Barbara J. Turner, MD, MSED

INTRODUCTION

The baby boomer generation, born from 1945 to 1965, accounts for 75% of the estimated 2.7 to 3.9 million persons with chronic hepatitis C virus (HCV) infection in the US.[1, 2, 3] Most HCV‐infected baby boomers do not know that they are infected.[4] With the advent of better‐tolerated, more‐effective therapies to treat chronic HCV infection,[5] and to reduce rates of complications such as cirrhosis, liver failure, and hepatocellular carcinoma,[6] universal 1‐time screening of baby boomers has been endorsed by the Centers for Disease Control and Prevention (CDC) and the United States Preventive Services Task Force.[1, 7] Hospitalized baby boomers may offer an important target for HCV screening. Our group conducted an anonymous HCV seroprevalence study of nearly 800 patients on general medicine and trauma services of 2 Philadelphia hospitals, and found that 8% had undiagnosed HCV infection, and 8% had diagnosed HCV. [8]

Little is known about barriers and facilitators to implementation of universal HCV screening of baby boomers. Lessons from implementing HIV screening offer a useful guide.[9] First, limited clinician knowledge and confusion about screening guidelines necessitated convenient, well‐designed educational programs.[10] Second, burdensome consent procedures were reduced by opt‐out consent for screening supplemented by patient education.[9] Third, electronic medical record (EMR) algorithms minimized burdens on staff by efficiently identifying and flagging eligible persons for screening.[11] Fourth, ancillary staff support for patient education and linkage to follow‐up care increased screening rates compared with usual care by physicians/staff.[11] Finally, routine human immunodeficiency virus (HIV) testing of inpatients increased rates of diagnosis, especially compared with physician referral systems.[12]

This article describes how HIV screening strategies informed the development in a baby boomer HCV screening and linkage to a care program in a safety‐net hospital serving a majority Hispanic population. We report results of the first 14 months of the screening program and linkage to care for chronically HCV‐infected persons after a minimum 10 months follow‐up. We also estimate costs for program implementation and maintenance to inform hospital administrators, healthcare policymakers, and clinicians about resources that may be required to effectively screen hospitalized baby boomers for HCV.

METHODS

RESULTS

Within 14 months, 6410 unique baby boomers were admitted with a mean age 56.4 years (standard deviation [SD] 5.7), 55.9% men, 59.1% Hispanic, 8.2% nonwhite, and 46.7% uninsured (Table 1). Among admitted patients, 729 (11.4%) had a previous HCV diagnosis and 1904 (29.7%) had been tested for HCV (Figure 1). Anti‐HCV antibody testing was completed for 3168 (49.4% of all admitted patients and 83.9% of never‐tested patients). After exclusions such as significant comorbidity or psychiatric admission, 95% of eligible persons were tested. Of screened patients, 240 (7.6%) were positive; these patients were significantly younger (P<0.0001) and more likely to be men (P<0.0001) and uninsured (P=0.002) (Table 1). Notably, 10% of men were anti‐HCV positive versus 4% of women. In this predominantly Hispanic cohort, no significant difference appeared by race‐ethnicity, but African Americans had a higher prevalence (10.4%) than other groups.

Figure 1

HCV RNA testing was completed for 214 (89.2%) anti‐HCVpositive patients, of whom 134 (62.6%) had detectable RNA, indicating chronic HCV infection (Figure 1). Overall, 4.2% of all eligible patients tested for HCV were chronically infected. No characteristics were significantly associated with chronic HCV, but persons with chronic infection tended to be younger, uninsured, and African American (Table 2).

Among patients with chronic HCV infection, 129 (96.3%) were counseled and follow‐up plans developed (Figure 2). By December 10, 2014, 108 (80.6%) patients had received follow‐up primary care, and 52 (38.8%) had care from a hepatologist. Five had initiated HCV‐specific treatment, but many others were awaiting approval for compassionate drug programs offering direct‐acting antivirals. Barriers to care included 82 (61.2%) uninsured, 45 (34%) problem drinkers, 22 (16%) homeless, and 25 (18.6%) incarcerated (not shown). The promotora addressed these issues by visiting homes or homeless shelters, assistance with obtaining county‐based or other types of insurance, offering alcohol risk‐reduction counseling, linking patients to alcohol‐treatment programs, and communicating with the county jail about follow‐up care.

Figure 2

Most of the developmental costs for the program were dedicated to developing EMR programs (Table 3). An optional cost was for the development of the tablet educational program about HCV. In regard to maintenance costs for the first 14 months, the majority was to support the program faculty, counseling/case management, and a nurse practitioner who helped with ordering tests. We also estimated costs for testing uninsured patients (45% of HCV antibody tested, 57% of HCV PCR tested, per Tables 1 and 2, respectively), as they must be borne by the hospital.

DISCUSSION

Implementation of universal HCV screening and linkage to care for hospitalized baby boomers utilizes a multicomponent infrastructure that reflects lessons learned from similar HIV programs. Use of an EMR algorithm to identify eligible patients and programs to automatically order HCV screening was a linchpin of our high testing rate and averted testing those who did not require screening. Of all 6410 baby boomers admitted to our safety‐net hospital, the EMR screen identified over 40% as ineligible due to prior diagnosis of HCV infection or prior HCV tests. Most of the additional 609 patients who were not tested were excluded due to comorbidities or admission to psychiatry. Overall, the EMR programs, tests ordered by the team, and opt‐out screening with education resulted in screening 95% of eligible patients. However, this program carries substantial costs, nearly $300,000 for the first 2 years, for unreimbursed services in this safety‐net hospital. The new guidelines for HCV screening[1, 2] are not accompanied by financial support either for program implementation or for screening and linkage to care for the uninsured, creating significant financial hurdles to achieve guideline compliance within already overtaxed public healthcare systems.

The infrastructure implemented in this hospital succeeded in achieving a higher rate of HCV screening of baby boomers than reported by other programs. In an emergency department in Birmingham, Alabama, a screening program for baby boomers tested 66% of 2325 persons who were HCV‐unaware.[17] In an outpatient clinic for men who have sex with men, only 54% of 1329 patients were screened for HCV.[18]

Among 3168 screened patients in our cohort, 7.6% were anti‐HCV antibody positive, which is over twice the prevalence of 3.5% (95% confidence interval: 2.2%‐4.8%) for anti‐HCVpositive tests in baby boomers based on National Health and Nutrition Examination Survey (NHANES) data from 2001 to 2010.[19] However, the Alabama emergency department study found that 11% of tested patients were anti‐HCV positive.[17] Although that study lacked race‐ethnicity data for half of the subjects, among those with this information, 13% of black and 7% of white subjects tested anti‐HCV positive. Compared with the Alabama study, the anti‐HCV prevalence in our cohort was somewhat lower for blacks (10.4%) but higher for non‐Hispanic whites (8.3%). Hispanics in our cohort had the lowest anti‐HCV prevalence (7.2%), whereas the Alabama study did not report this figure. National studies also find that the prevalence of anti‐HCVpositive results is twice as high for blacks compared with non‐Hispanic whites and Hispanics, and nearly twice as high for men compared with women.[19] In our cohort, the proportion of men with anti‐HCVpositive results was nearly 3 times that for women.

Diagnosis of chronic HCV infection requires 2 tests, similar to performing a Western blot test after a positive enzyme‐linked immunoassay for HIV. In a Veterans Affairs study, only 64% of patients with a positive anti‐HCV antibody test had a HCV RNA performed when reflex testing was not performed, and patients had to come in for a second test versus >90% of patients in sites that offer reflex testing.[20] At a somewhat increased price due to using more expensive PPTs ($96/100 PPT tubes vs $6.50/100 for serum red top tubes), both tests were performed on the same blood sample, resulting in 89% of anti‐HCV antibody‐positive patients being tested for HCV RNA.

Overall, 62% of patients in our cohort with a positive anti‐HCV antibody test had HCV RNA detected (viremic) compared with 71% of persons aged 20 years in an NHANES study from 2003 to 2010.[21] Several factors may contribute to this lower rate of chronic infection. In a study of HCV seropositive blood donors, Hispanics and non‐Hispanic whites were significantly more likely to have spontaneously cleared HCV infection than Asians and non‐Hispanic blacks.[22] Spontaneous clearance of HCV has also been associated with younger age at infection and HCV genotype 1.[23] Poorly understood genetic factors may also play a role.[24] The high rate of HCV clearance in our cohort reinforces the need to perform HCV RNA testing.

Overall, 4.2% of our cohort had chronic HCV infection. According to CDC estimates from 1999 to 2008 NHANES data, 2.74 million (3.25%) of 84.2 million US baby boomers have been infected with HCV, and 2.04 million (2.4%) have chronic infection.[1] Therefore, our safety‐net cohort of never‐tested baby boomers had over twice the prevalence of chronic HCV infection than the national estimate for this age group. This high proportion of chronic HCV may reflect our predominantly low‐income patient population. An analysis conducted by Milliman, Inc. using 2010 data estimated that half of all persons with undiagnosed HCV infection are uninsured.[25] This finding reinforces the need to conduct HCV screening in acute‐care settings such as hospitals, because the uninsured have poor access to ambulatory care.

Our chronic HCV‐infected cohort had many barriers to follow‐up care because most were uninsured and 15% were homeless. Our counselors addressed socioeconomic barriers to care[26] and concerns about the disease.[27] Many patients also had problem drinking based on either self‐report or documented in the medical record. Even moderate alcohol use may increase the risk of overall and liver‐related mortality from chronic HCV infection,[28] so our team offered brief alcohol counseling and partnered with healthcare providers and local Alcoholics Anonymous programs to offer support.

We linked 80% of newly diagnosed patients to primary care or hepatology providers, aided by a county‐level financial assistance program for healthcare services for uninsured residents, but it still required patients to pay out of pocket for care. Access to newer, highly effective, all‐oral therapy treatment[5] was slowed while awaiting US Food and Drug Administration approval in the first year of this project, then treatment provided only after lengthy applications to drug company assistance programs with priority given to persons with compensated cirrhosis.

Our project raises serious concerns for policymakers and payers. Should universal baby boomer HCV testing be undertaken without taking into account the financial and personnel resources required to implement this screening program or the substantial expenditures necessary to treat chronically infected persons? Although the Centers for Medicaid and Medicare Services pay for HCV screening costs,[29] our hospital had to cover costs for uninsured persons. Admittedly, Texas has the highest proportion of residents who are uninsured in the nation, but even in other states, Medicaid and other insurance programs are wrestling with how to deal with the high cost of HCV therapy.[30]

We acknowledge several limitations of this project. First, it was undertaken in only 1 hospital. Yet, our challenges and solutions are likely to be applicable to other hospitals nationally, especially those serving vulnerable populations. Second, patients in our cohort were usually admitted for comorbidities that needed to be managed before HCV infection could be addressed. However, persons with a poor prognosis, such as metastatic cancer, were excluded. We did not attempt to exclude other persons with serious comorbidities such as congestive heart failure, because the guidelines do not currently recommend this, and there may be benefits for patients, their families, and providers from knowing that an individual is chronically HCV infected even if they are not eligible to be treated. Third, the cost of the program was supported in part by a grant and would otherwise have to be borne by the hospital. Fourth, the EMR used by our hospital allows hundreds of admission order sets to be created and made automated order entry hard to implement. This is unlikely to be the situation in other hospitals using different types of EMRs.

It remains to be seen whether safety‐net hospitals with populations at greater risk of HCV infection can afford to support HCV testing and linkage to care. In view of several cost‐effectiveness studies that find screening and treating chronic HCV‐infected baby boomers cost‐effective within standard thresholds,[31, 32, 33] it may be important for policymakers and payers to consider lessons from HIV programs. Because HIV‐infected persons could not afford life‐saving medication, vigorous advocacy efforts led to legislation approving the Ryan White program in 1990 to fill gaps in HIV care that were not covered by other sources of support.[34] HCV infection is the most common blood‐borne infection in the nation, with potentially devastating consequences if ignored, but the underlying premise that universal HCV testing will save lives is in question if most of the individuals who are diagnosed with chronic HCV are low income, uninsured, or underinsured with limited access to curative medications. A rigorous public policy debate regarding both the merits of screening and the availability of treatment to those who are diagnosed is essential to the success of these programs.

INTRODUCTION

The baby boomer generation, born from 1945 to 1965, accounts for 75% of the estimated 2.7 to 3.9 million persons with chronic hepatitis C virus (HCV) infection in the US.[1, 2, 3] Most HCV‐infected baby boomers do not know that they are infected.[4] With the advent of better‐tolerated, more‐effective therapies to treat chronic HCV infection,[5] and to reduce rates of complications such as cirrhosis, liver failure, and hepatocellular carcinoma,[6] universal 1‐time screening of baby boomers has been endorsed by the Centers for Disease Control and Prevention (CDC) and the United States Preventive Services Task Force.[1, 7] Hospitalized baby boomers may offer an important target for HCV screening. Our group conducted an anonymous HCV seroprevalence study of nearly 800 patients on general medicine and trauma services of 2 Philadelphia hospitals, and found that 8% had undiagnosed HCV infection, and 8% had diagnosed HCV. [8]

Little is known about barriers and facilitators to implementation of universal HCV screening of baby boomers. Lessons from implementing HIV screening offer a useful guide.[9] First, limited clinician knowledge and confusion about screening guidelines necessitated convenient, well‐designed educational programs.[10] Second, burdensome consent procedures were reduced by opt‐out consent for screening supplemented by patient education.[9] Third, electronic medical record (EMR) algorithms minimized burdens on staff by efficiently identifying and flagging eligible persons for screening.[11] Fourth, ancillary staff support for patient education and linkage to follow‐up care increased screening rates compared with usual care by physicians/staff.[11] Finally, routine human immunodeficiency virus (HIV) testing of inpatients increased rates of diagnosis, especially compared with physician referral systems.[12]

This article describes how HIV screening strategies informed the development in a baby boomer HCV screening and linkage to a care program in a safety‐net hospital serving a majority Hispanic population. We report results of the first 14 months of the screening program and linkage to care for chronically HCV‐infected persons after a minimum 10 months follow‐up. We also estimate costs for program implementation and maintenance to inform hospital administrators, healthcare policymakers, and clinicians about resources that may be required to effectively screen hospitalized baby boomers for HCV.

METHODS

RESULTS

Within 14 months, 6410 unique baby boomers were admitted with a mean age 56.4 years (standard deviation [SD] 5.7), 55.9% men, 59.1% Hispanic, 8.2% nonwhite, and 46.7% uninsured (Table 1). Among admitted patients, 729 (11.4%) had a previous HCV diagnosis and 1904 (29.7%) had been tested for HCV (Figure 1). Anti‐HCV antibody testing was completed for 3168 (49.4% of all admitted patients and 83.9% of never‐tested patients). After exclusions such as significant comorbidity or psychiatric admission, 95% of eligible persons were tested. Of screened patients, 240 (7.6%) were positive; these patients were significantly younger (P<0.0001) and more likely to be men (P<0.0001) and uninsured (P=0.002) (Table 1). Notably, 10% of men were anti‐HCV positive versus 4% of women. In this predominantly Hispanic cohort, no significant difference appeared by race‐ethnicity, but African Americans had a higher prevalence (10.4%) than other groups.

Figure 1

HCV RNA testing was completed for 214 (89.2%) anti‐HCVpositive patients, of whom 134 (62.6%) had detectable RNA, indicating chronic HCV infection (Figure 1). Overall, 4.2% of all eligible patients tested for HCV were chronically infected. No characteristics were significantly associated with chronic HCV, but persons with chronic infection tended to be younger, uninsured, and African American (Table 2).

Among patients with chronic HCV infection, 129 (96.3%) were counseled and follow‐up plans developed (Figure 2). By December 10, 2014, 108 (80.6%) patients had received follow‐up primary care, and 52 (38.8%) had care from a hepatologist. Five had initiated HCV‐specific treatment, but many others were awaiting approval for compassionate drug programs offering direct‐acting antivirals. Barriers to care included 82 (61.2%) uninsured, 45 (34%) problem drinkers, 22 (16%) homeless, and 25 (18.6%) incarcerated (not shown). The promotora addressed these issues by visiting homes or homeless shelters, assistance with obtaining county‐based or other types of insurance, offering alcohol risk‐reduction counseling, linking patients to alcohol‐treatment programs, and communicating with the county jail about follow‐up care.

