Summary
Background:
Venous thromboembolism (VTE) is a significant cause of morbidity and mortality among patients with inflammatory bowel disease (IBD). However, data on national trends remain limited.
Aims:
To assess national trends in VTE-associated hospitalisations among patients with IBD as well as risk factors for, and mortality associated with, these events
Methods:
Using the U.S. Nationwide Inpatient Sample from 2000–2018, temporal trends in VTE were assessed using the National Cancer Institute’s Joinpoint Regression Program with estimates presented as the average annual percent change (AAPC) with 95% confidence intervals (CIs).
Results:
Between 2000 and 2018, there were 4,859,728 hospitalisations among patients with IBD, with 128,236 (2.6%) having a VTE, and 6352 associated deaths. The rate of VTE among hospitalised patients with IBD increased from 192 to 295 cases per 10,000 hospitalisations (AAPC 2.4%, 95%CI 1.4%, 3.4%, p < 0.001), and remained significant when stratified by ulcerative colitis (UC) and Crohn’s disease as well as by deep vein thrombosis and pulmonary embolism. On multivariable analysis, increasing age, male sex, UC (aOR: 1.30, 95%CI 1.26, 1.33), identifying as non-Hispanic Black, and chronic corticosteroid use (aOR: 1.22, 95%CI 1.16, 1.29) were associated with an increased risk of a VTE-associated hospitalisation.
Conclusion:
Rates of VTE-associated hospitalisations are increasing among patients with IBD. Continued efforts need to be placed on education and risk reduction.
1 |. INTRODUCTION
Inflammatory bowel disease (IBD), comprised of Crohn’s disease (CD) and ulcerative colitis (UC), is an immune mediated disease causing chronic intestinal inflammation. It affects more than 3 million individuals in the United States (U.S.) alone, and has a rising prevalence.1 Over the past two decades, there have been significant advances in the field, which have both improved care and decreased risk of complications. Despite these advances, little is known about the rate of VTE during this time, although VTE remains one of the most common and life-threatening complications associated with IBD.
VTEs, including pulmonary embolism (PE) and deep vein thrombosis (DVT), are a significant cause of morbidity, mortality and economic burden. Each year in the U.S., over 500,000 hospitalisations and 100,000 deaths are attributable to a VTE, and lead to an overall cost of 5–10 billion dollars.2–6
IBD confers an inherent elevation in VTE risk, including during periods of remission.7–10 This risk is further increased among individuals who are older, have ongoing inflammation, use corticosteroids, have had recent hospitalisation or surgery, or who have limited mobility.8 This is particularly important, as older adults are expected to comprise more than one-third of the IBD patient population in the coming decade, which may lead to increased rates of VTE.1,11
Overall, among the general population, data suggest that VTE rates are not significantly changing over time.12,13 Among patients with IBD however, only limited data exist. A recent study of patients with IBD in Manitoba Canada noted persisting rates of VTE (−0.7% per year) from 1985 to 2018, while another study of UC patients in the United Kingdom found that emergency room readmissions due to VTE decreased over time (1.72 to 0.68 per 1000 discharges).14,15 In order to better establish an evidence base on IBD-related VTE events, we conducted a large study in the U.S., assessing nationwide trends and risk factors for VTE-associated hospitalisations and mortality.
2 |. MATERIALS AND METHODS
2.1 |. Data source
We analysed data from the 2000 to 2018 U.S. Nationwide Inpatient Sample (NIS). The NIS is the largest publicly available all-payer database in the U.S., compiled by the Healthcare Cost and Utilisation Project (HCUP).16 The NIS provides a representative sampling of all hospital admissions, including both elective and emergent, and is de-identified, thus representing admission-level data without the ability to track individual patients over time. The NIS includes administrative and demographic data from a 20% sampling of hospitalisations in the U.S. compiled annually since 1988 based on data contributed by multiple statewide organisations.17,18 These hospitalisations are selected via a stratified systematic random sample to generate a population that can be weighted to represent the entire U.S. The NIS includes all medical specialties as well as academic, community, nonfederal, general and specialty-specific centres.15–18 The NIS contains a system of weights that allows for the calculation of national estimates.19 Additionally, the NIS previously utilised the International Classification of Diseases, 9th Edition, Clinical Modification (ICD-9CM) codes for procedure and diagnosis identification until October 2015. Subsequently, it switched to the International Classification of Diseases, 10th Edition (ICD-10). Given this change in coding, we converted ICD-9CM codes to ICD-10 using General Equivalence Mappings SAS programming (Cary, NC) provided by the National Center for Health and Centers for Medicare and Medicaid Services.20,21 Given the data from the NIS are de-identified and publicly available, the New York University Institutional Review Board deemed this work exempt from review.
2.2 |. Study population
From 2000 to 2018, we identified all-cause hospitalisations of patients in the NIS with International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) diagnosis codes for UC (556.x) or CD (555.x), as well as the International Classification of Diseases, 10th revision, Clinical Modification (ICD-10-CM) diagnosis codes for UC (K51.x) and CD (K50.x).22,23 We identified VTE with both ICD-9-CM and ICD-10-CM diagnosis codes for both PE and DVT, and included a population of patients with celiac disease for comparison (Table A1).24,25
2.3 |. Outcomes
Our primary outcome was the rate of VTE-associated hospitalisations from 2000 to 2018. Secondary outcomes included the rate of VTE-associated mortality, risk factors associated with the presence of VTE during hospitalisation, and risk factors for mortality among patients hospitalised with a VTE.
2.4 |. Patient and hospital characteristics
The analysis included demographic, hospital and clinical factors in the NIS. Demographic patient factors included patient age strata (≤18, 19–30, 31–40, 41–50, 51–65, 66–80, ≥81 years-old), sex, race (non-Hispanic White, non-Hispanic Black, Hispanic, other and unknown), insurance (Medicare, Medicaid, private, self-pay, no charge and other) and median household income quartile by ZIP code quartile.18 Comorbidities were calculated using the Agency for Healthcare Research and Quality comorbidity index, which includes comorbid conditions based on the Elixhauser Comorbidity index.26,27 Patients were categorised based on the number of comorbidities (0, 1 or ≥2). Patients were also classified by subtype of IBD (CD, UC or indeterminate colitis) based on ICD-9-CM and ICD-10-CM coding. Additional variables captured on ICD coding included chronic corticosteroid use, prior VTE, the presence of thrombophilia, Clostridioides difficile infection, as well as colorectal surgery or flexible sigmoidoscopy/colonoscopy during hospitalisation (Table A1).10
2.5 |. Data analysis
Demographic, clinical and hospital factors were ascertained from NIS, and weighted to reflect national estimates.18 Temporal trends in VTE were assessed over the 19-year timeframe using the National Cancer Institute’s Joinpoint Regression Program with estimates presented as the average annual percent change (AAPC).28 Univariable and multivariable logistic regression models with unadjusted (OR) and adjusted (aOR) odds ratios were then used to assess risk factors associated with the presence of VTE during hospitalisation, as well as overall mortality among IBD patients with a VTE. All statistical analyses were completed using SAS version 9.4 (Cary, NC).
2.6 |. Sensitivity analysis
In order to limit misclassification of IBD when analysing VTE-associated risk factors and mortality, a sensitivity analysis in which hospitalisations only associated with a primary or secondary diagnosis of IBD was performed. Additionally, in order to capture those with the highest likelihood of IBD flare, we further restricted our trend analysis to only include hospitalisations from the emergency room in which IBD was listed as primary diagnosis from 2007 to 2018. Stratification was also completed assessing UC versus CD, and DVT versus PE.
3 |. RESULTS
3.1 |. VTE-associated hospitalisation & mortality trend
Between 2000 and 2018, there were a total of 4,859,728 hospitalisations among patients with IBD. Hospitalised patients with IBD tended to be older, female, non-Hispanic White, have Medicare or private insurance, and have multiple comorbidities (Table 1). In total, 128,236 (2.6%) hospitalisations were associated with a VTE, resulting in 6352 deaths. The rate of VTE among hospitalised patients with IBD increased from 192 to 295 cases per 10,000 hospitalisations (AAPC: 2.4%, 95%CI: 1.4%, 3.4%, p < 0.001), and remained significant when stratified by UC (202 to 259 cases, AAPC: 1.8%, 95%CI: 0.9%, 2.7%, p < 0.001) versus CD (170 to 260 cases, AAPC: 2.7%, 95%CI: 1.4%, 4.0%, p < 0.001; Figure 1), and by DVT versus PE (Figure S1). This is in comparison to individuals with celiac disease, in which rates of VTE did not increase significantly over time (AAPC −0.3%, 95%CI −1.30%, 0.70%). Additionally, when restricting our analysis to only include hospitalisations from the emergency room (ER) in which IBD was listed as primary diagnosis, VTE rates did not increase over time, regardless of whether colorectal surgery was performed (AAPC −1.10%, 95%CI −5.80%,3.90%; p = 0.66 for ER admissions without colorectal surgery versus AAPC 2.30%, 95%CI −2.70%, 7.50%; p = 0.38 for ER admissions with colorectal surgery; Figure S2).
TABLE 1.
Demographics among hospitalised patients with IBD
| No VTE N (%) | VTE N (%) | |
|---|---|---|
| IBD category | ||
| Crohn’s disease | 2,988,947 (63.17%) | 70,267 (54.79%) |
| Ulcerative colitis | 1,711,884 (36.18%) | 57,174 (44.59%) |
| Indeterminate colitis | 30,659 (0.65%) | 795 (0.62%) |
| Age (years) | ||
| ≤ 18 | 35,327 (0.75%) | 289 (0.23%) |
| 19–30 | 730,434 (15.44%) | 9831 (7.67%) |
| 31–40 | 743,660 (15.72%) | 14,489 (11.30%) |
| 41–50 | 756,410 (15.99%) | 18,348 (14.31%) |
| 51–65 | 1,148,590 (24.28%) | 36,683 (28.61%) |
| 66–80 | 938,711 (19.84%) | 35,369 (27.58%) |
| ≥ 81 | 378,358 (8.00%) | 13,227 (10.31%) |
| Sex | ||
| Female | 2,713,188 (57.37%) | 69,431 (54.16%) |
| Male | 2,015,762 (42.63%) | 58,776 (45.84%) |
| Race | ||
| Non-Hispanic White | 3,281,712 (69.36%) | 90,931 (70.91%) |
| Non-Hispanic Black | 412,285 (8.71%) | 12,233 (9.54%) |
| Hispanic | 220,310 (4.66%) | 4920 (3.84%) |
| Other | 145,671 (3.08%) | 3391 (2.64%) |
| Unknown | 671,512 (14.19%) | 16,762 (13.07%) |
| Median household zip code income quartile | ||
| Highest | 1,306,492 (27.61%) | 26,889 (20.97%) |
| High | 1,199,318 (25.35%) | 30,146 (23.51%) |
| Low | 1,147,784 (24.26%) | 32,721 (25.52%) |
| Lowest | 989,170 (20.91%) | 36,029 (28.10%) |
| Missing | 88,727 (1.88%) | 2452 (1.91%) |
| Insurance status | ||
| Private | 2,002,393 (42.32%) | 46,217 (36.04%) |
| Medicare | 1,789,574 (37.82%) | 61,860 (48.24%) |
| Medicaid | 558,772 (11.81%) | 12,275 (9.57%) |
| Self-pay | 207,747 (4.39%) | 3747 (2.92%) |
| No charge | 22,845 (0.48%) | 462 (0.36%) |
| Other | 141,154 (2.98%) | 3428 (2.67%) |
| Chronic anticoagulation use | ||
| No | 4,562,264 (96.42%) | 113,545 (88.54%) |
| Yes | 169,226 (3.58%) | 14,692 (11.46%) |
| Chronic corticosteroid use | ||
| No | 4,515,780 (95.44%) | 120,493 (93.96%) |
| Yes | 215,710 (4.56%) | 7744 (6.04%) |
| Comorbidities | ||
| None | 1,091,922 (23.08%) | 26,748 (20.86%) |
| One | 1,187,825 (25.1%) | 32,355 (25.23%) |
| ≥ 2 | 2,451,738 (51.82%) | 69,133 (53.91%) |
| Cancer | ||
| No | 4,562,410 (96.43%) | 121,018 (94.37%) |
| Yes | 169,076 (3.57%) | 7219 (5.63%) |
| History of VTE | ||
| No | 4,517,656 (95.48%) | 112,978 (88.1%) |
| Yes | 213,835 (4.52%) | 15,258 (11.9%) |
| History of thrombophilia | ||
| No | 4,638,910 (98.04%) | 117,880 (91.92%) |
| Yes | 92,581 (1.96%) | 10,357 (8.08%) |
| Colorectal surgery | ||
| No | 4,366,566 (92.29%) | 118,780 (92.63%) |
| Yes | 364,925 (7.71%) | 9456 (7.37%) |
| Clostridioides difficile | ||
| No | 4,558,964 (96.35%) | 119,623 (93.28%) |
| Yes | 172,527 (3.65%) | 8613 (6.72%) |
| GI procedure | ||
| No GI procedure | 4,589,071 (96.99%) | 123,455 (96.27%) |
| Flex sig/colonoscopy | 142,420 (3.01%) | 4781 (3.73%) |
| Year category | ||
| 2000–2004 | 886,405 (18.73%) | 19,509 (15.21%) |
| 2005–2009 | 1,166,040 (24.64%) | 31,451 (24.53%) |
| 2010–2014 | 1,443,786 (30.51%) | 40,206 (31.35%) |
| 2014–2018 | 1,235,260 (26.11%) | 37,070 (28.91%) |
Abbreviations: Flex Sig, Flexible Sigmoidoscopy; GI, Gastrointestinal; IBD, Inflammatory Bowel Disease; VTE, Venous Thromboembolism.
FIGURE 1.
Rate of venous thromboembolism among hospitalised patients with IBD. CD, Crohn’s Disease; IBD, Inflammatory Bowel Disease; UC, Ulcerative Colitis; VTE, Venous Thromboembolism.
The rate of death among all hospitalised patients with IBD did not change significantly over time, including among those with a VTE (AAPC: 0.3%, 95% Cl −7.4%, 8.7%, p = 0.94; Figure 2). This also held true when stratifying by IBD subtype, with CD having an AAPC of −1.2% (95%CI −5.1%, 2.8%) and UC having an AAPC of 2.3% (95%CI −0.1%, 4.7%; Figure S3).
FIGURE 2.
Mortality rate among hospitalised patients with IBD. CD, Crohn’s Disease; IBD, Inflammatory Bowel Disease; UC, Ulcerative Colitis; VTE, Venous Thromboembolism.
3.2 |. Risk factors for VTE-associated hospitalisation
When assessing risk factors associated with the presence of a VTE during hospitalisation, older age, male sex (OR: 1.14, 95%CI 1.11, 1.18), identifying as non-Hispanic Black as compared to non-Hispanic White (OR: 1.07, 95%CI 1.02, 1.12), and having Medicare as compared to private insurance (OR: 1.50, 95%CI 1.45, 1.54) increased the odds of a concurrent VTE (Table 2). Additionally, higher odds of VTE were seen among hospitalised patients with UC as compared to patients with CD (OR: 1.42, 95%CI 1.38, 1.46). The presence of other disease characteristics such as Clostridioides difficile during hospitalisation, active malignancy, comorbidities, prior VTE, or history of thrombophilia also increased the odds of VTE. IBD-related factors, such as chronic corticosteroid use (OR: 1.35, 95%CI 1.28, 1.42), or having a flexible sigmoidoscopy or colonoscopy during hospitalisation (OR: 1.25, 95%CI 1.17, 1.33) were also associated with an increased risk of VTE-associated hospitalisations (Table 2).
