Real-world clinical and economic outcomes for patients with advanced non-small cell lung cancer enrolled in a clinical trial following comprehensive genomic profiling via liquid biopsy.

BACKGROUND: Oncology clinical trial enrollment is strongly recommended for patients with cancer who are not eligible for established and approved therapies. Many trials are specific to biomarker-targeted therapies, which are typically managed as specialty pharmacy services. Comprehensive genomic profiling (CGP) of advanced cancers has been shown to detect biomarkers, guide targeted treatment, improve outcomes, and result in the clinical trial enrollment of patients, which is modeled to offset pharmacy costs experienced by US payers, yet payer policy coverage remains inconsistent. A common concern limiting coverage of CGP by payers is the potential of identifying biomarkers beyond guideline-recommended treatments, which creates a perception that insurance companies are being positioned to "pay for research." However, these biomarkers can increase clinical trial eligibility, and specialty pharmacy management may have an interest in maximizing the clinical trial enrollment of members. OBJECTIVE: To investigate if clinical trial enrollment following liquid biopsy CGP for non-small cell lung cancer (NSCLC) is clinically and/or economically impactful from a payer claims perspective. METHODS: Clinical and economic outcomes were studied using a real-world clinical genomic database (including payer claims data) from patients with NSCLC who enrolled in clinical trials immediately following liquid biopsy CGP (using Guardant360) and matched NSCLC patient controls also tested with liquid biopsy CGP. RESULTS: Real-world overall survival was significantly (log-rank P < 0.0001) better for patients enrolled in clinical trials with similar costs of care, albeit with more outpatient encounters among those enrolled compared with matched controls. CONCLUSIONS: The results, together with previous analyses, suggest that, in addition to the clinical benefits associated with targeted therapies directed by CGP and other testing approaches, payers and specialty pharmacy managers may consider clinical trial direction and enrollment as a clinical and economic benefit of liquid biopsy CGP and adopt this into coverage decision frameworks and formularies.

Comparing the Centers for Medicare and Medicaid Services (CMS) enrollment data death dates to the National Death Index (NDI).

PURPOSE: In the United States, the National Death Index (NDI) is the most complete source of death information, while epidemiologic studies with mortality outcomes often rely on U.S. Medicare data for outcome ascertainment. The purpose of this study was to assess the agreement of death information between the Centers for Medicare & Medicaid Services (CMS) Medicare enrolment data and NDI. METHODS: Using Medicare and NDI data from 1999 through 2016, we identified Medicare beneficiaries who were reported dead in the CMS Medicare enrolment database (EDB) and Common Medicare Environment (CME), linked these beneficiaries to the NDI using CMS Health Insurance Claim number, and compared death dates between the two data sources. To assess agreement between our data sources, we calculated kappa scores; where a kappa of 1 indicates perfect agreement and a kappa of 0 indicates agreement equivalent to chance. We also examined CMS to NDI linkage and death date matching for stability over time. RESULTS: Of the 36 785 640, Medicare beneficiaries reported dead in CMS enrollment data from 1999 to 2016, 97.5% were linked to the NDI. A kappa score of 0.98 showed a near perfect agreement between NDI and CMS reported deaths. The percentage of linked cases exactly matching on death dates increased from 94.8% in 1999 to 99.4% in 2016. CONCLUSIONS: Our findings suggest strong concordance between death dates as recorded by CMS enrollment data and the NDI in the entire Medicare population.

Mortality Among Parkinson's Disease Patients Treated With Pimavanserin or Atypical Antipsychotics: An Observational Study in Medicare Beneficiaries.