Figure 2

Most of the developmental costs for the program were dedicated to developing EMR programs (Table 3). An optional cost was for the development of the tablet educational program about HCV. In regard to maintenance costs for the first 14 months, the majority was to support the program faculty, counseling/case management, and a nurse practitioner who helped with ordering tests. We also estimated costs for testing uninsured patients (45% of HCV antibody tested, 57% of HCV PCR tested, per Tables 1 and 2, respectively), as they must be borne by the hospital.

DISCUSSION

Implementation of universal HCV screening and linkage to care for hospitalized baby boomers utilizes a multicomponent infrastructure that reflects lessons learned from similar HIV programs. Use of an EMR algorithm to identify eligible patients and programs to automatically order HCV screening was a linchpin of our high testing rate and averted testing those who did not require screening. Of all 6410 baby boomers admitted to our safety‐net hospital, the EMR screen identified over 40% as ineligible due to prior diagnosis of HCV infection or prior HCV tests. Most of the additional 609 patients who were not tested were excluded due to comorbidities or admission to psychiatry. Overall, the EMR programs, tests ordered by the team, and opt‐out screening with education resulted in screening 95% of eligible patients. However, this program carries substantial costs, nearly $300,000 for the first 2 years, for unreimbursed services in this safety‐net hospital. The new guidelines for HCV screening[1, 2] are not accompanied by financial support either for program implementation or for screening and linkage to care for the uninsured, creating significant financial hurdles to achieve guideline compliance within already overtaxed public healthcare systems.

The infrastructure implemented in this hospital succeeded in achieving a higher rate of HCV screening of baby boomers than reported by other programs. In an emergency department in Birmingham, Alabama, a screening program for baby boomers tested 66% of 2325 persons who were HCV‐unaware.[17] In an outpatient clinic for men who have sex with men, only 54% of 1329 patients were screened for HCV.[18]

Among 3168 screened patients in our cohort, 7.6% were anti‐HCV antibody positive, which is over twice the prevalence of 3.5% (95% confidence interval: 2.2%‐4.8%) for anti‐HCVpositive tests in baby boomers based on National Health and Nutrition Examination Survey (NHANES) data from 2001 to 2010.[19] However, the Alabama emergency department study found that 11% of tested patients were anti‐HCV positive.[17] Although that study lacked race‐ethnicity data for half of the subjects, among those with this information, 13% of black and 7% of white subjects tested anti‐HCV positive. Compared with the Alabama study, the anti‐HCV prevalence in our cohort was somewhat lower for blacks (10.4%) but higher for non‐Hispanic whites (8.3%). Hispanics in our cohort had the lowest anti‐HCV prevalence (7.2%), whereas the Alabama study did not report this figure. National studies also find that the prevalence of anti‐HCVpositive results is twice as high for blacks compared with non‐Hispanic whites and Hispanics, and nearly twice as high for men compared with women.[19] In our cohort, the proportion of men with anti‐HCVpositive results was nearly 3 times that for women.

Diagnosis of chronic HCV infection requires 2 tests, similar to performing a Western blot test after a positive enzyme‐linked immunoassay for HIV. In a Veterans Affairs study, only 64% of patients with a positive anti‐HCV antibody test had a HCV RNA performed when reflex testing was not performed, and patients had to come in for a second test versus >90% of patients in sites that offer reflex testing.[20] At a somewhat increased price due to using more expensive PPTs ($96/100 PPT tubes vs $6.50/100 for serum red top tubes), both tests were performed on the same blood sample, resulting in 89% of anti‐HCV antibody‐positive patients being tested for HCV RNA.

Overall, 62% of patients in our cohort with a positive anti‐HCV antibody test had HCV RNA detected (viremic) compared with 71% of persons aged 20 years in an NHANES study from 2003 to 2010.[21] Several factors may contribute to this lower rate of chronic infection. In a study of HCV seropositive blood donors, Hispanics and non‐Hispanic whites were significantly more likely to have spontaneously cleared HCV infection than Asians and non‐Hispanic blacks.[22] Spontaneous clearance of HCV has also been associated with younger age at infection and HCV genotype 1.[23] Poorly understood genetic factors may also play a role.[24] The high rate of HCV clearance in our cohort reinforces the need to perform HCV RNA testing.

Overall, 4.2% of our cohort had chronic HCV infection. According to CDC estimates from 1999 to 2008 NHANES data, 2.74 million (3.25%) of 84.2 million US baby boomers have been infected with HCV, and 2.04 million (2.4%) have chronic infection.[1] Therefore, our safety‐net cohort of never‐tested baby boomers had over twice the prevalence of chronic HCV infection than the national estimate for this age group. This high proportion of chronic HCV may reflect our predominantly low‐income patient population. An analysis conducted by Milliman, Inc. using 2010 data estimated that half of all persons with undiagnosed HCV infection are uninsured.[25] This finding reinforces the need to conduct HCV screening in acute‐care settings such as hospitals, because the uninsured have poor access to ambulatory care.

Our chronic HCV‐infected cohort had many barriers to follow‐up care because most were uninsured and 15% were homeless. Our counselors addressed socioeconomic barriers to care[26] and concerns about the disease.[27] Many patients also had problem drinking based on either self‐report or documented in the medical record. Even moderate alcohol use may increase the risk of overall and liver‐related mortality from chronic HCV infection,[28] so our team offered brief alcohol counseling and partnered with healthcare providers and local Alcoholics Anonymous programs to offer support.

We linked 80% of newly diagnosed patients to primary care or hepatology providers, aided by a county‐level financial assistance program for healthcare services for uninsured residents, but it still required patients to pay out of pocket for care. Access to newer, highly effective, all‐oral therapy treatment[5] was slowed while awaiting US Food and Drug Administration approval in the first year of this project, then treatment provided only after lengthy applications to drug company assistance programs with priority given to persons with compensated cirrhosis.

Our project raises serious concerns for policymakers and payers. Should universal baby boomer HCV testing be undertaken without taking into account the financial and personnel resources required to implement this screening program or the substantial expenditures necessary to treat chronically infected persons? Although the Centers for Medicaid and Medicare Services pay for HCV screening costs,[29] our hospital had to cover costs for uninsured persons. Admittedly, Texas has the highest proportion of residents who are uninsured in the nation, but even in other states, Medicaid and other insurance programs are wrestling with how to deal with the high cost of HCV therapy.[30]

We acknowledge several limitations of this project. First, it was undertaken in only 1 hospital. Yet, our challenges and solutions are likely to be applicable to other hospitals nationally, especially those serving vulnerable populations. Second, patients in our cohort were usually admitted for comorbidities that needed to be managed before HCV infection could be addressed. However, persons with a poor prognosis, such as metastatic cancer, were excluded. We did not attempt to exclude other persons with serious comorbidities such as congestive heart failure, because the guidelines do not currently recommend this, and there may be benefits for patients, their families, and providers from knowing that an individual is chronically HCV infected even if they are not eligible to be treated. Third, the cost of the program was supported in part by a grant and would otherwise have to be borne by the hospital. Fourth, the EMR used by our hospital allows hundreds of admission order sets to be created and made automated order entry hard to implement. This is unlikely to be the situation in other hospitals using different types of EMRs.

It remains to be seen whether safety‐net hospitals with populations at greater risk of HCV infection can afford to support HCV testing and linkage to care. In view of several cost‐effectiveness studies that find screening and treating chronic HCV‐infected baby boomers cost‐effective within standard thresholds,[31, 32, 33] it may be important for policymakers and payers to consider lessons from HIV programs. Because HIV‐infected persons could not afford life‐saving medication, vigorous advocacy efforts led to legislation approving the Ryan White program in 1990 to fill gaps in HIV care that were not covered by other sources of support.[34] HCV infection is the most common blood‐borne infection in the nation, with potentially devastating consequences if ignored, but the underlying premise that universal HCV testing will save lives is in question if most of the individuals who are diagnosed with chronic HCV are low income, uninsured, or underinsured with limited access to curative medications. A rigorous public policy debate regarding both the merits of screening and the availability of treatment to those who are diagnosed is essential to the success of these programs.

