key: cord-0933629-8h53rqmv
authors: Pearson, Lauren N; Johnson, Stacy A; Greene, Dina N; Chambliss, Allison B; Farnsworth, Christopher W; French, Deborah; Herman, Daniel S; Kavsak, Peter A; Merril, Anna E; Lo, Sheng-Ying (Margaret); Lyon, Martha E; SoRelle, Jeffrey A; Schmidt, Robert L
title: Side-effects of COVID-19 on patient care: An INR story
date: 2021-03-24
journal: J Appl Lab Med
DOI: 10.1093/jalm/jfab025
sha: 1f6a7239dae03adf6f8951f48037971209dab7ca
doc_id: 933629
cord_uid: 8h53rqmv

BACKGROUND: Numerous studies have documented reduced access to patient care due to the COVID-19 pandemic including access to a diagnostic or screening tests, prescription medications, and treatment for an ongoing condition. In the context of clinical management for venous thromboembolism, this could result in suboptimal therapy with warfarin. We aimed to determine the impact of the pandemic on utilization of International normalized ratio (INR) testing and the percentage of high and low results. METHODS: INR data from 11 institutions were extracted to compare testing volume and the percentage of INR results ≥3.5 and ≤1.5 between a pre-pandemic period (January-June 2019, period 1) and a portion of the COVID-19 pandemic period (January-June 2020, period 2). The analysis was performed for inpatient and outpatient cohorts. RESULTS: Testing volumes showed relatively little change in January and February, followed by a significant decrease in March, April and May, and then returned to baseline in June. Outpatient testing showed a larger percentage decrease in testing volume compared to inpatient testing. At 10 of the 11 study sites we observed an increase in the percentage of abnormal high INR results as test volumes decreased, primarily among outpatients. CONCLUSION: The COVID-19 pandemic impacted INR testing among outpatients which may be attributable to several factors. Increased supratherapeutic INR results during the pandemic period when there was reduced laboratory utilization and access to care is concerning because of the risk of adverse bleeding events in this group of patients. This could be mitigated in the future by offering drive through testing and/or widespread implementation of home INR monitoring.

Restrictions and distancing policies during the COVID-19 pandemic reduced access to healthcare services. We found that the shutdown was associated with a decrease in testing and an increase in abnormal results for a commonly utilized and clinically actionable laboratory test (INR) . This trend was consistent at laboratories across North America. These results provide insight into the in the side effects of reduced access to routine care and can inform planning to improve care during future periods with reduced access to care. The target INR varies depending on the indication for anticoagulation.

Subtherapeutic and supratherapeutic INR response to warfarin pose risks to patients' health. A subtherapeutic INR (<2.0) portends increased risk of thrombosis, whereas adverse bleeding events are the primary concern with a supratherapeutic INR (>4.0). Achieving the optimal target INR is a challenge due to patient compliance, drug-drug interactions, and pharmacogenomic factors, among others. (2, 3) Maintaining a target INR requires longitudinal monitoring because of variability in these factors over time. Many institutions have protocols for how to adjust dosing based on INR results. Numerous strategies may be used to guide warfarin therapy including inpatient and outpatient anticoagulation management services, computer-aided dosing decision support, and patient self-management. (4) According to the National Center for Health Statistics, up to 38% of individuals surveyed using The Research and Development Survey indicated reduced access to care due to the COVID-19 pandemic.(5) Up to 6.4% of respondents indicated reduced access to a diagnostic or screening tests, 3 .2% experienced reduced access to prescription medications, and 6.2% reported reduced access to treatment for an ongoing condition. In the context of clinical management for VTE, this could result in suboptimal therapy with warfarin. We aimed to determine the impact of the COVID-19 pandemic on utilization of INR testing and the percentage of high and low results.

INR data from 11 institutions were extracted to compare testing volume and the percentage of supratherapeutic results between a pre-pandemic period (January-June 2019, period 1) and a portion of the COVID-19 pandemic period (January-June 2020, period 2). The set of institutions was a convenience sample selected with the goal to have a broad geographical distribution and a sufficient sample size to show broad patterns in testing. Ten of the 11 laboratories obtained data by querying the laboratory information system (LIS) and one laboratory queried the electronic health record. Each laboratory preprared a summary (number of results by month, stratified by patient type and result category (normal vs abnormal) and submitted the resulting tables to the authors at the University of Utah (LP, RLS) who compiled the results into a single database and performed the analysis. Both lab-based and point-of-care test results were included. We determined the median and interquartile range (IQR) for monthly INR test volume and percent of supratherapeutic INR results (INR results greater than or equal to 3.5) and INR results less than or equal to 1.5. These cutoffs were chosen to select for INR results that may be clinically actionable.