OBJECTIVE: Pimavanserin, a serotonin 5-HT2 antagonist, is indicated for treatment of hallucinations and delusions associated with Parkinson's disease psychosis. In premarketing trials in patients with Parkinson's disease psychosis, 11% of patients died during open-label pimavanserin treatment. Antipsychotics, which are used off-label in Parkinson's disease psychosis, increase mortality in dementia patients. The authors compared mortality with pimavanserin and atypical antipsychotics in a large database. METHODS: This was a retrospective new-user cohort study of Medicare beneficiaries with Parkinson's disease initiating pimavanserin (N=3,227) or atypical antipsychotics (N=18,442) from April 2016 to March 2019. All-cause mortality hazard ratios and 95% confidence intervals were estimated for pimavanserin compared with atypical antipsychotics, using segmented proportional hazards regression over 1-180 and 181+ days of treatment. Potential confounding was addressed through inverse probability of treatment weighting (IPTW). RESULTS: Pimavanserin users had a mean age of approximately 78 years, and 45% were female. Before IPTW, some comorbidities were more prevalent in atypical antipsychotic users; after IPTW, comorbidities were well balanced between groups. In the first 180 days of treatment, mortality was approximately 35% lower with pimavanserin than with atypical antipsychotics (hazard ratio=0.65, 95% CI=0.53, 0.79), with approximately one excess death per 30 atypical antipsychotic-treated patients; however, during treatment beyond 180 days, there was no additional mortality advantage with pimavanserin (hazard ratio=1.05, 95% CI=0.82, 1.33). Pimavanserin showed no mortality advantage in nursing home patients. CONCLUSIONS: Pimavanserin use was associated with lower mortality than atypical antipsychotic use during the first 180 days of treatment, but only in community-dwelling patients, not nursing home residents.

Risk of Guillain-Barré Syndrome Following Recombinant Zoster Vaccine in Medicare Beneficiaries.

Importance: Guillain-Barré syndrome can be reported after vaccination. This study assesses the risk of Guillain-Barré syndrome after administration of recombinant zoster vaccine (RZV or Shingrix), which is administered in 2 doses 2 to 6 months apart. Objective: Use Medicare claims data to evaluate risk of developing Guillain-Barré syndrome following vaccination with zoster vaccine. Design, Setting, and Participants: This case series cohort study included 849 397 RZV-vaccinated and 1 817 099 zoster vaccine live (ZVL or Zostavax)-vaccinated beneficiaries aged 65 years or older. Self-controlled analyses included events identified from 2 113 758 eligible RZV-vaccinated beneficiaries 65 years or older. We compared the relative risk of Guillain-Barré syndrome after RZV vs ZVL, followed by claims-based and medical record-based self-controlled case series analyses to assess risk of Guillain-Barré syndrome during a postvaccination risk window (days 1-42) compared with a control window (days 43-183). In self-controlled analyses, RZV vaccinees were observed from October 1, 2017, to February 29, 2020. Patients were identified in the inpatient, outpatient procedural (including emergency department), and office settings using Medicare administrative data. Exposures: Vaccination with RZV or ZVL vaccines. Main Outcomes and Measures: Guillain-Barré syndrome was identified in Medicare administrative claims data, and cases were assessed through medical record review using the Brighton Collaboration case definition. Results: Amongst those who received RZV vaccinees, the mean age was 74.8 years at first dose, and 58% were women, whereas among those who received the ZVL vaccine, the mean age was 74.3 years, and 60% were women. In the cohort analysis we detected an increase in risk of Guillain-Barré syndrome among RZV vaccinees compared with ZVL vaccinees (rate ratio [RR], 2.34; 95% CI, 1.01-5.41; P = .047). In the self-controlled analyses, we observed 24 and 20 cases during the risk and control period, respectively. Our claims-based analysis identified an increased risk in the risk window compared with the control window (RR, 2.84; 95% CI, 1.53-5.27; P = .001), with an attributable risk of 3 per million RZV doses (95% CI, 0.62-5.64). Our medical record-based analysis confirmed this increased risk (RR, 4.96; 95% CI, 1.43-17.27; P = .01). Conclusions and Relevance: Findings of this case series cohort study indicate a slightly increased risk of Guillain-Barré syndrome during the 42 days following RZV vaccination in the Medicare population, with approximately 3 excess Guillain-Barré syndrome cases per million vaccinations. Clinicians and patients should be aware of this risk, while considering the benefit of decreasing the risk of herpes zoster and its complications through an efficacious vaccine, as risk-benefit balance remains in favor of vaccination.

Risk of serious spinal adverse events associated with epidural corticosteroid injections in the Medicare population.

BACKGROUND: Epidural corticosteroid injections (ESIs) are widely performed and have an unquantified risk of serious spinal adverse events (SSAEs). We sought to determine the rate of SSAEs following ESI and to compare the rates by spinal level, injection approach and corticosteroid formulation. METHODS: We included patients enrolled in Medicare parts A and B who had an ESI between 1 January 2009 and 30 September 2015. We identified potential cases as patients with spine-related diagnoses within 3 days after the first eligible ESI. Event categorization as probable, possible or non-case was based on review of medical records. The rates of probable and possible cases were expressed per 1 000 000 patients overall, and by spinal level, injection approach and corticosteroid formulation. A score test was used to compare these rates. RESULTS: We identified 1 355 957 eligible ESIs during the study period. Of the 110 potential cases, 43 were selected for medical record review and 11 were categorized as probable, yielding a rate of 8.1 per 1 000 000 patients (95% CI 4.5 to 14.5). Risk of SSAEs was statistically higher with cervical/thoracic injections (29.4, 95% CI 12.5 to 68.8) compared with lumbar/sacral injections (5.1, 95% CI 2.3 to 11.0) (p value 0.001). Event rates for lumbar/sacral non-transforaminal injections was 8.8 (95% CI 4.0 to 19.1). Event rates for particulate (7.5, 95% CI 3.9 to 14.2) and non-particulate formulations (13.1, 95% CI 3.6 to 47.9) appeared similar (p value 0.47). CONCLUSION: Between 2009 and 2015, rates of SSAEs following ESI in the Medicare population were low. Patients receiving cervical/thoracic ESIs were at higher risk of SSAE than those receiving lumbar/sacral ESIs. Event rates were similar for each corticosteroid formulation.

Guillain-Barré Syndrome After High-Dose Influenza Vaccine Administration in the United States, 2018-2019 Season.

BACKGROUND: The Vaccine Safety Datalink (VSD) identified a statistical signal for an increased risk of Guillain-Barré syndrome (GBS) in days 1-42 after 2018-2019 high-dose influenza vaccine (IIV3-HD) administration. We evaluated the signal using Medicare. METHODS: We conducted early- and end-of-season claims-based self-controlled risk interval analyses among Medicare beneficiaries ages ≥65 years, using days 8-21 and 1-42 postvaccination as risk windows and days 43-84 as control window. The VSD conducted chart-confirmed analyses. RESULTS: Among 7 453 690 IIV3-HD vaccinations, we did not detect a statistically significant increased GBS risk for either the 8- to 21-day (odds ratio [OR], 1.85; 95% confidence interval [CI], 0.99-3.44) or 1- to 42-day (OR, 1.31; 95% CI, 0.78-2.18) risk windows. The findings from the end-of-season analyses were fully consistent with the early-season analyses for both the 8- to 21-day (OR, 1.64; 95% CI, 0.92-2.91) and 1- to 42-day (OR, 1.12; 95% CI, 0.70-1.79) risk windows. The VSD's chart-confirmed analysis, involving 646 996 IIV3-HD vaccinations, with 1 case each in the risk and control windows, yielded a relative risk of 1.00 (95% CI, 0.06-15.99). CONCLUSIONS: The Medicare analyses did not exclude an association between IIV3-HD and GBS, but it determined that, if such a risk existed, it was similar in magnitude to prior seasons. Chart-confirmed VSD results did not confirm an increased risk of GBS.

Comparative Stroke, Bleeding, and Mortality Risks in Older Medicare Patients Treated with Oral Anticoagulants for Nonvalvular Atrial Fibrillation.

BACKGROUND: Nonvitamin K antagonist oral anticoagulants (NOACs) are alternatives to warfarin in patients with nonvalvular atrial fibrillation. Randomized trials compared NOACs with warfarin, but none have compared individual NOACs against each other for safety and effectiveness. METHODS: We performed a retrospective new-user cohort study of patients with nonvalvular atrial fibrillation enrolled in US Medicare who initiated warfarin (n = 183,318), or a standard dose of dabigatran (150 mg twice daily; n = 86,198), rivaroxaban (20 mg once daily; n = 106,389), or apixaban (5 mg twice daily; n = 73,039) between October 2010 and September 2015. Propensity score-adjusted Cox proportional hazards regression was used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for the outcomes of thromboembolic stroke, intracranial hemorrhage, major extracranial bleeding, and all-cause mortality, comparing each NOAC with warfarin, and with each other NOAC. RESULTS: Compared with warfarin, each NOAC was associated with reduced risks of thromboembolic stroke (20%-29% reduction; P = .002 [dabigatran], P < 0.001 [rivaroxaban, apixaban]), intracranial hemorrhage (35%-62% reduction; P < 0.001 [each NOAC]), and mortality (19%-34% reduction; P < .001 [each NOAC]). The NOACs were similar for thromboembolic stroke but rivaroxaban was associated with increased risks of intracranial hemorrhage (vs dabigatran: HR = 1.71; 95% CI, 1.35-2.17), major extracranial bleeding (vs dabigatran: HR = 1.32; 95% CI, 1.21-1.45; vs apixaban: HR = 2.70; 95% CI, 2.38-3.05), and death (vs dabigatran: HR = 1.12; 95% CI, 1.01-1.24; vs apixaban: HR = 1.23; 95% CI, 1.09-1.38). Dabigatran was associated with reduced risk of intracranial hemorrhage (HR = 0.70; 95% CI ,0.53-0.94) and increased risk of major extracranial bleeding (HR = 2.04; 95% CI, 1.78-2.32) compared with apixaban. CONCLUSIONS: Among patients treated with standard-dose NOAC for nonvalvular atrial fibrillation and warfarin users with similar baseline characteristics, dabigatran, rivaroxaban, and apixaban were associated with a more favorable benefit-harm profile than warfarin. Among NOAC users, dabigatran and apixaban were associated with a more favorable benefit-harm profile than rivaroxaban.

Stroke, Bleeding, and Mortality Risks in Elderly Medicare Beneficiaries Treated With Dabigatran or Rivaroxaban for Nonvalvular Atrial Fibrillation.

Importance: Dabigatran and rivaroxaban are non-vitamin K oral anticoagulants approved for stroke prevention in patients with nonvalvular atrial fibrillation (AF). There are no randomized head-to-head comparisons of these drugs for stroke, bleeding, or mortality outcomes. Objective: To compare risks of thromboembolic stroke, intracranial hemorrhage (ICH), major extracranial bleeding including major gastrointestinal bleeding, and mortality in patients with nonvalvular AF who initiated dabigatran or rivaroxaban treatment for stroke prevention. Design, Setting, and Participants: Retrospective new-user cohort study of 118 891 patients with nonvalvular AF who were 65 years or older, enrolled in fee-for-service Medicare, and who initiated treatment with dabigatran or rivaroxaban from November 4, 2011, through June 30, 2014. Differences in baseline characteristics were adjusted using stabilized inverse probability of treatment weights based on propensity scores. The data analysis was performed from May 7, 2015, through June 30, 2016. Exposures: Dabigatran, 150 mg, twice daily; rivaroxaban, 20 mg, once daily. Main Outcomes and Measures: Adjusted hazard ratios (HRs) for the primary outcomes of thromboembolic stroke, ICH, major extracranial bleeding including major gastrointestinal bleeding, and mortality, with dabigatran as reference. Adjusted incidence rate differences (AIRDs) were also estimated. Results: A total of 52 240 dabigatran-treated and 66 651 rivaroxaban-treated patients (47% female) contributed 15 524 and 20 199 person-years of on-treatment follow-up, respectively, during which 2537 primary outcome events occurred. Rivaroxaban use was associated with a statistically nonsignificant reduction in thromboembolic stroke (HR, 0.81; 95% CI, 0.65-1.01; P = .07; AIRD = 1.8 fewer cases/1000 person-years), statistically significant increases in ICH (HR, 1.65; 95% CI, 1.20-2.26; P = .002; AIRD = 2.3 excess cases/1000 person-years) and major extracranial bleeding (HR, 1.48; 95% CI, 1.32-1.67; P < .001; AIRD = 13.0 excess cases/1000 person-years), including major gastrointestinal bleeding (HR, 1.40; 95% CI, 1.23-1.59; P < .001; AIRD = 9.4 excess cases/1000 person-years), and with a statistically nonsignificant increase in mortality (HR, 1.15; 95% CI, 1.00-1.32; P = .051; AIRD = 3.1 excess cases/1000 person-years). In patients 75 years or older or with CHADS2 score greater than 2, rivaroxaban use was associated with significantly increased mortality compared with dabigatran use. The excess rate of ICH with rivaroxaban use exceeded its reduced rate of thromboembolic stroke. Conclusions and Relevance: Treatment with rivaroxaban 20 mg once daily was associated with statistically significant increases in ICH and major extracranial bleeding, including major gastrointestinal bleeding, compared with dabigatran 150 mg twice daily.