INTRODUCTION

The baby boomer generation, born from 1945 to 1965, accounts for 75% of the estimated 2.7 to 3.9 million persons with chronic hepatitis C virus (HCV) infection in the US.[1, 2, 3] Most HCV‐infected baby boomers do not know that they are infected.[4] With the advent of better‐tolerated, more‐effective therapies to treat chronic HCV infection,[5] and to reduce rates of complications such as cirrhosis, liver failure, and hepatocellular carcinoma,[6] universal 1‐time screening of baby boomers has been endorsed by the Centers for Disease Control and Prevention (CDC) and the United States Preventive Services Task Force.[1, 7] Hospitalized baby boomers may offer an important target for HCV screening. Our group conducted an anonymous HCV seroprevalence study of nearly 800 patients on general medicine and trauma services of 2 Philadelphia hospitals, and found that 8% had undiagnosed HCV infection, and 8% had diagnosed HCV. [8]

Little is known about barriers and facilitators to implementation of universal HCV screening of baby boomers. Lessons from implementing HIV screening offer a useful guide.[9] First, limited clinician knowledge and confusion about screening guidelines necessitated convenient, well‐designed educational programs.[10] Second, burdensome consent procedures were reduced by opt‐out consent for screening supplemented by patient education.[9] Third, electronic medical record (EMR) algorithms minimized burdens on staff by efficiently identifying and flagging eligible persons for screening.[11] Fourth, ancillary staff support for patient education and linkage to follow‐up care increased screening rates compared with usual care by physicians/staff.[11] Finally, routine human immunodeficiency virus (HIV) testing of inpatients increased rates of diagnosis, especially compared with physician referral systems.[12]

This article describes how HIV screening strategies informed the development in a baby boomer HCV screening and linkage to a care program in a safety‐net hospital serving a majority Hispanic population. We report results of the first 14 months of the screening program and linkage to care for chronically HCV‐infected persons after a minimum 10 months follow‐up. We also estimate costs for program implementation and maintenance to inform hospital administrators, healthcare policymakers, and clinicians about resources that may be required to effectively screen hospitalized baby boomers for HCV.

METHODS

RESULTS

Within 14 months, 6410 unique baby boomers were admitted with a mean age 56.4 years (standard deviation [SD] 5.7), 55.9% men, 59.1% Hispanic, 8.2% nonwhite, and 46.7% uninsured (Table 1). Among admitted patients, 729 (11.4%) had a previous HCV diagnosis and 1904 (29.7%) had been tested for HCV (Figure 1). Anti‐HCV antibody testing was completed for 3168 (49.4% of all admitted patients and 83.9% of never‐tested patients). After exclusions such as significant comorbidity or psychiatric admission, 95% of eligible persons were tested. Of screened patients, 240 (7.6%) were positive; these patients were significantly younger (P<0.0001) and more likely to be men (P<0.0001) and uninsured (P=0.002) (Table 1). Notably, 10% of men were anti‐HCV positive versus 4% of women. In this predominantly Hispanic cohort, no significant difference appeared by race‐ethnicity, but African Americans had a higher prevalence (10.4%) than other groups.

Figure 1

HCV RNA testing was completed for 214 (89.2%) anti‐HCVpositive patients, of whom 134 (62.6%) had detectable RNA, indicating chronic HCV infection (Figure 1). Overall, 4.2% of all eligible patients tested for HCV were chronically infected. No characteristics were significantly associated with chronic HCV, but persons with chronic infection tended to be younger, uninsured, and African American (Table 2).

Among patients with chronic HCV infection, 129 (96.3%) were counseled and follow‐up plans developed (Figure 2). By December 10, 2014, 108 (80.6%) patients had received follow‐up primary care, and 52 (38.8%) had care from a hepatologist. Five had initiated HCV‐specific treatment, but many others were awaiting approval for compassionate drug programs offering direct‐acting antivirals. Barriers to care included 82 (61.2%) uninsured, 45 (34%) problem drinkers, 22 (16%) homeless, and 25 (18.6%) incarcerated (not shown). The promotora addressed these issues by visiting homes or homeless shelters, assistance with obtaining county‐based or other types of insurance, offering alcohol risk‐reduction counseling, linking patients to alcohol‐treatment programs, and communicating with the county jail about follow‐up care.

Figure 2

Most of the developmental costs for the program were dedicated to developing EMR programs (Table 3). An optional cost was for the development of the tablet educational program about HCV. In regard to maintenance costs for the first 14 months, the majority was to support the program faculty, counseling/case management, and a nurse practitioner who helped with ordering tests. We also estimated costs for testing uninsured patients (45% of HCV antibody tested, 57% of HCV PCR tested, per Tables 1 and 2, respectively), as they must be borne by the hospital.

DISCUSSION

Implementation of universal HCV screening and linkage to care for hospitalized baby boomers utilizes a multicomponent infrastructure that reflects lessons learned from similar HIV programs. Use of an EMR algorithm to identify eligible patients and programs to automatically order HCV screening was a linchpin of our high testing rate and averted testing those who did not require screening. Of all 6410 baby boomers admitted to our safety‐net hospital, the EMR screen identified over 40% as ineligible due to prior diagnosis of HCV infection or prior HCV tests. Most of the additional 609 patients who were not tested were excluded due to comorbidities or admission to psychiatry. Overall, the EMR programs, tests ordered by the team, and opt‐out screening with education resulted in screening 95% of eligible patients. However, this program carries substantial costs, nearly $300,000 for the first 2 years, for unreimbursed services in this safety‐net hospital. The new guidelines for HCV screening[1, 2] are not accompanied by financial support either for program implementation or for screening and linkage to care for the uninsured, creating significant financial hurdles to achieve guideline compliance within already overtaxed public healthcare systems.

The infrastructure implemented in this hospital succeeded in achieving a higher rate of HCV screening of baby boomers than reported by other programs. In an emergency department in Birmingham, Alabama, a screening program for baby boomers tested 66% of 2325 persons who were HCV‐unaware.[17] In an outpatient clinic for men who have sex with men, only 54% of 1329 patients were screened for HCV.[18]

Among 3168 screened patients in our cohort, 7.6% were anti‐HCV antibody positive, which is over twice the prevalence of 3.5% (95% confidence interval: 2.2%‐4.8%) for anti‐HCVpositive tests in baby boomers based on National Health and Nutrition Examination Survey (NHANES) data from 2001 to 2010.[19] However, the Alabama emergency department study found that 11% of tested patients were anti‐HCV positive.[17] Although that study lacked race‐ethnicity data for half of the subjects, among those with this information, 13% of black and 7% of white subjects tested anti‐HCV positive. Compared with the Alabama study, the anti‐HCV prevalence in our cohort was somewhat lower for blacks (10.4%) but higher for non‐Hispanic whites (8.3%). Hispanics in our cohort had the lowest anti‐HCV prevalence (7.2%), whereas the Alabama study did not report this figure. National studies also find that the prevalence of anti‐HCVpositive results is twice as high for blacks compared with non‐Hispanic whites and Hispanics, and nearly twice as high for men compared with women.[19] In our cohort, the proportion of men with anti‐HCVpositive results was nearly 3 times that for women.

Diagnosis of chronic HCV infection requires 2 tests, similar to performing a Western blot test after a positive enzyme‐linked immunoassay for HIV. In a Veterans Affairs study, only 64% of patients with a positive anti‐HCV antibody test had a HCV RNA performed when reflex testing was not performed, and patients had to come in for a second test versus >90% of patients in sites that offer reflex testing.[20] At a somewhat increased price due to using more expensive PPTs ($96/100 PPT tubes vs $6.50/100 for serum red top tubes), both tests were performed on the same blood sample, resulting in 89% of anti‐HCV antibody‐positive patients being tested for HCV RNA.

Overall, 62% of patients in our cohort with a positive anti‐HCV antibody test had HCV RNA detected (viremic) compared with 71% of persons aged 20 years in an NHANES study from 2003 to 2010.[21] Several factors may contribute to this lower rate of chronic infection. In a study of HCV seropositive blood donors, Hispanics and non‐Hispanic whites were significantly more likely to have spontaneously cleared HCV infection than Asians and non‐Hispanic blacks.[22] Spontaneous clearance of HCV has also been associated with younger age at infection and HCV genotype 1.[23] Poorly understood genetic factors may also play a role.[24] The high rate of HCV clearance in our cohort reinforces the need to perform HCV RNA testing.