We determined the impact of the pandemic by comparing the testing volumes and the percentage of supratherapuetic results for each month in period 1 and period 2. We calculated the percent change in testing volume ( ) and the change in results ( ) above and below the cutoffs for each month during the pandemic period at each study site relative to the same month from 2019. We also calculated the median percentage change in volume ( ) and median percentage change in results ( ) over all locations. We calculated these statistics ( and ) for three cohorts: all patients, inpatients and outpatients.

Data from all sites were aggregated and five-point summaries were calculated (minimum, 25 th percentile, median, 75 th percentile, maximum) for each statistic by month for each cohort. The monthly change was visualized by creating box plots of the percent change in volume and results by month. We also tested for a relationship between and using hierarchical regression with location as a random effect and plotted the relationship between and for each site. In hierarchical regression, one assumes that there is a linear relationship between variables ( and ) for each site, but that the relationship can vary by site. This type of regression analysis determines whether there is a broad relationship between the variables of interest (e.g. is the relationship between and generally positive or negative?). This method of analysis was chosen because we would expect results within a hospital to be correlated more than results across hospitals.

Statistical analysis was performed using Stata 16.2 (Stata Corp, LLP). Hierarchical regression was performed using the mixed command as implemented by Stata.

Characteristics of Participating Institutions: Eleven institutions participated in the study ( Table   1 ). The institutions were dispersed geographically across the United States (N=9) and Canada (N=2 Figure 1 , Figure 2 Table 1C , Figure 1 ).

We tested for a relationship between the percent change in testing volume ( ) and the volume was smaller among inpatients, potentially due to the fact that patients necessitating hospitalization require more frequent testing due to their acute illnesses and concern for coagulopathy complicating COVID-19 infection (7, 8) .

We observed a decrease in INR testing volume in both inpatients and outpatients. This was consistent across all hospitals (Supplementary Figure 1) . The decrease in volume was most likely due to reduced monitoring; however, there are other potential explanations. For example, a reduction in volume could be caused by a disruption of service (e.g., due to a covid outbreak amon laboratory staff).

We conducted a poll across all contributing laboratories and found that none had a disruption of service during the pandemic period. Testing volume could have decreased due to efforts to switch patients to direct oral anticoagulants that do not require monitoring. We were unable to collect data on prescribing patterns from all contributors but we did perform an audit at the University of Utah and found that prescribing patterns were unchanged. We also found that testing volumes for a range of tests showed a similar pattern to INR. Thus, it is unlikely that the decrease was due to a change in prescribing patterns.

The testing pattern showed a sharp decrease followed by a fast return to normal testing volume so it is unlikely that the decrease in testing was due to covid associated mortality.

We observed an increase in the proportion of high INR results among outpatients during the pandemic period. This observation may reflect a shift in the study population resulting from selection bias for patients prescribed warfarin who require frequent INR testing. More worrisome is the possibility that there was voluntary avoidance of the healthcare system by patients due to a fear of contagion. This fear may have influenced healthcare providers and clinic staff as well, leading to impaired acess to testing due to closed medical practices or pharmacists working remotely. Considering the majority of patients on warfarin are outpatients, avoidance of testing, or reduced access to testing, would disproportionately affect patients on warfarin. Although this study is not designed to correlate our findings with patient outcomes, increased supratherapeutic INR results during the pandemic period when there was reduced laboratory utilization and access to care is concerning because of the risk of adverse bleeding events in this group of patients.

Our study has several strengths and weaknesses. We believe our results are widely generalizable based on the broad sample of both inpatient and outpatient INR results from academic and nonacademic practice settings across a wide geographic area in the United States and Canada. 

Venous thromboembolism: a public health concern

American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy

Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis

Guidance for the practical management of warfarin therapy in the treatment of venous thromboembolism

Impact of COVID-19 Pandemic on Laboratory Utilization

Venous thromboembolism in patients with COVID-19: Systematic review and meta-analysis

Risk of venous thromboembolism in patients with COVID-19: A systematic review and meta-analysis

COVID-19 coagulopathy, thrombosis, and bleeding

COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection