a b s t r a c t

Study objective: To assess trends over time in red blood cell (RBC) transfusion practice among emergency depart- ment (ED) patients with gastrointestinal (GI) bleeding within an integrated healthcare system, inclusive of 21 EDs.

Methods: Retrospective cohort of ED patients diagnosed with GI bleeding between July 1st, 2012 and September 30th, 2016. The primary outcome was receipt of an RBC transfusion in the ED. Secondary outcomes included 90- day rates of RBC transfusion, repeat ED visits, rehospitalization, and all-cause mortality. Logistic regression was used to obtain confounder-adjusted outcome rates.

Results: A total of 24,868 unique patient encounters were used for the primary analysis. The median hemoglobin level in the ED prior to RBC transfusion decreased from 7.5 g/dl to 6.9 g/dl in the first versus last twelve months of the study period (p b 0.0001). A small trend was observed in the overall adjusted rate of ED RBC transfusion (ab- solute quarterly change of -0.1%, R2 = 0.18, p = 0.0001) largely attributable to the subgroup of patients with hemoglobin nadirs between 7.0 and 9.9 g/dl (absolute quarterly change of -0.4%, R2 = 0.38, p b 0.0001). Rates of RBC transfusions through 90 days likewise decreased (absolute quarterly change of -0.4%, R2 = 0.85, p b 0.0001) with stable to decreased corresponding rates of repeat ED visits, rehospitalizations and mortality. Conclusion: Rates of ED RBC transfusion decreased over time among patients with GI bleeding, particularly in those with hemoglobin nadirs between 7.0 and 9.9 g/dl. These findings suggest that ED providers are willing to adopt evidence-based restrictive RBC transfusion recommendations for patients with GI bleeding.

(C) 2019

Introduction

Background

Gastrointestinal (GI) bleeding is a common and occasionally life- threatening reason for emergency department (ED) care. Traditionally, transfusion of allogeneic red blood cells (RBC) has been recommended in the setting of GI bleeding with moderate or Severe anemia (e.g. he- moglobin levels b10 g/dl) owing to associations between the severity of anemia and mortality, as well as theoretical hemostatic benefits at

Abbreviations: CI, confidence interval; ED, emergency department; EHR, electronic health record; GI, gastrointestinal; INR, international normalized ratio; IQR, interquartile range; KPNC, Kaiser Permanente Northern California; RBC, red blood cell.

* Corresponding author at: Department of Emergency Medicine, Kaiser Permanente Medical Center, 3600 Broadway, Oakland, CA 94611, USA.

E-mail address: [email protected] (D.G. Mark).

higher Hemoglobin levels [1-4]. However, these theoretical benefits have been challenged [5], and over the past decade guideline support for a more restrictive approach to RBC transfusion in acute GI bleeding has emerged (e.g. using hemoglobin transfusion thresholds of b7 to 8 g/dl, absent overt circulatory shock or active ischemia), supported by evidence demonstrating both reduced Healthcare utilization and equivalent safety, with possible Mortality benefits [6-11]. At the same time, restrictive RBC transfusion practices have gained widespread en- dorsement for a variety of other conditions [12-17].

Study significance

Ultimately, knowledge translation is often a slow and incomplete process [18], and high rates of guideline-discordant transfusion practice within EDs have been recently documented [19,20]. Since most studies supporting restrictive transfusion practice have been conducted outside of the ED setting, it is understandable that ED clinicians would approach

https://doi.org/10.1016/j.ajem.2019.06.019

0735-6757/(C) 2019

the concept of restrictive transfusion cautiously [21]. Patients with GI bleeding, however, do have an evidentiary base for restrictive transfu- sion that includes the ED setting [6,8], and thus may be harbingers of ED clinician willingness to adopt restrictive transfusion practices.

Goals of this investigation

We sought to examine trends over time in RBC transfusion practice among ED patients diagnosed with GI bleeding within an integrated health system during a period when clinical trial data (beginning in 2013 [6]) and subsequent guidelines increasingly supported a restric- tive approach to RBC transfusion in patients with GI bleeding. We hy- pothesized that the proportion of ED patients with GI bleeding who received RBC transfusions during their ED stay would decrease over time, and that this effect would be primarily observed among the sub- group of patients with ED hemoglobin nadirs in the 7.0 to 9.9 g/dl range, given the contemporaneously evolving evidence highlighted above. We further hypothesized that decreases in RBC transfusion rates would persist though the index hospitalization and out to 90 days, without associated changes in downstream healthcare utiliza- tion (hospital or ED readmission) or all-cause mortality.

Materials and methods

Study setting and design

We conducted a retrospective cohort study using electronic health records (EHR) from Kaiser Permanente Northern California (KPNC), an integrated health system which includes twenty-one medical center- based EDs, staffed by board-certified (or board-eligible) emergency physicians, serving a total population of 4 million health plan members with over 1.2 million annual ED visits [22]. KP members represent ap- proximately 33% of the population in areas served and are highly repre- sentative of the surrounding population [23]. In 2015 the annual census of the 21 EDs ranged from 28,000 to 121,000, median 57,000 (interquar- tile range, 38,000-61,000). All medical centers are considered non- academic and community-based, though seven sites have at least one active graduate medical education program, four of which have residen- cies in either internal or Family Medicine.

In 2010, KPNC initiated a comprehensive blood conservation educa- tional program targeting emergency physicians, hospitalists, anesthesi- ologists and surgeons regarding the management of anemia, adoption of evidence-based transfusion practices, and implementation of blood transfusion guidelines across its facilities [24]. To further support these efforts, in May 2012 electronic Clinical decision support was integrated into the EHR which recommended (but did not mandate) transfusion of the minimum number of RBC units to return patients to an evidence-based safe hemoglobin range (e.g. above 7 g/dl in stable pa- tients without cardiac ischemia, or above 8 g/dl in stable patients with cardiac ischemia). Notably, however, active bleeding was a listed excep- tion to guideline adherence, and no specific educational program or de- cision support was provided for the management of patients with active bleeding.

All KPNC hospitals, clinics and EDs employ a common EHR (Epic, Ve- rona, WI) which was fully deployed for inpatient use in 2010. Data were derived principally from the KPNC Virtual Data Warehouse, a research database resource that centralizes data from EHRs and other legacy health system source files into standardized formats and data tables [25]. All data were electronically extracted from the EHR using unique encounter and medical record numbers. Manual chart review was not used for data validation except where noted as previously performed. The study was approved with a waiver for informed consent by the KPNC Institutional Review Board, which has jurisdiction over all hospi- tals in this report.

Cohort selection

To assemble the study cohort, we identified all adult KPNC health plan members who presented to a KPNC ED between July 1st, 2012 and September 30th, 2016. The July 1st, 2012 starting point was chosen due to limitations in clearly separating ED from inpatient-based diag- nostic codes prior to this date. Patients were eligible for principal cohort inclusion if they had an International Classification of Diseases, 9th revi- sion (ICD-9) or 10th Revision (ICD-10) ED physician-coded diagnosis of GI bleeding (supplemental appendix Table e1), laboratory measure- ment of a complete blood count while in the ED, and continuous KPNC health plan membership for 90 days (excepting loss of coverage due to death) following the index visit to allow for capture of 90-day out- come events. The principal cohort was further restricted to only include the first study-eligible ED encounter to allow for per-patient analyses of 90-day outcomes. Patients were also stratified a priori by their hemo- globin nadir in the ED into three categories, with cut-offs determined by relevance to restrictive transfusion evidence and guidelines; hemo- globin 6.9 g/dl or less; hemoglobin between 7.0 and 9.9 g/dl (the sub- group of prime interest) and hemoglobin of 10.0 g/dl and above.

Patient characteristics

Patient-level variables included age, sex, comorbid diseases, antico- agulant use, and Laboratory measurements obtained during the ED stay. Laboratory values included platelet counts (nadir), hemoglobin levels (nadir) and International Normalized Range (INR) values for pro- thrombin time (peak). Comorbidities were obtained from the active problem list at the time of the ED visit and were categorized using the health care utilization Project Elixhauser Comorbidity Software (www.ahrq.gov/data/hcup) [26]. Anticoagulant use was defined as a prescription fill for warfarin or a direct oral anticoagulant (rivaroxaban, apixaban, dabigatran) in the 90 days prior to the index ED visit using data from an internal prescription database. For additional risk adjust- ment we also determined if patients received GI endoscopy (upper and/or lower) using corresponding Common Procedural Terminology billing codes.

Outcome measures

All outcomes are reported as a percentage of study population per study quarter (rate), adjusted for confounders as noted below. The pri- mary outcome of interest was the receipt of any RBC transfusion during the ED stay. Secondary outcomes included any RBC transfusion during the index hospitalization (inclusive of the ED stay), as well as any RBC transfusion, repeat ED visit, repeat hospital admission or death within 90 days following the index ED visit. RBC transfusion events were iden- tified from blood bank transfusion records including ED, inpatient, and outpatient encounters though the 90-day endpoint. The RBC transfusion data have been previously validated [27]. Repeat ED visits or hospital admissions were determined from the KPNC EHR, supplemented by queries of a claims-based database to capture events occurring outside of KPNC. Mortality was determined using a composite death database of internal KPNC mortality statistics cross-referenced with state (Cali- fornia Death Index) and federal (Social Security Death Index) data.

Data analysis

Data are presented as medians with interquartile ranges (IQR) or proportions with 95% confidence intervals (CI). Missing INR values were imputed using the median (normal range) value for the cohort, under the assumption that a lack of INR measurement represented clin- ical assumption of normal range values, and thus was not missing at random [28]. Unadjusted differences between multiple proportions and medians were assessed using the chi-squared and Kruskal-Wallis rank test, respectively. P values of 0.005 or less were considered

statistically significant to provide a greater degree of confidence in the results [29]. Bonferroni adjustment was added for the hemoglobin nadir subgroup analyses (p value of 0.001 or less considered statistically significant).

Mixed-effects logistic regression models were used to provide ad- justed rates of RBC transfusion. The models included age, lowest hemo- globin value, lowest platelet value, highest INR value, sex, comorbidities (iron-deficient anemia, congestive heart failure, chronic lung disease, chronic kidney disease stage 3 or higher, diabetes, malignancy), antico- agulant use, and performance of GI endoscopy (during the respective outcome timeframe) as patient-level fixed effects. Continuous variables (age and laboratory values) were modeled using restricted cubic splines. An interaction term between anticoagulant prescription and highest INR value was used to help differentiate between INR elevations due to intrinsic coagulation factor deficiencies from those due to antico- agulant use. The index visit facility was treated as a random effect to ac- count for any lack of independence at the hospital level. Additional adjustment for clustering by provider did not improve the model goodness-of-fit, as determined by the likelihood ratio test, likely due to the low number of transfusions ordered by any given provider.

Adjusted rates for both repeat ED visits and hospital admissions through 90 days were determined using logistic regression models in- cluding age, baseline laboratory values and Elixhauser-categorized co- morbidities. Given the very low observed mortality rates, a more parsimonious logistic regression model was used to avoid overfitting (age, hemoglobin nadir, malignancy). For these three models, introduc- ing index treating facility as a random-effect did not result in significant improvement in model goodness-of-fit, as determined by the likelihood ratio test, and thus fixed effect models were used. Multicollinearity in all models was assessed using the variance inflation factor.

Using the logistic regression models described above, adjusted rates of the respective outcomes were summarized by study quarter (3- month interval). These adjusted rates were plotted (rate per quarter), and the magnitude of trend over time was determined using the slope

of the best fit linear line, reported in absolute and relative terms (the lat- ter using a baseline value indicated by the y-intercept of the line). Strength and consistency of observed trends was reported using the co- efficient of determination (R²), and statistical significance was deter- mined by regressing the study time unit (quarter) against corresponding adjusted rates.

Sensitivity analyses were performed by 1) including both patients without continuous health plan membership or with multiple eligible ED encounters during the study period to assess for principal cohort se- lection bias (reporting ED and index hospitalization RBC transfusion outcomes only, adjusting for same patient correlations) and

2) restricting analysis to principal cohort patients who were hospital- ized at the index ED visit (to exclude patients with lower-risk GI bleeds and assess for effect modification). Statistical analyses were performed using Stata Version 13.1 (StataCorp LLC, College Station, Texas, USA).

Results

Principal cohort selection and characteristics

Out of 34,202 ED patients with both a complete blood count and a di- agnosis of GI bleeding during the study period, 24,868 eligible principal cohort encounters were identified after exclusions for multiple ED visits (n = 5892) and absence of continuous health plan membership for 90 subsequent days (n = 3442). Of these, 2457 (9.9%) had an index ED he- moglobin nadir value of 6.9 g/dl or less, 7752 (31.2%) had values be- tween 7.0 and 9.9 g/dl, and 14,660 (59.0%) had values of 10.0 g/dl of greater. A CONSORT diagram of study cohort selection is presented in Fig. 1.

The median age was 67 years, 50.1% were female, and 22.2% had a history of Iron deficiency anemia. A total of 13.2% patients underwent RBC transfusion during the ED visit, while 32.1% underwent RBC trans- fusion through 90 days. The annualized median hemoglobin nadir in the ED did not vary significantly over the course of the study (range

ED encounters for patients aged > 18 years, between July 1st 2012 and September 30th 2016 with an ICD-coded ED diagnosis of gastrointestinal bleeding and a hemoglobin result during the ED visit (n=34,202)

First ED visit in study period (n=28,310)

Active health plan membership in the three months following the index ED visit, except in cases of death (n = 24,868)

“Principal cohort”

Hemoglobin nadir in ED 6.9 g/dl and under (n=2,457)

Hemoglobin nadir in ED between

7.0 and 9.9 g/dl (n=7,752)

Hemoglobin nadir in ED 10.0 g/dl and greater (n=14,660)

Admitted to the hospital at index visit (n=5,449)

Admitted to the hospital at index visit (n=6,793)

Admitted to the hospital at index visit (n=2,239)

Fig. 1. CONSORT diagram of principal cohort and subgroup selection.

Table 1

Cohort characteristics by year (n = 24,868).

Year	All years	2012	2013	2014	2015	2016	P value
# of patients	24,868	2976	5642	5795	5812	4643
Age (median, IQR)	67 (52-79)	66 (52-79)	67 (52-79)	67 (53-79)	66 (52-79)	66 (52-79)	0.57
Female (%)	50.1	49.7	50.0	51.2	49.4	49.8	0.34
Iron-deficient anemia (%)	22.2	24.7	23.3	23.9	22.4	17.1	b0.001
Congestive heart failure (%)	10.6	10.9	10.9	10.6	10.4	10.1	0.74
Chronic lung disease (%)	22.4	21.7	22.1	22.9	22.2	22.8	0.65
Chronic kidney disease (%)	21.3	20.7	21.5	22.2	21.8	19.6	0.017
Diabetes (%)	20.8	20.7	21.2	20.7	21.4	19.9	0.42
Malignancy (%)	2.9	3.6	3.2	3.2	2.9	3.0	0.35
Warfarin prescription (%)	10.7	10.6	10.6	10.7	10.4	11.1	0.85
Direct oral anticoagulant prescription (%)	0.5	0.4	0.4	0.4	0.7	0.5	0.13
Platelet count x103 (median, IQR)	204	199	201	205	206	208	b0.001
	(158-256)	(151-251)	(155-252)	(159-258)	(161-256)	(161-259)
Hemoglobin g/dL (median, IQR)	10.9	10.9	10.8	10.8	10.9	11.0	0.42
	(8.4-13.1)	(8.6-13.1)	(8.6-13.1)	(8.4-13.0)	(8.3-13.2)	(8.1-13.2)
INR (median, IQR)	1.1 (1.0-1.2)	1.1 (1.0-1.2)	1.0 (1.0-1.2)	1.1 (1.0-1.2)	1.1 (1.0-1.2)	1.1 (1.0-1.2)	b0.001
Endoscopy in the ED (%)	6.7	4.2	6.0	5.5	8.2	9.1	b0.001
Endoscopy during index hospitalization (%)	37.4	30.2	32.1	36.5	42.1	43.8	b0.001
Endoscopy within 90 days (%)	48.6	46.0	46.8	45.2	51.1	53.3	b0.001
Discharged home from ED (%)	41.8	40.7	41.8	39.8	42.2	44.4	b0.001
ED length of stay in hours, (median, IQR)	4.4 (3.1-6.6)	4.4 (3.1-6.5)	4.5 (3.1-6.7)	4.3 (3.0-6.4)	4.4 (3.1-6.5)	4.6 (3.1-7.0)	b0.001
RBC transfusion in the ED (%)	13.2	13.7	13.9	12.7	13.4	12.7	0.22
Hemoglobin nadir among those transfused in ED, g/dl (median,	7.2 (6.2-8.1)	7.4 (6.4-8.3)	7.5 (6.4-8.4)	7.2 (6.2-8.2)	7.1 (6.1-7.9)	6.9 (6.0-7.7)	b0.001
IQR) RBC transfusion during index hospitalization (%)	29.4	31.7	31.2	29.8	28.2	26.9	b0.001
RBC transfusion within 90 days (%)	32.1	34.8	33.8	32.5	30.7	29.2	b0.001
Repeat ED visit 90 days (%)	30.0	30.7	29.1	29.4	31.0	30.3	0.15
Days to next ED visit (median, IQR)	22 (5-70)	23 (7-50)	21 (7-47)	21 (6-48)	22 (7-51)	23 (7-50)	0.65
Rehospitalization within 90 days (%)	16.5	17.4	16.8	16.2	16.6	15.8	0.35
90-day mortality (%)	0.3	0.7	0.5	0.3	0.2	0.2	b0.001

Abbreviations: ED - emergency department; RBC - red blood cell; INR - international normalized ratio; IQR - interquartile range.

10.8-11.0 g/dl), nor was there a statistically significant quarterly trend (odds ratio = 0.99, 95% CI 0.99-1.0, p = 0.07). However, the annualized median hemoglobin prior to ED RBC transfusion did decrease during the study period, starting at 7.5 g/dl in the first 12 months and ending at

6.9 g/dl in the final 12 months, resulting in an average annual decrease of just over 0.1 g/dl (p b 0.0001). Demographics and unadjusted out- comes for the overall cohort are presented in an annualized format in Table 1, and by hemoglobin nadir strata in Table 2. The quarterly

distribution of principal cohort eligible ED encounters was well bal- anced and is presented in supplemental appendix Fig. e1.

Primary and secondary outcomes

Results for the principal cohort are presented in Table 3. For the pri- mary outcome of regression model-adjusted rates of RBC transfusion during the index ED visit, we observed a small (absolute quarterly

Table 2

Primary cohort characteristics by hemoglobin nadir strata in the ED.

	ED hemoglobin nadir <=6.9 g/dl (n =	ED hemoglobin nadir 7.0-9.9 g/dl (n =	ED hemoglobin nadir >=10.0 g/dl (n =
	2457)	7752)	14,660)
Age (median, IQR)	71 (60-81)	72 (60-82)	62 (46-76)
Female (%)	48.4	50.2	50.5
Iron-deficient anemia (%)	50.0	36.1	10.2
Congestive heart failure (%)	19.5	15.0	6.7
Chronic lung disease (%)	22.8	24.1	21.4
Diabetes (%)	31.9	27.6	15.4
Chronic kidney disease (%)	35.8	30.1	14.2
Cancer (%)	4.3	4.3	2.2
Warfarin prescription (%)	10.7	10.7	10.7
Direct oral anticoagulant prescription (%)	0.5	0.5	0.5
Platelet count, x103 (median, IQR)	178 (126-246)	181 (134-236)	217 (177-264)
Hemoglobin, g/dL (median, IQR)	6.2 (5.5-6.6)	8.4 (7.8-9.2)	12.8 (11.5-14.0)
INR (median, IQR)	1.2 (1.1-1.6)	1.2 (1.0-1.3)	1.1 (1.0-1.2)
Endoscopy in the ED (%)	6.3	7.9	6.2
Endoscopy during index hospitalization (%)	61.4	55.5	23.9
Endoscopy within 90 days (%)	67.8	61.6	38.4
Discharged home from ED (%)	8.9	12.4	62.8
ED length of stay in hours, (median, IQR)	4.7 (3.5-7.0)	4.9 (3.6-7.2)	4.1 (2.8-6.3)
RBC transfusion in the ED (%)	59.9	21.6	1.0
RBC transfusion during index hospitalization (%)	97.0	57.8	3.1
RBC transfusion within 90 days (%)	97.4	62.3	5.1
Repeat ED visit 90 days (%)	38.4	35.0	26.0
Days to next visit (median, IQR)	24 (10-47)	22 (8-48)	21 (5-51)
Rehospitalization at 90 days (%)	27.5	23.2	11.1
90-day mortality (%)	0.8	0.6	0.1

Abbreviations: ED - emergency department; RBC - red blood cell; INR - international normalized ratio; IQR - interquartile range.

Table 3

Principal cohort analysis results (n = 24,868).

Adjusted range y-Intercept (baseline) Absolute quarterly change (slope) Relative quarterly change R² P value

RBC transfusion in ED	10.5-15.5%	14.2%	-0.1%	-0.7%	0.18	b0.0001
Subgroup 1 (Hgb <=6.9 g/dl)	52.1-70.6%	63.1%	-0.4%	-0.6%	0.13	b0.0001
Subgroup 2 (Hgb 7.0-9.9 g/dl)	14.3-27.3%	25.4%	-0.4%	-1.6%	0.38	b0.0001
Subgroup 3 (Hgb >= 10.0 g/dl)	0.4-1.8%	1.4%	-0.04%	-4.0%	0.34	b0.0001
RBC transfusion during index hospitalization	25.1-31.9%	32.8%	-0.4%	-1.1%	0.82	b0.0001
RBC transfusion in 90 days	28.2-35.0%	35.7%	-0.4%	-1.1%	0.85	b0.0001
90-day repeat ED visit	27.9-33.3%	29.5%	+0.06%	+0.2%	0.05	b0.0001
90-day rehospitalization	13.9-18.4%	17.2%	-0.08%	-0.5%	0.11	b0.0001
90-day mortality	0.1-0.9%	0.6%	-0.03%	-4.7%	0.61	b0.0001

Results are presented using the best fit linear line to the plotted data of adjusted outcomes rates (as determined by the respective logistic regression models) and where the adjusted out- come rate = (bx + y) and b = absolute quarterly change (slope), x = quarter (time) and y = intercept (baseline). Relative quarterly changes are calculated by dividing the absolute quarterly change by the extrapolated baseline values (y-intercept).

Abbreviations - ED = emergency department; Hgb = hemoglobin; RBC = red blood cell.

change of -0.1%) and weak (R² = 0.18) overall trend during the study period. However, there was a larger (absolute quarterly change of

-0.4%) and stronger (R² = 0.82) trend towards decreasing RBC transfu- sions during the index hospitalization, and this persisted out to 90 days. At the same time, rates of 90-day repeat ED visits and rehospitalizations remained relatively unchanged without notable linear trends (R² of 0.05 and 0.11, respectively). 90-day mortality rates, which remained consis- tently below 1%, did demonstrate a trend towards lower rates over time. Plots of adjusted rates used in the primary analysis are presented in Fig. 2 (RBC transfusions), and Fig. 3 (90-day repeat ED visits, rehospitalizations and mortality).

Subgroup analyses

Subgroup analysis stratified by hemoglobin nadir values in the ED revealed a larger (absolute quarterly change of -0.4%) and more con- sistent (R² = 0.38) trend towards decrease in ED RBC transfusions among the subgroup of prime interest, patients with values between

7.0 and 9.9 g/dl, as compared to the overall cohort. A very small (abso- lute quarterly change of -0.04%) but similarly consistent (R² = 0.34) trend was seen towards decreased transfusion among patients with he- moglobin values of 10.0 g/dl and above. No consistent change in ED RBC transfusions was seen among patients with hemoglobin nadir values of

6.9 g/dl or less (R² of 0.13). For secondary outcomes, similar trends were seen in each hemoglobin nadir subgroup as compared to the primary cohort (data not shown).

Sensitivity analyses

Two sensitivity analyses were performed, neither of which substan- tially altered the findings. The first assessed for principal cohort selec- tion bias by analyzing all 34,202 encounters (including patients without continuous health plan membership or repeated ED encoun- ters) and found no difference in results for RBC transfusions while in the ED or during the index hospitalization (Table 4). The second assessed for effect modification by restricting the analysis to principal cohort patients who were hospitalized at the index encounter (thus ex- cluding patients with lower-risk GI bleeds) and likewise did not demon- strate any changes in magnitude or strength of the observed trends, including 90-day outcomes (Table 5).

Discussion

In this retrospective cohort, the proportion of patients presenting to the ED with GI bleeding who subsequently underwent RBC transfusion steadily decreased over the course of several years. This apparent practice change was evident not only in the ED setting (most notable among pa- tients with hemoglobin nadirs between 7.0 and 9.9 g/dl) but also during the index hospitalization and up to 90 days following the index encoun- ter, inclusive of the Outpatient setting. Accordingly, there was a gradual and steady lowering of the annualized median hemoglobin nadir value among patients with GI bleeding who were transfused in the ED.

Fig. 2. Adjusted rates of RBC transfusion while in the ED, during the index hospitalization and through 90 days (principal cohort, n = 24,868).

Adjusted RBC transfusion rates

40.00%

35.00%

30.00%

25.00%

20.00%

15.00%

10.00%

5.00%

0.00%

RBC ED transfusions

RBC index transfusions

RBC 90d transfusions

2012 Q3

2012 Q4

2013 Q1

2013 Q2

2013 Q3

2013 Q4

2014 Q1

2014 Q2

2014 Q3

2014 Q4

2015 Q1

2015 Q2

2015 Q3

2015 Q4

2016 Q1

2016 Q2

2016 Q3

Fig. 3. Adjusted rates of 90-day events, including repeat emergency department visits, rehospitalizations and mortality (principal cohort, n = 24,868).

Adjusted 90-day event rates

40.00%

35.00%

30.00%

25.00%

20.00%

15.00%

10.00%

5.00%

0.00%

90d rehospitalizations

90d mortality

90d repeat ED visits

2012 Q3

2012 Q4

2013 Q1

2013 Q2

2013 Q3

2013 Q4

2014 Q1

2014 Q2

2014 Q3

2014 Q4

2015 Q1

2015 Q2

2015 Q3

2015 Q4

2016 Q1

2016 Q2

2016 Q3

The observed decrease in ED RBC transfusion among GI bleeding pa- tients with hemoglobin nadirs between 7.0 and 9.9 g/dl is consistent with evolving guidelines supporting hemoglobin “triggers” of 7.0 or

8.0 g/dl for RBC transfusion in acute GI bleeding, and is perhaps repre- sentative of a growing awareness and acceptance of these guidelines by ED physicians over time [9-11]. This is particularly notable in the context of earlier studies demonstrating poor adherence to restrictive transfusion practice recommendations among ED physicians [19,20]. These findings also complement data demonstrating an increase in ane- mia tolerance and restrictive RBC transfusion practice for all hospital- ized patients at the health system level [24].

In terms of utilization and safety, the proportion of patients with a rehospitalization or repeat ED visits out to 90 days was constant over time, suggesting that restrictive RBC transfusion practice did not result in increased utilization and/or morbidity, consistent with existing liter- ature [30,31]. Similarly, mortality was decreased over time, a finding which, while possibly attributable to general temporal trends [32], is consistent with clinical trial findings supporting the safety and potential Survival benefit of restrictive transfusion practices among patients with GI bleeding [6,7]. Thus, while none of these findings are evidence of non-inferiority or benefit in themselves, given the observational nature of this study, they are reassuring in the context of similar findings from other health-system and patient population settings. Additionally, a re- cent large observational study from our health system had similar out- come findings in association with increased restrictive transfusion practice among a heterogenous hospitalized patient population [33].

Study strengths include the multicenter composition and large size of the cohort, both of which bolster the internal validity of the results. While unknown or unmeasured factors are a limitation in any adjusted analysis, and particularly in this study given the limitations of electronic retrospective data, we were able to control for age, comorbidities, pri- mary hematologic laboratory values, anticoagulant use, endoscopy (encompassing interventions to decrease bleeding rates and risk), and

facility level variation in practice. While there was a notable increase in endoscopy rates over the course of the study, largely driven by more procedures being performed during the ED visit and index hospi- talization, these interventions were controlled for in all the models ex- cepting mortality. Though it is conceivable that increased endoscopy rates may have played a role in supporting a restrictive transfusion ap- proach and/or decreasing downstream utilization and mortality, con- temporaneous studies examining early endoscopy for either upper or lower GI bleeding have not demonstrated associated decreased rates of downstream re-bleeding, RBC transfusions or mortality [34-38].

Additional limitations of this study include an inability to reliably stratify into upper versus lower GI sources of bleeding (including the type of endoscopy performed), unavailability of reliable antiplatelet medication use data (owing to over-the-counter aspirin use), lack of al- ternative measures of altered coagulation status (e.g. thromboelastography), and lack of control for other potentially con- founding variables related to transfusion decisions, given the limits of the available retrospective electronic data as noted above (e.g. hemody- namic instability, apparent volume of blood loss, clinical symptoms at- tributable to anemia, personal healthcare preferences). However, it is unlikely that the prevalence and/or relative proportions of these un- measured factors varied significantly over the course of the study. Addi- tionally, previous predictive modeling work on the likelihood of RBC transfusions among hospitalized patients, and more specifically among patients with GI bleeding, demonstrated that measures of sever- ity of illness contributed minimal predictive value beyond that provided by the Admission hemoglobin level alone [39]. Likewise, while it is pos- sible that a relatively small group of patients with GI bleeding were missed due to alternative Diagnostic coding (e.g. anemia, hemorrhagic shock), these occurrences are unlikely to have altered the findings. Fi- nally, the study involved patients treated within an integrated health system, which may have increased clinician comfort with deferral of transfusion, particularly among outpatients. However, the results were

Table 4

Sensitivity analysis, including both patients with multiple ED visits during study and those without continuous health plan coverage through 90 days (n = 34,225).

Adjusted range y-Intercept (baseline) Absolute quarterly change Relative quarterly change R² P value

RBC transfusion in ED	12.5-18.2%	16.3%	-0.06%	-0.4%	0.05	0.008
RBC transfusion during index hospitalization	29.6-36.0%	36.1%	-0.3%	-0.8%	0.64	b0.0001

Results are presented using the best fit linear line to the graphed data, where the adjusted outcome rate = bx + y and b = absolute quarterly change (slope), x = quarter (time) and y = intercept (baseline). Relative quarterly changes are calculated by dividing the absolute quarterly change by the extrapolated baseline values (y-intercept).

Abbreviations - ED = emergency department; RBC = red blood cell.

Table 5

Sensitivity analysis restricted to patients hospitalized at the index ED visit (n = 14,480).

	Adjusted range	y-Intercept (baseline)	Absolute quarterly change (slope)	Relative quarterly change R2 P value
RBC transfusion in ED	15.8-21.1%	20.3%	-0.1%	-0.5%	0.12	0.0007
RBC transfusion during index hospitalization	42.3-51.4%	51.4%	-0.5%	-1.0%	0.82	b0.0001
RBC transfusion in 90 days	44.7-54.0%	54.0%	-0.5%	-0.9%	0.87	b0.0001
90-day repeat ED visit	30.7-36.7%	31.7%	+0.09%	+0.3%	0.05	b0.0001
90-day rehospitalization	17.3-22.1%	21.2%	-0.05%	-0.2%	0.03	0.003
90-day mortality	0.1-1.4%	0.9%	-0.05%	-5.5%	0.52	b0.0001

Results are presented using the best fit linear line to the graphed data, where the adjusted outcome rate = bx + y and b = absolute quarterly change (slope), x = quarter (time) and y = intercept (baseline). Relative quarterly changes are calculated by dividing the absolute quarterly change by the extrapolated baseline values (y-intercept).

Abbreviations - ED = emergency department; RBC = red blood cell.

consistent when restricting the analysis to patients hospitalized at the index encounter, thus improving the potential generalizability of the findings to non-integrated systems as well.

It is also notable that these observations were made in the context of

an active system-wide blood product conservation initiative. However, the initiative did not promote restrictive transfusion for patients with uncontrolled active bleeding. Rather, when clinicians placed electronic orders for RBC transfusion in the ED or hospital, active bleeding was pre- sented as a specific exclusion criterion alongside recommended hemo- globin “transfusion trigger” thresholds. Thus, it is likely that some passive diffusion of evidence and practice guidelines specific to GI bleeding had a role to play, albeit primed by a framework supporting general restrictive transfusion practices.

Conclusions

We observed a gradual decrease in the proportion of ED patients with GI bleeding who subsequently underwent RBC transfusion, with- out corresponding increases in measures of utilization or mortality. The largest decrease in rates of ED RBC transfusion was observed among patients with hemoglobin nadirs between 7.0 and 9.9 g/dl, cor- responding to the clinical scenarios most likely to be impacted by evolv- ing clinical evidence and guidelines. These findings suggest that ED physicians are willing to adopt restrictive transfusion practices for pa- tients with GI bleeding and can serve as benchmarks for future efforts concerning optimal transfusion practices in the setting of GI bleeding [7,8].

Prior presentations

None.

Funding source

National Heart, Lung, and Blood InstituteR01HL126130.

Author contribution statement

DGM, MER, DRV and NHR conceived the study. NHR obtained re- search funding. JH, CP, GJE and NHR abstracted the data variables, in- cluding quality control. DGM and NHR managed the data, including statistical analysis. DGM drafted the manuscript, and all authors con- tributed substantially to its revision. DGM takes responsibility for the paper as a whole.

Declaration of Competing Interest

DGM, MER, DRV, NHR, JH, CP and GJE report no conflicts of interest.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi. org/10.1016/j.ajem.2019.06.019.

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