Overall, 4.2% of our cohort had chronic HCV infection. According to CDC estimates from 1999 to 2008 NHANES data, 2.74 million (3.25%) of 84.2 million US baby boomers have been infected with HCV, and 2.04 million (2.4%) have chronic infection.[1] Therefore, our safety‐net cohort of never‐tested baby boomers had over twice the prevalence of chronic HCV infection than the national estimate for this age group. This high proportion of chronic HCV may reflect our predominantly low‐income patient population. An analysis conducted by Milliman, Inc. using 2010 data estimated that half of all persons with undiagnosed HCV infection are uninsured.[25] This finding reinforces the need to conduct HCV screening in acute‐care settings such as hospitals, because the uninsured have poor access to ambulatory care.

Our chronic HCV‐infected cohort had many barriers to follow‐up care because most were uninsured and 15% were homeless. Our counselors addressed socioeconomic barriers to care[26] and concerns about the disease.[27] Many patients also had problem drinking based on either self‐report or documented in the medical record. Even moderate alcohol use may increase the risk of overall and liver‐related mortality from chronic HCV infection,[28] so our team offered brief alcohol counseling and partnered with healthcare providers and local Alcoholics Anonymous programs to offer support.

We linked 80% of newly diagnosed patients to primary care or hepatology providers, aided by a county‐level financial assistance program for healthcare services for uninsured residents, but it still required patients to pay out of pocket for care. Access to newer, highly effective, all‐oral therapy treatment[5] was slowed while awaiting US Food and Drug Administration approval in the first year of this project, then treatment provided only after lengthy applications to drug company assistance programs with priority given to persons with compensated cirrhosis.

Our project raises serious concerns for policymakers and payers. Should universal baby boomer HCV testing be undertaken without taking into account the financial and personnel resources required to implement this screening program or the substantial expenditures necessary to treat chronically infected persons? Although the Centers for Medicaid and Medicare Services pay for HCV screening costs,[29] our hospital had to cover costs for uninsured persons. Admittedly, Texas has the highest proportion of residents who are uninsured in the nation, but even in other states, Medicaid and other insurance programs are wrestling with how to deal with the high cost of HCV therapy.[30]

We acknowledge several limitations of this project. First, it was undertaken in only 1 hospital. Yet, our challenges and solutions are likely to be applicable to other hospitals nationally, especially those serving vulnerable populations. Second, patients in our cohort were usually admitted for comorbidities that needed to be managed before HCV infection could be addressed. However, persons with a poor prognosis, such as metastatic cancer, were excluded. We did not attempt to exclude other persons with serious comorbidities such as congestive heart failure, because the guidelines do not currently recommend this, and there may be benefits for patients, their families, and providers from knowing that an individual is chronically HCV infected even if they are not eligible to be treated. Third, the cost of the program was supported in part by a grant and would otherwise have to be borne by the hospital. Fourth, the EMR used by our hospital allows hundreds of admission order sets to be created and made automated order entry hard to implement. This is unlikely to be the situation in other hospitals using different types of EMRs.

It remains to be seen whether safety‐net hospitals with populations at greater risk of HCV infection can afford to support HCV testing and linkage to care. In view of several cost‐effectiveness studies that find screening and treating chronic HCV‐infected baby boomers cost‐effective within standard thresholds,[31, 32, 33] it may be important for policymakers and payers to consider lessons from HIV programs. Because HIV‐infected persons could not afford life‐saving medication, vigorous advocacy efforts led to legislation approving the Ryan White program in 1990 to fill gaps in HIV care that were not covered by other sources of support.[34] HCV infection is the most common blood‐borne infection in the nation, with potentially devastating consequences if ignored, but the underlying premise that universal HCV testing will save lives is in question if most of the individuals who are diagnosed with chronic HCV are low income, uninsured, or underinsured with limited access to curative medications. A rigorous public policy debate regarding both the merits of screening and the availability of treatment to those who are diagnosed is essential to the success of these programs.

Longer term and higher doses of opioid analgesics (OAs) have been associated with multiple adverse outcomes such as loss of work, cognitive decline, and poor function.[1, 2, 3, 4] One of the most widely reported complications of opioid therapy is drug overdose.[5, 6, 7, 8, 9] In population‐based studies, daily morphine equivalent doses >100 mg have been associated with significantly increased risk of drug overdose.[5, 6, 7, 8, 9, 10] Among health maintenance organization (HMO) enrollees filling at least 2 prescriptions for opioids, our group reported that daily opioid doses 100 mg were associated with approximately threefold greater adjusted odds of drug overdose.[10] We also observed over a twofold increase in odds of drug overdose for lower daily doses of 50 to 99 mg if the patient also received a high total opioid dose (>1830 mg) over a 6‐month period. This analysis suggests that clinicians may need to monitor not only daily dose but also total dose of opioids to reduce the risk of drug overdose.

Yet drug overdose represents only a small subset of all hospitalizations for persons receiving long‐term or higher doses of opioids for noncancer pain. These patients have significant demand for urgent care services, including hospitalization, for diverse reasons such as adverse effects of opioids, underlying cause of chronic pain, and comorbidities such as mental health disorders.[11] In a cohort of elderly primary care patients who were high hospital utilizers, Freund and colleagues reported that chronic pain and depression were the most common conditions co‐occurring with their other comorbidities.[12] However, little is known about the association of opioid dose with the risk of all‐cause hospitalization for patients with noncancer pain.

In this article we examined hospitalizations for a national cohort of HMO enrollees with noncancer pain who filled at least 2 prescriptions for schedule II or III opioids over a 3.5‐year timeframe. This retrospective cohort analysis aims to identify clinically useful opioid dose measures for clinicians, administrators, and policymakers to use in identifying patients at increased risk of future hospitalization who may warrant interventions to reduce this risk.

METHODS

RESULTS

Of 87,688 study subjects, 54.8% were women, and the mean age was 53.8 years (standard deviation [SD]=5.5). Nearly half of the cohort resided in Southern states (Table 1). In the baseline 6‐month interval, the most common chronic noncancer pain conditions were musculoskeletal involving large joint arthritis/arthralgia (38.4%) and back pain (28.2%). In regard to mental health and substance use conditions, both anxiety/PTSD and depression were diagnosed in approximately 7% of the cohort, whereas psychosis, and alcohol and other substance use disorders were each diagnosed in <2%. In the baseline interval, 12.7% of subjects were hospitalized. The majority of patients received a daily opioid dose of 20 to 49 mg, and the median total dose was 450 mg. The median percent of time exposed to opioids was 6.7% among all study subjects and 70% for those with a high total dose (>1830 mg).

In the 3 study years, an average of 12% of the cohort was hospitalized yearly (Table 2), or 1120 hospitalizations per 10,000 person‐years. Among those who were hospitalized, inpatient days averaged 6.5 (SD=8.5). The highest proportion of hospitalized subjects was 6.5%, occurring in the 6‐month interval immediately following the first opioid treatment interval. In subsequent 6‐month intervals, hospitalization rates were relatively stable, ranging from 5.2% to 6.1% (Table 2). As shown, future hospitalization rates increased monotonically, with increasing total or daily dose within each 6‐month interval.

In unadjusted analyses, a significant interaction between daily dose and total dose (P<0.001) revealed that, within each daily dose category, the odds of hospitalization differed by total dose (all P<0.05, Table 3). When the total dose was >1830 mg, the odds of future hospitalization rose monotonically with increasing daily dose (i.e., <20, 2049, 5099, 100 mg): 1.33, 1.84, 1.96, and 2.08 (P<0.05 for all comparisons vs no opioids). On the other hand, when the total dose was 450 mg or less, all daily dose categories including a very high daily dose (100 mg) were not associated with future hospitalization (all P>0.05 vs no opioids). When the total dose was 451 to 1830 mg, a nonlinear association with hospitalization appeared with higher odds for lower daily doses. For the outcome of hospital days per 6‐month interval, increasing daily dose was also associated with more hospital days per 6‐month interval when the total dose was high (>1830 mg), whereas for lower total doses, daily dose was weakly positive or even protective versus no opioids.

In the model adjusting for all covariates (Table 4), the interaction between total dose and daily dose was also significant (P=0.002). When the total dose was high (>1830 mg), the adjusted odds of future hospitalization were significantly increased by 35% to 44% for daily doses of 20 to 49 mg or greater versus no opioids (P<0.05 for all comparisons). When the total dose was <1830 mg, the majority of daily dose categories were not significantly associated with hospitalization. Similarly, in the fully adjusted analysis of hospital days, the number of inpatient days were increased by 28% to 48% when the total dose was >1830 mg and daily dose was >20 mg, but these associations were nonsignificant or protective when the total dose was lower.