TABLE 2.
Factors associated with VTE among hospitalised patients with IBD
| Variable | Unadjusted OR (95% CI) |
Adj. ORa (95% CI) |
|---|---|---|
| Age in years | ||
| <18 | 0.61 (0.46, 0.80) | 0.59 (0.45, 0.78) |
| 18–30 | 1.00 (Reference) | 1.00 (Reference) |
| 31–40 | 1.45 (1.36, 1.54) | 1.42 (1.34, 1.51) |
| 41–50 | 1.80 (1.70, 1.91) | 1.72 (1.62, 1.82) |
| 51–65 | 2.37 (2.25, 2.50) | 2.15 (2.04, 2.28) |
| 66–80 | 2.80 (2.65, 2.96) | 2.31 (2.17, 2.46) |
| >80 | 2.60 (2.43, 2.77) | 2.08 (1.93, 2.24) |
| Sex | ||
| Female | 1.00 (Reference) | 1.00 (Reference) |
| Male | 1.14 (1.11, 1.18) | 1.12 (1.10, 1.16) |
| IBD subtype | ||
| Crohn’s disease | 1.00 (Reference) | 1.00 (Reference) |
| Ulcerative colitis | 1.42 (1.38, 1.46) | 1.30 (1.26, 1.33) |
| Indeterminate colitis | 1.10 (0.95, 1.28) | 1.14 (0.98, 1.33) |
| Race | ||
| Non-Hispanic White | 1.00 (Reference) | 1.00 (Reference) |
| Non-Hispanic Black | 1.07 (1.02, 1.12) | 1.24 (1.18, 1.30) |
| Hispanic | 0.81 (0.75, 0.86) | 0.88 (0.82, 0.94) |
| Other | 0.84 (0.77, 0.91) | 0.89 (0.82, 0.97) |
| Unknown | 0.90 (0.86, 0.95) | 1.02 (0.97, 1.07) |
| Median household zip code income quartile | ||
| Highest | 1.00 (Reference) | 1.00 (Reference) |
| High | 0.99 (0.95, 1.03) | 0.97 (0.94, 1.01) |
| Low | 0.95 (0.92, 0.99) | 0.93 (0.90, 0.97) |
| Lowest | 0.99 (0.95, 1.02) | 0.96 (0.92, 1.00) |
| Missing | 1.00 (0.91, 1.10) | 0.98 (0.89, 1.08) |
| Insurance status | ||
| Private | 1.00 (Reference) | 1.00 (Reference) |
| Medicare | 1.50 (1.45, 1.54) | 1.09 (1.05, 1.14) |
| Medicaid | 0.95 (0.91, 1.00) | 1.04 (0.99, 1.09) |
| Self-pay | 0.78 (0.72, 0.85) | 0.88 (0.82, 0.96) |
| No charge | 0.88 (0.71, 1.08) | 0.99 (0.80, 1.22) |
| Other | 1.05 (0.96, 1.15) | 1.05 (0.87, 1.61) |
| Malignancy | ||
| No | 1.00 (Reference) | 1.00 (Reference) |
| Yes | 1.61 (1.52, 1.70) | 1.44 (1.36, 1.53) |
| Clostridioides difficile | ||
| No | 1.00 (Reference) | 1.00 (Reference) |
| Yes | 1.90 (1.81, 2.00) | 1.61 (1.53, 1.69) |
| Comorbidities | ||
| None | 1.00 (Reference) | 1.00 (Reference) |
| One | 1.11 (1.07, 1.15) | 1.02 (0.98, 1.05) |
| ≥2 | 1.15 (1.11, 1.19) | 0.98 (0.95, 1.01) |
| History of VTE | ||
| No | 1.00 (Reference) | 1.00 (Reference) |
| Yes | 2.85 (2.74, 2.97) | 1.75 (1.66, 1.84) |
| Chronic corticosteroid use | ||
| No | 1.00 (Reference) | 1.00 (Reference) |
| Yes | 1.35 (1.28, 1.42) | 1.22 (1.16, 1.29) |
| Chronic anticoagulation use | ||
| No | 1.00 (Reference) | 1.00 (Reference) |
| Yes | 3.49 (3.34, 3.64) | 2.09 (1.98, 2.21) |
| History of thrombophilia | ||
| No | 1.00 (Reference) | 1.00 (Reference) |
| Yes | 4.40 (4.19, 4.62) | 3.48 (3.30, 3.66) |
| Colorectal surgery | ||
| No | 1.00 (Reference) | 1.00 (Reference) |
| Yes | 0.95 (0.91, 1.00) | 1.03 (0.98, 1.09) |
| Flex sig/colonoscopy | ||
| No | 1.00 (Reference) | 1.00 (Reference) |
| Yes | 1.25 (1.17, 1.33) | 1.21 (1.13, 1.29) |
| Year | ||
| 2000–2004 | 1.00 (Reference) | 1.00 (Reference) |
| 2005–2009 | 1.23 (1.17, 1.29) | 1.15 (1.10, 1.21) |
| 2010–2014 | 1.27 (1.21, 1.32) | 1.08 (1.03, 1.14) |
| 2014–2018 | 1.36 (1.30, 1.43) | 1.11 (1.06, 1.17) |
Adjusted for all variables listed in the table.