Assessment of bony nasolacrimal parameters among Asians.

PURPOSE: A case series evaluating racial differences in the nasolacrimal region and quantifying the anterior lacrimal crest thickness and minimum nasolacrimal duct diameter in Asians. METHODS: Facial or orbital CT scans of 90 consecutive patients were retrospectively reviewed. Evidence of lacrimal fossa tumor or trauma excluded a patient. Using 3-dimensional image software, the thickness of the anterior lacrimal crest, narrowest diameter of the nasolacrimal duct, vertical diameter of the lacrimal sac fossa, frontonasal angle, and inter-frontozygomatic suture distance were measured in axial, sagittal, and coronal planes. RESULTS: Inter- and intraobserver correlation of a sample data proved reliability via intraclass correlation coefficient (0.706-0.917). Southeast Asians had a wider inter-frontozygomatic suture distance than South Asian and Occidental races (p = 0.025). Vertical lacrimal fossa diameter, anterior lacrimal crest thickness, and narrowest nasolacrimal duct diameter did not differ significantly between right and left sides or among ethnic groups. Narrower nasolacrimal duct diameter was significantly associated with decreased inter-frontozygomatic suture distance (p < 0.001), namely in patients with narrower faces. The anterior lacrimal crest thickness was significantly affected by the nasal configuration and thicker in patients with more acute frontonasal angle (p = 0.026). CONCLUSIONS: There is no significant difference in nasolacrimal duct diameter among ethnic groups, which may predispose one to nasolacrimal duct obstruction. But, this is significantly associated with inter-frontozygomatic suture distance, suggesting that a wider face is associated with wider nasolacrimal duct diameter. An acute frontonasal angle predicts a thicker anterior lacrimal crest for surgical preparation during dacryocystorhinostomy.

Assessment of iris surface features and their relationship with iris thickness in Asian eyes.

PURPOSE: To assess iris surface features in Asian eyes and examine their associations with iris thickness measured by anterior segment optical coherence tomography (AS OCT). DESIGN: Cross-sectional study. PARTICIPANTS: We recruited 250 subjects from the Singapore Malay Eye Study. METHODS: We obtained standardized slit-lamp photographs and developed a grading system assessing iris crypts (by number and size), furrows (by number and circumferential extent), and color (higher grade denoting darker iris). Vertical and horizontal cross-sections of the anterior chamber were imaged using AS OCT. Intragrader and intergrader agreements in the grading of iris surface were assessed by weighted κ (κ(w)) statistic. Associations of the average iris thickness with the grade of iris features were assessed using linear regression analysis. MAIN OUTCOME MEASURES: Frequency and size of iris crypts, furrows, and color; iris thickness at 750 µm (IT750) and 2000 µm (IT2000) from the scleral spur; and maximum iris thickness (ITM) averaged from the 4 quarters. RESULTS: Three hundred sixty-four eyes had complete and gradable data for crypts and color; 330 eyes were graded for furrows. The grading scheme showed good intragrader (crypt κ(w) = 0.919, furrow κ(w) =0.901, color κ(w) = 0.925) and intergrader (crypt κ(w) = 0.775, furrow κ(w) = 0.836, color κ(w) = 0.718) agreements. Higher crypt grade was associated independently with thinner IT750 (ß [change in iris thickness per grade higher] = -0.007; P = 0.029), IT2000 (ß = -0.018; P < 0.001), and ITM (ß = -0.012; P < 0.001). More extensive furrows were associated with thicker IT750 (ß = 0.022; P < 0.001). Darker iris was also associated with thicker IT750 (ß = 0.014; P = 0.001). CONCLUSIONS: Iris surface features, assessed and measured from slit-lamp photographs, correlate well with iris thickness. Irises with more crypts are thinner; irises with more extensive furrows and darker color are thicker peripherally. These findings may provide another means to assess angle closure risk based on iris features.