In a sensitivity analysis, we examined the percentage of days covered by filled opioid prescriptions within a 6‐month interval for subjects receiving high‐dose therapy (Table 5). Compared with no opioid therapy, the adjusted odds of future hospitalization were 5% greater for low total opioid dose (11830 mg) and 21% greater for high total dose (>1830 mg) when the duration of treatment was shorter (50% of the 6‐month interval). However, the odds were increased by 41% to 51% for a high total dose (>1830 mg), with longer periods of treatment (>50% of the interval). For hospital days as the outcome, subjects with high total doses (>1830 mg) and longer periods of treatment (>50% of the interval) had 41% to 71% more hospital days per 6‐month interval than those with no opioid therapy.

DISCUSSION

In a national cohort of HMO enrollees who filled at least 2 prescriptions for OAs, 12% were hospitalized annually. Other studies of opioid users have focused on only a fraction of these hospitalizations. For example, a recent Agency for Healthcare Research and Quality study reported that the rate of hospitalization for complications from accidental or deliberate overuse of opioids more than doubled from 11.7/10,000 in 1993 to 29.5/10,000 in 2010.[20] However, in our cohort, the all‐cause hospitalization rate was 1120 per 10,000 person‐years, or over 40 times greater than the rate for complications from overuse of opioids. By comparison, hospitalization for heart failure was only 32.8/10,000 nationally in 2010.[21] Thus, our study confirms the significant demand for hospital care by patients treated with opioids. A novel finding of our study is that the total dose of prescriptions filled over 6 months is significantly associated with an increased risk of future hospitalization. When the total dose within 6 months was in the top quartile (>1830 mg in our cohort), the adjusted odds of future hospitalization ranged from 35% to 44% greater than no opioids for daily opioid doses above 20 mg/day. On the other hand, when the total dose was 1830 mg, the daily opioid dose was only weakly associated with future hospitalization. These associations were similar for hospital days per 6‐month interval as the outcome.

Edlund and colleagues examined the total dose of opioids in a national cohort of veterans with chronic noncancer pain who filled at least 1 opioid prescription.[22] In 2011, the 60th percentile for the total opioid dose for these veterans was 3610 mg within a year, which is roughly equivalent to our top quartile (1830 mg) over a 6‐month interval. These data support replicating our study in veterans to evaluate whether a similarly increased risk of hospitalization appears for those with high total opioid doses. In support of a concern among veterans, a population‐based, cross‐sectional study of hospitalized veterans reported a high rate of chronic opioid therapy (90 days) in the 6 months prior to hospitalization.[23]

Other studies have reported increased risk of hospitalization with chronic opioid therapy. Among 1045 patients followed up to 1‐year post‐transplantation, long‐term opioids were associated with up to a sixfold greater risk of at least 4 admissions within that year.[24] Among 13,127 Danish adults on opioid therapy, the odds of future hospitalization from injuries were increased by 74% for long‐term therapy and 46% for short‐term therapy versus no opioids and by threefold and 1.6‐fold, respectively, for hospitalization due to toxicity/poisoning.[9] However, none of these studies examined the dose of opioids.

In a sensitivity analysis, we found that when a subject received a high total opioid dose within 6 months, treatment for more than 50% of the interval (i.e., >3 months) was associated with a significantly increased risk of future hospitalization and significantly more hospital days. Because the strongest evidence for the benefit of opioids for chronic noncancer pain comes from trials of <3 months,[25] these data lend additional support to recommendations to minimize both dose and duration of opioid therapy.

Our study has several limitations. First, we did not assess the immediate risk of hospitalization after starting opioid therapy. Second, our outcome of hospitalization represents only 1 measure of risk. Thus, our data should not be regarded as supporting short‐term use of high‐dose opioids over 100 to 120 mg per day.[26] In an earlier study, we reported that either a high daily dose (100 mg) or a moderately high daily dose (5099 mg) plus a high total dose (>1830 mg) increased the risk of drug overdose.[10] Third, we could not examine the reason for hospitalizations in this analysis. Therefore, we cannot presume that opioid therapy caused these hospitalizations, but it likely serves as a proxy for other factors such as disability and mental health disorders that increase risk of hospitalization. However, we did adjust for pain conditions as well as mental health and substance abuse disorders that are known to increase the risk of hospitalization in other cohorts.[27, 28, 29, 30] In a national veterans study, the most common clinical conditions associated with long‐term opioid therapy were major depression and PTSD.[22] Last, we did also not consider the number of prescribers of opioids. In a Medicare study, 1 versus 4 prescribers of OAs increased patients' annual hospitalization rate from 1.6% to 4.8%, respectively.[31]

Although the total opioid dose categories observed for our study population may differ from those in other cohorts, these data offer additional evidence for clinicians to consider this measure when assessing risk for hospitalization, and among subjects on high total doses, the percentage of time on opioids offers an additional measure of risk. Because opioid users with noncancer pain are heavy consumers of healthcare services,^32,33 public health benefits and reductions in costs of care may be substantial if opportunities can be identified to reduce hospital utilization by persons treated with higher doses of OAs.

Disclosures

The work on this project was supported by an intramural grant from the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant 1UL TR001120. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors report no conflicts of interest.

Longer term and higher doses of opioid analgesics (OAs) have been associated with multiple adverse outcomes such as loss of work, cognitive decline, and poor function.[1, 2, 3, 4] One of the most widely reported complications of opioid therapy is drug overdose.[5, 6, 7, 8, 9] In population‐based studies, daily morphine equivalent doses >100 mg have been associated with significantly increased risk of drug overdose.[5, 6, 7, 8, 9, 10] Among health maintenance organization (HMO) enrollees filling at least 2 prescriptions for opioids, our group reported that daily opioid doses 100 mg were associated with approximately threefold greater adjusted odds of drug overdose.[10] We also observed over a twofold increase in odds of drug overdose for lower daily doses of 50 to 99 mg if the patient also received a high total opioid dose (>1830 mg) over a 6‐month period. This analysis suggests that clinicians may need to monitor not only daily dose but also total dose of opioids to reduce the risk of drug overdose.

Yet drug overdose represents only a small subset of all hospitalizations for persons receiving long‐term or higher doses of opioids for noncancer pain. These patients have significant demand for urgent care services, including hospitalization, for diverse reasons such as adverse effects of opioids, underlying cause of chronic pain, and comorbidities such as mental health disorders.[11] In a cohort of elderly primary care patients who were high hospital utilizers, Freund and colleagues reported that chronic pain and depression were the most common conditions co‐occurring with their other comorbidities.[12] However, little is known about the association of opioid dose with the risk of all‐cause hospitalization for patients with noncancer pain.

In this article we examined hospitalizations for a national cohort of HMO enrollees with noncancer pain who filled at least 2 prescriptions for schedule II or III opioids over a 3.5‐year timeframe. This retrospective cohort analysis aims to identify clinically useful opioid dose measures for clinicians, administrators, and policymakers to use in identifying patients at increased risk of future hospitalization who may warrant interventions to reduce this risk.

METHODS

RESULTS

Of 87,688 study subjects, 54.8% were women, and the mean age was 53.8 years (standard deviation [SD]=5.5). Nearly half of the cohort resided in Southern states (Table 1). In the baseline 6‐month interval, the most common chronic noncancer pain conditions were musculoskeletal involving large joint arthritis/arthralgia (38.4%) and back pain (28.2%). In regard to mental health and substance use conditions, both anxiety/PTSD and depression were diagnosed in approximately 7% of the cohort, whereas psychosis, and alcohol and other substance use disorders were each diagnosed in <2%. In the baseline interval, 12.7% of subjects were hospitalized. The majority of patients received a daily opioid dose of 20 to 49 mg, and the median total dose was 450 mg. The median percent of time exposed to opioids was 6.7% among all study subjects and 70% for those with a high total dose (>1830 mg).

In the 3 study years, an average of 12% of the cohort was hospitalized yearly (Table 2), or 1120 hospitalizations per 10,000 person‐years. Among those who were hospitalized, inpatient days averaged 6.5 (SD=8.5). The highest proportion of hospitalized subjects was 6.5%, occurring in the 6‐month interval immediately following the first opioid treatment interval. In subsequent 6‐month intervals, hospitalization rates were relatively stable, ranging from 5.2% to 6.1% (Table 2). As shown, future hospitalization rates increased monotonically, with increasing total or daily dose within each 6‐month interval.