Abbreviations: Adj., Adjusted; CI, Confidence Interval; Flex Sig, Flexible Sigmoidoscopy; IBD, Inflammatory Bowel Disease; OR, Odds Ratio; VTE, Venous Thromboembolism.
Inclusive of all variables on multivariable analysis, many of these same factors remained significant. More specifically, history of a prior VTE (aOR: 1.75, 95%CI 1.66, 1.84) or thrombophilia (aOR: 3.48, 95%CI 3.30, 3.66) was associated with the highest odds of a VTE-associated hospitalisation (Table 2). Additionally, having UC as compared to having CD remained a significant predictor of VTE (aOR: 1.30, 95%CI 1.26, 1.33). Demographic factors that remained independent predictors included older age as compared to individuals aged 18–30years old (age 31–40: aOR 1.42, 95%CI 1.34, 1.51; age 41–50: aOR 1.72, 95%CI 1.62, 1.82; age 51–65: aOR 2.15, 95%CI 2.04, 2.28; age 66–80: aOR 2.31, 95%CI 2.17, 2.46; age > 80: aOR 2.08, 95%CI 1.93, 2.24), male sex (aOR: 1.12, 95%CI 1.10, 1.16), non-Hispanic Black as compared to non-Hispanic White (aOR: 1.24, 95%CI 1.18, 1.30), and having Medicare as compared to private insurance (aOR: 1.09, 95%CI 1.05, 1.14). Having Clostridioides difficile (aOR: 1.61, 95%CI 1.53, 1.69) or a flexible sigmoidoscopy/colonoscopy during hospitalisation (aOR: 1.21, 95%CI 1.13, 1.29), as well as a history of chronic corticosteroid use (aOR: 1.22, 95%CI 1.16, 1.29) also remained significant predictors of VTE. On sensitivity analysis, similar results were seen when restricting our population to only include hospitalised patients who had IBD listed as a primary or secondary diagnosis (Table S1).
3.3 |. Risk factors for mortality among IBD patients with VTE
Among all hospitalised patients with IBD, the presence of VTE significantly increased the odds of death by more than 2.5 times (aOR: 2.68, 95%CI 2.51, 2.85). Among only those hospitalised with a VTE, individuals who were older than 40years as compared to those aged 18–30years, or identified as Hispanic as compared to non-Hispanic White (OR: 1.43, 95%CI 1.11, 1.84), had higher odds of death (Table 3). Patients with UC also had higher odds of death from VTE (OR: 1.48, 95%CI 1.32, 1.66), as did patients without private insurance. Additionally, requiring colorectal surgery or having Clostridioides difficile during hospitalisation were also associated with increased odds of death from VTE.
TABLE 3.
Odds of mortality among IBD patients hospitalised with VTE
| Variable | Unadjusted OR (95% CI) |
Adj. ORa
(95% CI) |
|---|---|---|
| Age in years | ||
| <18 | – | – |
| 18–30 | 1.00 (Reference) | 1.00 (Reference) |
| 31–40 | 1.26 (0.82, 1.94) | 0.98 (0.85, 1.12) |
| 41–50 | 1.63 (1.10, 2.42) | 1.02 (0.89, 1.16) |
| 51–65 | 2.97 (2.09, 4.24) | 1.11 (0.98, 1.25) |
| 66–80 | 4.60 (3.23, 6.55) | 1.10 (0.96, 1.27) |
| >80 | 5.56 (3.84, 8.06) | 1.29 (1.09, 1.52) |
| Sex | ||
| Female | 1.00 (Reference) | 1.00 (Reference) |
| Male | 1.05 (0.94, 1.18) | 1.14 (1.08, 1.20) |
| IBD subtype | ||
| Crohn’s disease | 1.00 (Reference) | 1.00 (Reference) |
| Ulcerative colitis | 1.48 (1.32, 1.66) | 1.02 (0.96, 1.09) |
| Indeterminate colitis | 1.71 (0.92, 3.17) | 0.96 (0.67, 1.38) |
| Race | ||
| Non-Hispanic White | 1.00 (Reference) | 1.00 (Reference) |
| Non-Hispanic Black | 1.05 (0.87, 1.26) | 1.03 (0.93, 1.15) |
| Hispanic | 1.43 (1.11, 1.84) | 1.22 (1.03, 1.43) |
| Other | 1.06 (0.76, 1.49) | 1.23 (1.01, 1.48) |
| Unknown | 0.67 (0.56, 0.82) | 1.10 (0.99, 1.22) |
| Median household zip code income quartile | ||
| Highest | 1.00 (Reference) | 1.00 (Reference) |
| High | 1.08 (0.92, 1.25) | 0.97 (0.89, 1.05) |
| Low | 1.08 (0.92, 1.26) | 0.95 (0.87, 1.03) |
| Lowest | 1.14 (0.97, 1.33) | 0.98 (0.90, 1.07) |
| Missing | 1.26 (0.85, 1.87) | 0.88 (0.70, 1.11) |
| Insurance status | ||
| Private | 1.00 (Reference) | 1.00 (Reference) |
| Medicare | 2.31 (2.01, 2.67) | 1.21 (1.11, 1.32) |
| Medicaid | 1.35 (1.06, 1.71) | 1.07 (0.96, 1.19) |
| Self-pay | 1.62 (1.14, 2.30) | 1.02 (0.85, 1.21) |
| No charge | 2.79 (1.28, 6.08) | 1.00 (0.62, 1.63) |
| Other | 1.39 (0.94, 2.06) | 1.04 (0.87, 1.25) |
| Malignancy | ||
| No | 1.00 (Reference) | 1.00 (Reference) |
| Yes | 1.97 (1.63, 2.38) | 0.92 (0.81, 1.04) |
| Clostridioides difficile | ||
| No | 1.00 (Reference) | 1.00 (Reference) |
