysis is a known, rare serious side effect of statin monotherapy and of statin-fibrate combination therapy. OBJECTIVE: To examine Food and Drug Administration's (FDA's) postmarketing database for cases of rhabdomyolysis in relation to monotherapy and combination use and calculate reporting rates for this event. DESIGN: Domestic cases of statin- and statin/gemfibrozil-associated rhabdomyolysis were culled from FDA's database and reviewed. Rhabdomyolysis was defined by CPK > or = 10,000 IU/L, myopathic signs and symptoms and clinical diagnosis of rhabdomyolysis. Reporting rates, consisting of number of reported cases/number of prescriptions for each drug, were then calculated to determine whether the reporting of rhabdomyolysis cases was commensurate with extent of use of each statin in the population. SETTING: Cases were obtained from the FDA adverse event reporting system (AERS) database. PATIENTS: NA. MAIN OUTCOME MEASURES: Number of rhabdomyolysis cases were evaluated, along with outcomes, such as renal failure, dialysis and death. RESULTS: Of 866 total reported cases, 482 (56%) were associated with monotherapy and 384 (44%) related to combination therapy. More than 80% of reported cases for each drug resulted in hospitalization for renal failure and dialysis. 80 patients expired from events related directly to rhabdomyolysis. Reporting rates for all statins, except for cerivastatin, were similar and much lower than 1 per 100,000 prescriptions. The cerivastatin-reporting rate was much higher at 4.24/100,000 prescriptions. CONCLUSIONS: Rhabdomyolysis is a rare, serious side effect of statin monotherapy and of statin-fibrate combination therapy. Clinicians need to remain cognizant of this potential adverse event and discuss signs and symptoms of muscle toxicity with patients in order improve the benefits-to-risks of treating dyslipidemia with statins.