In unadjusted analyses, a significant interaction between daily dose and total dose (P<0.001) revealed that, within each daily dose category, the odds of hospitalization differed by total dose (all P<0.05, Table 3). When the total dose was >1830 mg, the odds of future hospitalization rose monotonically with increasing daily dose (i.e., <20, 2049, 5099, 100 mg): 1.33, 1.84, 1.96, and 2.08 (P<0.05 for all comparisons vs no opioids). On the other hand, when the total dose was 450 mg or less, all daily dose categories including a very high daily dose (100 mg) were not associated with future hospitalization (all P>0.05 vs no opioids). When the total dose was 451 to 1830 mg, a nonlinear association with hospitalization appeared with higher odds for lower daily doses. For the outcome of hospital days per 6‐month interval, increasing daily dose was also associated with more hospital days per 6‐month interval when the total dose was high (>1830 mg), whereas for lower total doses, daily dose was weakly positive or even protective versus no opioids.

In the model adjusting for all covariates (Table 4), the interaction between total dose and daily dose was also significant (P=0.002). When the total dose was high (>1830 mg), the adjusted odds of future hospitalization were significantly increased by 35% to 44% for daily doses of 20 to 49 mg or greater versus no opioids (P<0.05 for all comparisons). When the total dose was <1830 mg, the majority of daily dose categories were not significantly associated with hospitalization. Similarly, in the fully adjusted analysis of hospital days, the number of inpatient days were increased by 28% to 48% when the total dose was >1830 mg and daily dose was >20 mg, but these associations were nonsignificant or protective when the total dose was lower.

In a sensitivity analysis, we examined the percentage of days covered by filled opioid prescriptions within a 6‐month interval for subjects receiving high‐dose therapy (Table 5). Compared with no opioid therapy, the adjusted odds of future hospitalization were 5% greater for low total opioid dose (11830 mg) and 21% greater for high total dose (>1830 mg) when the duration of treatment was shorter (50% of the 6‐month interval). However, the odds were increased by 41% to 51% for a high total dose (>1830 mg), with longer periods of treatment (>50% of the interval). For hospital days as the outcome, subjects with high total doses (>1830 mg) and longer periods of treatment (>50% of the interval) had 41% to 71% more hospital days per 6‐month interval than those with no opioid therapy.

DISCUSSION

In a national cohort of HMO enrollees who filled at least 2 prescriptions for OAs, 12% were hospitalized annually. Other studies of opioid users have focused on only a fraction of these hospitalizations. For example, a recent Agency for Healthcare Research and Quality study reported that the rate of hospitalization for complications from accidental or deliberate overuse of opioids more than doubled from 11.7/10,000 in 1993 to 29.5/10,000 in 2010.[20] However, in our cohort, the all‐cause hospitalization rate was 1120 per 10,000 person‐years, or over 40 times greater than the rate for complications from overuse of opioids. By comparison, hospitalization for heart failure was only 32.8/10,000 nationally in 2010.[21] Thus, our study confirms the significant demand for hospital care by patients treated with opioids. A novel finding of our study is that the total dose of prescriptions filled over 6 months is significantly associated with an increased risk of future hospitalization. When the total dose within 6 months was in the top quartile (>1830 mg in our cohort), the adjusted odds of future hospitalization ranged from 35% to 44% greater than no opioids for daily opioid doses above 20 mg/day. On the other hand, when the total dose was 1830 mg, the daily opioid dose was only weakly associated with future hospitalization. These associations were similar for hospital days per 6‐month interval as the outcome.

Edlund and colleagues examined the total dose of opioids in a national cohort of veterans with chronic noncancer pain who filled at least 1 opioid prescription.[22] In 2011, the 60th percentile for the total opioid dose for these veterans was 3610 mg within a year, which is roughly equivalent to our top quartile (1830 mg) over a 6‐month interval. These data support replicating our study in veterans to evaluate whether a similarly increased risk of hospitalization appears for those with high total opioid doses. In support of a concern among veterans, a population‐based, cross‐sectional study of hospitalized veterans reported a high rate of chronic opioid therapy (90 days) in the 6 months prior to hospitalization.[23]

Other studies have reported increased risk of hospitalization with chronic opioid therapy. Among 1045 patients followed up to 1‐year post‐transplantation, long‐term opioids were associated with up to a sixfold greater risk of at least 4 admissions within that year.[24] Among 13,127 Danish adults on opioid therapy, the odds of future hospitalization from injuries were increased by 74% for long‐term therapy and 46% for short‐term therapy versus no opioids and by threefold and 1.6‐fold, respectively, for hospitalization due to toxicity/poisoning.[9] However, none of these studies examined the dose of opioids.

In a sensitivity analysis, we found that when a subject received a high total opioid dose within 6 months, treatment for more than 50% of the interval (i.e., >3 months) was associated with a significantly increased risk of future hospitalization and significantly more hospital days. Because the strongest evidence for the benefit of opioids for chronic noncancer pain comes from trials of <3 months,[25] these data lend additional support to recommendations to minimize both dose and duration of opioid therapy.

Our study has several limitations. First, we did not assess the immediate risk of hospitalization after starting opioid therapy. Second, our outcome of hospitalization represents only 1 measure of risk. Thus, our data should not be regarded as supporting short‐term use of high‐dose opioids over 100 to 120 mg per day.[26] In an earlier study, we reported that either a high daily dose (100 mg) or a moderately high daily dose (5099 mg) plus a high total dose (>1830 mg) increased the risk of drug overdose.[10] Third, we could not examine the reason for hospitalizations in this analysis. Therefore, we cannot presume that opioid therapy caused these hospitalizations, but it likely serves as a proxy for other factors such as disability and mental health disorders that increase risk of hospitalization. However, we did adjust for pain conditions as well as mental health and substance abuse disorders that are known to increase the risk of hospitalization in other cohorts.[27, 28, 29, 30] In a national veterans study, the most common clinical conditions associated with long‐term opioid therapy were major depression and PTSD.[22] Last, we did also not consider the number of prescribers of opioids. In a Medicare study, 1 versus 4 prescribers of OAs increased patients' annual hospitalization rate from 1.6% to 4.8%, respectively.[31]

Although the total opioid dose categories observed for our study population may differ from those in other cohorts, these data offer additional evidence for clinicians to consider this measure when assessing risk for hospitalization, and among subjects on high total doses, the percentage of time on opioids offers an additional measure of risk. Because opioid users with noncancer pain are heavy consumers of healthcare services,^32,33 public health benefits and reductions in costs of care may be substantial if opportunities can be identified to reduce hospital utilization by persons treated with higher doses of OAs.

Disclosures

The work on this project was supported by an intramural grant from the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant 1UL TR001120. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors report no conflicts of interest.

Longer term and higher doses of opioid analgesics (OAs) have been associated with multiple adverse outcomes such as loss of work, cognitive decline, and poor function.[1, 2, 3, 4] One of the most widely reported complications of opioid therapy is drug overdose.[5, 6, 7, 8, 9] In population‐based studies, daily morphine equivalent doses >100 mg have been associated with significantly increased risk of drug overdose.[5, 6, 7, 8, 9, 10] Among health maintenance organization (HMO) enrollees filling at least 2 prescriptions for opioids, our group reported that daily opioid doses 100 mg were associated with approximately threefold greater adjusted odds of drug overdose.[10] We also observed over a twofold increase in odds of drug overdose for lower daily doses of 50 to 99 mg if the patient also received a high total opioid dose (>1830 mg) over a 6‐month period. This analysis suggests that clinicians may need to monitor not only daily dose but also total dose of opioids to reduce the risk of drug overdose.

Yet drug overdose represents only a small subset of all hospitalizations for persons receiving long‐term or higher doses of opioids for noncancer pain. These patients have significant demand for urgent care services, including hospitalization, for diverse reasons such as adverse effects of opioids, underlying cause of chronic pain, and comorbidities such as mental health disorders.[11] In a cohort of elderly primary care patients who were high hospital utilizers, Freund and colleagues reported that chronic pain and depression were the most common conditions co‐occurring with their other comorbidities.[12] However, little is known about the association of opioid dose with the risk of all‐cause hospitalization for patients with noncancer pain.