| Yes | 2.93 (2.51, 3.44) | 1.63 (1.42, 1.86) |
| Comorbidities | ||
| None | 1.00 (Reference) | 1.00 (Reference) |
| One | 1.06 (0.90, 1.26) | 0.95 (0.87, 1.03) |
| ≥2 | 1.1 (0.95, 1.28) | 0.92 (0.85, 1.00) |
| Chronic corticosteroid use | ||
| No | 1.00 (Reference) | 1.00 (Reference) |
| Yes | 0.54 (0.4, 0.74) | 1.03 (0.92, 1.17) |
| Chronic anticoagulation use | ||
| No | 1.00 (Reference) | 1.00 (Reference) |
| Yes | 0.40 (0.31, 0.51) | 1.08 (0.99, 1.19) |
| Colorectal surgery | ||
| No | 1.00 (Reference) | 1.00 (Reference) |
| Yes | 2.18 (1.84, 2.58) | 1.22 (1.08, 1.38) |
| Flex sig/colonoscopy | ||
| No | 1.00 (Reference) | 1.00 (Reference) |
| Yes | 1.01 (0.7, 1.35) | 1.41 (1.20, 1.67) |
| Year | ||
| 2000–2004 | 1.00 (Reference) | 1.00 (Reference) |
| 2005–2009 | 1.07 (0.88, 1.29) | 0.76 (0.68, 0.85) |
| 2010–2014 | 1.35 (1.13, 1.61) | 0.57 (0.51, 0.63) |
| 2014–2018 | 1.34 (1.12, 1.60) | 0.54 (0.48, 0.60) |
Adjusted for all variables listed in the table.
Abbreviations: Adj., Adjusted; CI, Confidence Interval; Flex Sig, Flexible Sigmoidoscopy; IBD, Inflammatory Bowel Disease; OR, Odds Ratio; VTE, Venous Thromboembolism.
On multivariable analysis, as above, age over 80years-old, males (aOR: 1.14, 95%CI 1.08, 1.20) and Hispanic individuals (aOR: 1.22, 95%CI 1.03, 1.43) had higher odds of death when hospitalised with a VTE. Additionally, having Clostridioides difficile, Medicare insurance, or requiring a flexible sigmoidoscopy/colonoscopy or colorectal surgery during hospitalisation remained significant predictors of mortality. Having UC, however, was not associated with an increased risk of death on multivariable analysis, and on sensitivity analysis, similar results were seen (Table S2).
4 |. DISCUSSION
In this nationwide study, we found that among all-cause hospitalisations for patients with IBD, VTE rates increased significantly in the past two decades, without significant improvement in mortality. Older age, male sex, identifying as non-Hispanic Black as compared to non-Hispanic White, UC as compared to CD and chronic corticosteroid use were some of the factors independently predictive of a VTE-associated hospitalisation. Additionally, the presence of a VTE during hospitalisation increased the odds of death more than two-fold, with higher risk among patients who were male, had colorectal surgery, Clostridioides difficile infection, or a flexible sigmoidoscopy/colonoscopy during hospitalisation.
As the IBD patient population is ageing, interventions focused on reducing IBD-related complications are becoming increasingly important. VTE, in particular, needs to be a focus, as it is one of the more common complications, carries significant morbidity and mortality and occurs more often among older individuals. Additionally, due to the increasing availability and use of JAK inhibitors, VTE-associated hospitalisations may continue to rise, particularly among older adults with concomitant cardiovascular comorbidities.29
In our study, despite advances in medical knowledge, and increasing awareness of the risk of VTE in IBD as highlighted in the 2014 Canadian Association of Gastroenterology’s consensus statement, we found that the rate of VTE among all hospitalised patients with IBD significantly increased from the years 2000 to 2018.30 Despite publication of these guidelines, prior data from Manitoba suggest similar findings, noting a persistently high rate of VTE among patients with IBD.14 When restricting our analysis to only include admissions from the ER with a primary indication of IBD, although the rates of VTE did not increase, they remained persistently elevated over time. This difference in findings between our main and sensitivity analysis, however, may reflect the inability to capture hospitalisations in which an IBD-related complication rather than IBD itself is listed as a primary diagnosis (e.g., abscess, obstruction, C. difficile), may reflect the exclusion of VTE events not related to an IBD-flare, or be reflective of the limited time horizon allowed in our sensitivity analysis. In all, these findings, coupled with a lack of improvement in mortality among IBD patients hospitalised with a VTE, underscore the importance of further education and intervention.
In order to target future preventative efforts, it is important to identify IBD patients at highest risk for VTE. From prior studies, we know that factors such as disease activity, history of VTE, corticosteroid use and older age increase the risk of VTE in IBD.8 In our study, we analogously saw an increased risk with these factors, and noted an increasing proportion of older adults (≥65 years old) and emergency room visits throughout the study period. Additionally, we noted an increased risk among those with UC as compared to CD, males as compared to females, and those identifying as non-Hispanic Black as compared to non-Hispanic White. This increased risk among patients with UC has been previously reported, and may be reflective of a higher inflammatory burden during hospitalisation.31–35 Regarding sex, although data have been conflicting, some studies have shown a small increased risk of VTE among males, which was similarly observed in our study.31,36 Although the underlying pathophysiology remains unknown, research suggests a sex-specific genetic predisposition as a potential cause for this increased risk.37 Additionally, prior studies have also shown individuals identifying as Black as compared to White to have 30%–100% higher incidence rates of VTE.38,39 This may reflect limitations in access and barriers to care that not only prevent proper diagnosis and management of VTE, but also may lead to additional comorbidities that can further contribute to its development.39 Additional factors that remained independently associated with increased odds of VTE-associated hospitalisation included the presence of Clostridioides difficile, further supporting the evidence for infections as risk factors for VTE, as well as the completion of a flexible sigmoidoscopy/colonoscopy during hospitalisation, which we used as a surrogate for disease flare.10,40 Of note, a diagnosis code for chronic anticoagulation was also found to be independently associated with the presence of a VTE during hospitalisation, likely reflecting the initiation or use of chronic anticoagulation as a result of VTE occurrence.
In addition to the high rate of morbidity associated with VTE, as well as the large economic burden, prior data have shown an increased risk of mortality as a result of VTE.34 In our study, we found that among all patients hospitalised with IBD, the presence of a VTE increased the odds of mortality by more than twofold, which is similar to findings from the Manitoba cohort.14 Furthermore, individuals who had a VTE during hospitalisation had a higher risk of mortality if they were older (>80years old), male, had colorectal surgery or flexible sigmoidoscopy/colonoscopy during hospitalisation, or had Clostridioides difficile. This is in line with prior data, showing that increasing age, disease activity, male sex and active infection, all increase the risk of death among hospitalised patients with VTE.10,41
In order to shift this trajectory and decrease the rate of VTE-associated hospitalisations, measures need to be implemented to ensure all hospitalised patients with IBD who do not have major bleeding receive pharmacologic VTE prophylaxis. Prior data have shown that use of pharmacologic VTE prophylaxis can not only decrease risk of VTE during hospitalisation but post-discharge as well.42,43 Despite this, minor haematochezia significantly deters the use of pharmacologic prophylaxis during hospitalisation, further increasing the risk of VTE.7,44 In order to increase both patient and provider adherence, studies have shown that checklists and ‘smart’ order sets may significantly improve the rates of pharmacologic VTE prophylaxis use, as well as having a pharmacist present on rounds.45–47 Other studies have also looked to provide practice guidelines to patients during hospitalisation, but did not show an improvement in the rate of VTE prophylaxis or VTE events as a result of intervention. This, however, may have been due to the small number of patients included in the study, as well as the format in which the information was provided.48 Further research should assess the effects of educating both patients and providers as to the safety of pharmacologic prophylaxis, as well as the risk of VTE in IBD, in order to decrease future occurrence.
A major strength of this study was the ability to assess nearly 4.9 million hospitalisations across the U.S. among patients with IBD. This allows for generalisability, as NIS offers the unique ability to assess population-level temporal trends. Additionally, the use of NIS also limits referral and reporting biases, which can often be present in single-center studies and voluntary registries.17 Furthermore, the presence of similar findings when stratifying by UC and CD, by DVT and PE and when only including patients with a primary or secondary diagnosis of IBD, further strengthen our findings, and minimise the likelihood of misclassifications. Last, the increasing rates of VTE observed over time appear unique to IBD, as individuals with celiac disease do not have increasing rates of VTE. This, in addition to studies showing stable to slower increases in VTE rates among the general population, further support this notion and decrease the likelihood that our findings are attributable to an overall increased recognition, diagnosis or coding of VTE.14,49 However, it is still possible, that our findings may in part be the result of an increasing ascertainment of minor VTE events over time.
There are, however, limitations which should be noted. Although the use of large databases allows the assessment of national trends, reliance on ICD coding limits the ability to obtain granular level data pertaining to specific medications such as biologics or oral contraceptive use, VTE prophylaxis use or disease activity. Additionally, although outcomes and variables used are based upon previously accepted ICD classifications, their accuracy cannot be confirmed via chart review. Furthermore, NIS represents admission-level data with an inability to follow patients longitudinally over time, therefore one patient may account for more than one hospitalisation. Last, cross-sectional analysis limits the ability to discern temporality, as in the case of chronic anticoagulation use. In this example, patients on chronic anticoagulation were found to have a higher risk of VTE during hospitalisation. This association is likely the result of patients with VTE requiring chronic anticoagulation, rather than the converse, however, cross-sectional analysis limits our ability to discern.
In a large nationwide study assessing trends of VTE among hospitalised patients with IBD, we found that the rate of VTE increased over the past two decades, without significant improvement in mortality. As the IBD patient population is ageing, this rate may continue to increase, further emphasising the need for continued education regarding the elevated risk of VTE in IBD, as well as the safety of pharmacologic prophylaxis use. Future studies should focus on designing interventions to limit the occurrence of VTE in IBD, focusing on those at highest risk.