In this article we examined hospitalizations for a national cohort of HMO enrollees with noncancer pain who filled at least 2 prescriptions for schedule II or III opioids over a 3.5‐year timeframe. This retrospective cohort analysis aims to identify clinically useful opioid dose measures for clinicians, administrators, and policymakers to use in identifying patients at increased risk of future hospitalization who may warrant interventions to reduce this risk.

METHODS

RESULTS

Of 87,688 study subjects, 54.8% were women, and the mean age was 53.8 years (standard deviation [SD]=5.5). Nearly half of the cohort resided in Southern states (Table 1). In the baseline 6‐month interval, the most common chronic noncancer pain conditions were musculoskeletal involving large joint arthritis/arthralgia (38.4%) and back pain (28.2%). In regard to mental health and substance use conditions, both anxiety/PTSD and depression were diagnosed in approximately 7% of the cohort, whereas psychosis, and alcohol and other substance use disorders were each diagnosed in <2%. In the baseline interval, 12.7% of subjects were hospitalized. The majority of patients received a daily opioid dose of 20 to 49 mg, and the median total dose was 450 mg. The median percent of time exposed to opioids was 6.7% among all study subjects and 70% for those with a high total dose (>1830 mg).

In the 3 study years, an average of 12% of the cohort was hospitalized yearly (Table 2), or 1120 hospitalizations per 10,000 person‐years. Among those who were hospitalized, inpatient days averaged 6.5 (SD=8.5). The highest proportion of hospitalized subjects was 6.5%, occurring in the 6‐month interval immediately following the first opioid treatment interval. In subsequent 6‐month intervals, hospitalization rates were relatively stable, ranging from 5.2% to 6.1% (Table 2). As shown, future hospitalization rates increased monotonically, with increasing total or daily dose within each 6‐month interval.

In unadjusted analyses, a significant interaction between daily dose and total dose (P<0.001) revealed that, within each daily dose category, the odds of hospitalization differed by total dose (all P<0.05, Table 3). When the total dose was >1830 mg, the odds of future hospitalization rose monotonically with increasing daily dose (i.e., <20, 2049, 5099, 100 mg): 1.33, 1.84, 1.96, and 2.08 (P<0.05 for all comparisons vs no opioids). On the other hand, when the total dose was 450 mg or less, all daily dose categories including a very high daily dose (100 mg) were not associated with future hospitalization (all P>0.05 vs no opioids). When the total dose was 451 to 1830 mg, a nonlinear association with hospitalization appeared with higher odds for lower daily doses. For the outcome of hospital days per 6‐month interval, increasing daily dose was also associated with more hospital days per 6‐month interval when the total dose was high (>1830 mg), whereas for lower total doses, daily dose was weakly positive or even protective versus no opioids.

In the model adjusting for all covariates (Table 4), the interaction between total dose and daily dose was also significant (P=0.002). When the total dose was high (>1830 mg), the adjusted odds of future hospitalization were significantly increased by 35% to 44% for daily doses of 20 to 49 mg or greater versus no opioids (P<0.05 for all comparisons). When the total dose was <1830 mg, the majority of daily dose categories were not significantly associated with hospitalization. Similarly, in the fully adjusted analysis of hospital days, the number of inpatient days were increased by 28% to 48% when the total dose was >1830 mg and daily dose was >20 mg, but these associations were nonsignificant or protective when the total dose was lower.

In a sensitivity analysis, we examined the percentage of days covered by filled opioid prescriptions within a 6‐month interval for subjects receiving high‐dose therapy (Table 5). Compared with no opioid therapy, the adjusted odds of future hospitalization were 5% greater for low total opioid dose (11830 mg) and 21% greater for high total dose (>1830 mg) when the duration of treatment was shorter (50% of the 6‐month interval). However, the odds were increased by 41% to 51% for a high total dose (>1830 mg), with longer periods of treatment (>50% of the interval). For hospital days as the outcome, subjects with high total doses (>1830 mg) and longer periods of treatment (>50% of the interval) had 41% to 71% more hospital days per 6‐month interval than those with no opioid therapy.

DISCUSSION

In a national cohort of HMO enrollees who filled at least 2 prescriptions for OAs, 12% were hospitalized annually. Other studies of opioid users have focused on only a fraction of these hospitalizations. For example, a recent Agency for Healthcare Research and Quality study reported that the rate of hospitalization for complications from accidental or deliberate overuse of opioids more than doubled from 11.7/10,000 in 1993 to 29.5/10,000 in 2010.[20] However, in our cohort, the all‐cause hospitalization rate was 1120 per 10,000 person‐years, or over 40 times greater than the rate for complications from overuse of opioids. By comparison, hospitalization for heart failure was only 32.8/10,000 nationally in 2010.[21] Thus, our study confirms the significant demand for hospital care by patients treated with opioids. A novel finding of our study is that the total dose of prescriptions filled over 6 months is significantly associated with an increased risk of future hospitalization. When the total dose within 6 months was in the top quartile (>1830 mg in our cohort), the adjusted odds of future hospitalization ranged from 35% to 44% greater than no opioids for daily opioid doses above 20 mg/day. On the other hand, when the total dose was 1830 mg, the daily opioid dose was only weakly associated with future hospitalization. These associations were similar for hospital days per 6‐month interval as the outcome.

Edlund and colleagues examined the total dose of opioids in a national cohort of veterans with chronic noncancer pain who filled at least 1 opioid prescription.[22] In 2011, the 60th percentile for the total opioid dose for these veterans was 3610 mg within a year, which is roughly equivalent to our top quartile (1830 mg) over a 6‐month interval. These data support replicating our study in veterans to evaluate whether a similarly increased risk of hospitalization appears for those with high total opioid doses. In support of a concern among veterans, a population‐based, cross‐sectional study of hospitalized veterans reported a high rate of chronic opioid therapy (90 days) in the 6 months prior to hospitalization.[23]

Other studies have reported increased risk of hospitalization with chronic opioid therapy. Among 1045 patients followed up to 1‐year post‐transplantation, long‐term opioids were associated with up to a sixfold greater risk of at least 4 admissions within that year.[24] Among 13,127 Danish adults on opioid therapy, the odds of future hospitalization from injuries were increased by 74% for long‐term therapy and 46% for short‐term therapy versus no opioids and by threefold and 1.6‐fold, respectively, for hospitalization due to toxicity/poisoning.[9] However, none of these studies examined the dose of opioids.

In a sensitivity analysis, we found that when a subject received a high total opioid dose within 6 months, treatment for more than 50% of the interval (i.e., >3 months) was associated with a significantly increased risk of future hospitalization and significantly more hospital days. Because the strongest evidence for the benefit of opioids for chronic noncancer pain comes from trials of <3 months,[25] these data lend additional support to recommendations to minimize both dose and duration of opioid therapy.

Our study has several limitations. First, we did not assess the immediate risk of hospitalization after starting opioid therapy. Second, our outcome of hospitalization represents only 1 measure of risk. Thus, our data should not be regarded as supporting short‐term use of high‐dose opioids over 100 to 120 mg per day.[26] In an earlier study, we reported that either a high daily dose (100 mg) or a moderately high daily dose (5099 mg) plus a high total dose (>1830 mg) increased the risk of drug overdose.[10] Third, we could not examine the reason for hospitalizations in this analysis. Therefore, we cannot presume that opioid therapy caused these hospitalizations, but it likely serves as a proxy for other factors such as disability and mental health disorders that increase risk of hospitalization. However, we did adjust for pain conditions as well as mental health and substance abuse disorders that are known to increase the risk of hospitalization in other cohorts.[27, 28, 29, 30] In a national veterans study, the most common clinical conditions associated with long‐term opioid therapy were major depression and PTSD.[22] Last, we did also not consider the number of prescribers of opioids. In a Medicare study, 1 versus 4 prescribers of OAs increased patients' annual hospitalization rate from 1.6% to 4.8%, respectively.[31]

Although the total opioid dose categories observed for our study population may differ from those in other cohorts, these data offer additional evidence for clinicians to consider this measure when assessing risk for hospitalization, and among subjects on high total doses, the percentage of time on opioids offers an additional measure of risk. Because opioid users with noncancer pain are heavy consumers of healthcare services,^32,33 public health benefits and reductions in costs of care may be substantial if opportunities can be identified to reduce hospital utilization by persons treated with higher doses of OAs.

Disclosures

The work on this project was supported by an intramural grant from the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant 1UL TR001120. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors report no conflicts of interest.