Supplementary Material
Additional supporting information will be found online in the Supporting Information section.
FUNDING INFORMATION
No study funding. ASF: Consultant for GLG, M3, Janssen, Guidepoint; Research Support: Crohn’s and Colitis Foundation. KEL: None. JC: NIH, CDC, SCAN Health Plan. JD: NIH. DH: Consultant: Abbvie, BMS, Janssen, Pfizer, Takeda, UCB; Research Support: Janssen, Pfizer. FR: None. JDW: Royalties UpToDate, Research support: Merck. AMF: None. AS: Freenome Inc. and Medtronic. TW: Medical Advisory Board, Delfina Inc.
APPENDIX
TABLE A1.
ICD-9-CM and ICD-10-CM codes used in our study
| Description | ICD-9-CM codes | ICD-10-CM codes |
|---|---|---|
| PE | 415.11, 415.12, 415.13, 415.19, 673.2, 673.20, 673.21, 673.22, 673.23, 673.24, 673.8, 673.80, 673.81, 673.82, 673.83, 673.84 | I26.01, I26.02, I26.09, I26.90, I26.92, I26.99, O88.211, O88.212, O88.213, O88.219, O88.22, O88.23, O88.811, O88.812, O88.813, O88.819, O88.82, O88.83 |
| DVT | 451.11, 451.19, 451.81, 451.83, 453.2, 453.4, 453.40, 453.41, 453.42, 453.8, 453.82, 453.83, 453.84, 453.85, 453.86, 453.87, 453.89, 453.9, 671.3, 671.30, 671.31, 671.32, 671.33, 671.34, 671.4, 671.40, 671.41, 671.42, 671.43, 671.44, 671.5, 671.50, 671.51, 671.52, 671.53, 671.54 | I80.10, I80.11, I80.12, I80.13, I80.201, I80.202, I80.203, I80.209, I80.211, I80.212, I80.213, I80.219, I80.221, I80.222, I80.223, I80.229, I80.231, I80.232, I80.233, I80.239, I80.291, I80.292, I80.293, I80.299, I80.8, I82.210, I82.220, I82.290, I82.401, I82.402, I82.403, I82.409, I82.411, I82.412, I82.413, I82.419, I82.421, I82.422, I82.423, I82.429, I82.431, I82.432, I82.433, I82.439, I82.441, I82.442, I82.443, I82.449, I82.491, I82.492, I82.493, I82.499, I82.4Y1, I82.4Y2, I82.4Y3, I82.4Y9, I82.4Z1, I82.4Z2, I82.4Z3, I82.4Z9, I82.601, I82.602, I82.603, I82.609, I82.621, I82.622, I82.623, I82.629, I82.890, I82.90, I82.91, I82.A11, I82.A12, I82.A13, I82.A19, I82.B11, I82.B12, I82.B13, I82.B19, I82C11, I82.C12, I82. C13, I82.C19, O22.30, O22.31, O22.32, O22.33, O22.50, O22.51, O22.52, O22.53, O22.91, O22.92, O22.93, O87.1, O87.3 |
| Chronic Corticosteroid Use | V58.65, V87.45 | Z92.241, Z79.52, Z79.5 |
| Personal History of VTE | V12.51, V12.55 | Z86.711, Z86.718 |
| Colorectal Surgery | Small bowel resection (45.61–45.63), colorectal resection (17.3, 45.71–45.79, 45.81–45.83, 48.40–48.49, 48.50–48.59, or 48.61–48.69), fistula repair (46.74, 46.76, 48.73, 48.93, 49.11, 49.12, 49.73, 57.83, 58.43, or 70.72–70.74) | Small bowel resection (45.61–45.63), colorectal resection (17.3, 45.71–45.79, 45.81–45.83, 48.40–48.49, 48.50–48.59, or 48.61–48.69), fistula repair (46.74, 46.76, 48.73, 48.93, 49.11, 49.12, 49.73, 57.83, 58.43, or 70.72–70.74) |
| Thrombophilia | 273.8, 286.9, 289.8, 289.81, 289.82 | D68.51, D68.52, D68.59, D68.61, D68.62, D68.69 |
| Clostridioides difficile | 008.45 | A04.7, A04.71, A04.72 |
| Colonoscopy or Flex Sig | 45.23, 45.24 | 0DJD8ZZ |
| Celiac Disease | 579.0 | K90.0 |
Abbreviations: DVT, Deep Venous Thrombosis; Flex Sig, Flexible Sigmoidoscopy; ICD-9-CM, International Classification of Diseases, 9th revision, Clinical Modification; ICD-10-CM, International Classification of Diseases, 10th revision, Clinical Modification; PE, Pulmonary Embolism; VTE, Venous Thromboembolism.
Footnotes
Declaration of personal interests: None.
DATA AVAILABILITY STATEMENT
Data Transparency Statement: #10; All data are from the Healthcare Cost and Utilization Project (HCUP), which are publicly available (https://www.hcup-us.ahrq.gov/nisoverview.jsp). #10;
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This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Data Transparency Statement: #10; All data are from the Healthcare Cost and Utilization Project (HCUP), which are publicly available (https://www.hcup-us.ahrq.gov/nisoverview.jsp). #10;