Alcohol use disorder pharmacotherapy and treatment in primary care (ADaPT-PC) trial: Impact on identified barriers to implementation.

Background: A minority of individuals meeting diagnostic criteria for alcohol use disorders (AUD) receive any type of formal treatment. Developing options for AUD treatment within primary care settings is imperative to increase treatment access. A multi-faceted implementation intervention including provider and patient education, clinician reminders, development of local champions and ongoing facilitation was designed to enhance access to AUD pharmacotherapy in primary care settings at three large Veterans Health Administration (VHA) facilities. This qualitative study compared pre-implementation barriers to post-implementation barriers identified via provider interviews to identify those barriers addressed and not addressed by the intervention to better understand the limited impact of the intervention. Methods: Following the nine-month implementation period, primary care providers at the three participating facilities took part in qualitative interviews to collect perceptions regarding which pre-implementation barriers had and had not been successfully addressed by the intervention. Participants included 20 primary care providers from three large VHA facilities. Interviews were coded using common coding techniques for qualitative data using the Consolidated Framework for Implementation Research (CFIR) codebook. Summary reports were created for each CFIR construct for each facility and the impact of each CFIR construct on implementation was coded as positive, neutral, or negative. Results: Some barriers identified during pre-implementation interviews were no longer identified as barriers in the post-implementation interviews. These included Relative Advantage, Relative Priority, and Knowledge & Beliefs about the Innovation. However, Compatibility, Design Quality & Packaging, and Available Resources remained barriers at the end of the implementation period. No substantial new barriers were identified. Conclusions: The implementation intervention appears to have been successful at addressing barriers that could be mitigated with traditional educational approaches. However, the intervention did not adequately address structural and organizational barriers to implementation. Recommendations for enhancing future interventions are provided.

Effect of Pharmacogenomic Testing for Drug-Gene Interactions on Medication Selection and Remission of Symptoms in Major Depressive Disorder: The PRIME Care Randomized Clinical Trial.

Importance: Selecting effective antidepressants for the treatment of major depressive disorder (MDD) is an imprecise practice, with remission rates of about 30% at the initial treatment. Objective: To determine whether pharmacogenomic testing affects antidepressant medication selection and whether such testing leads to better clinical outcomes. Design, Setting, and Participants: A pragmatic, randomized clinical trial that compared treatment guided by pharmacogenomic testing vs usual care. Participants included 676 clinicians and 1944 patients. Participants were enrolled from 22 Department of Veterans Affairs medical centers from July 2017 through February 2021, with follow-up ending November 2021. Eligible patients were those with MDD who were initiating or switching treatment with a single antidepressant. Exclusion criteria included an active substance use disorder, mania, psychosis, or concurrent treatment with a specified list of medications. Interventions: Results from a commercial pharmacogenomic test were given to clinicians in the pharmacogenomic-guided group (n = 966). The comparison group received usual care and access to pharmacogenomic results after 24 weeks (n = 978). Main Outcomes and Measures: The co-primary outcomes were the proportion of prescriptions with a predicted drug-gene interaction written in the 30 days after randomization and remission of depressive symptoms as measured by the Patient Health Questionnaire-9 (PHQ-9) (remission was defined as PHQ-9 ≤ 5). Remission was analyzed as a repeated measure across 24 weeks by blinded raters. Results: Among 1944 patients who were randomized (mean age, 48 years; 491 women [25%]), 1541 (79%) completed the 24-week assessment. The estimated risks for receiving an antidepressant with none, moderate, and substantial drug-gene interactions for the pharmacogenomic-guided group were 59.3%, 30.0%, and 10.7% compared with 25.7%, 54.6%, and 19.7% in the usual care group. The pharmacogenomic-guided group was more likely to receive a medication with a lower potential drug-gene interaction for no drug-gene vs moderate/substantial interaction (odds ratio [OR], 4.32 [95% CI, 3.47 to 5.39]; P < .001) and no/moderate vs substantial interaction (OR, 2.08 [95% CI, 1.52 to 2.84]; P = .005) (P < .001 for overall comparison). Remission rates over 24 weeks were higher among patients whose care was guided by pharmacogenomic testing than those in usual care (OR, 1.28 [95% CI, 1.05 to 1.57]; P = .02; risk difference, 2.8% [95% CI, 0.6% to 5.1%]) but were not significantly higher at week 24 when 130 patients in the pharmacogenomic-guided group and 126 patients in the usual care group were in remission (estimated risk difference, 1.5% [95% CI, -2.4% to 5.3%]; P = .45). Conclusions and Relevance: Among patients with MDD, provision of pharmacogenomic testing for drug-gene interactions reduced prescription of medications with predicted drug-gene interactions compared with usual care. Provision of test results had small nonpersistent effects on symptom remission. Trial Registration: ClinicalTrials.gov Identifier: NCT03170362.

Reduced alcohol use in patients prescribed pioglitazone.

BACKGROUND AND OBJECTIVES: Alcohol use disorder (AUD) is common and causes significant morbidity and mortality. Currently approved medications are moderately effective. Novel medications are needed to address AUD. Preliminary data suggests pioglitazone may reduce alcohol use. METHODS: Veterans seen at the Minneapolis VA Health Care System, who were prescribed pioglitazone for diabetes between October 1, 2015 and September 30, 2016, were identified using a national VA database (N = 49). Further chart review was performed to identify all Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) scores prior to starting pioglitazone. Hierarchical Linear models were used to compare all AUDIT-C scores on and off pioglitazone and compare the change in AUDIT-C scores over time before and during pioglitazone was prescribed. AUDIT-C scores were nested within subject with fixed effects for pioglitazone and random intercept and slope for time. RESULTS: Forty-nine patients were prescribed pioglitazone and had AUDIT-C scores of 3 or more. The estimated mean AUDIT-C score prior to receiving pioglitazone was 3.98 (95% confidence interval [CI]: 3.51-4.44) and this was reduced to 2.89 (95% CI: 2.46-3.32), reflecting a significant change F(1, 323) = 43.3, p < .001 in the score. The primary reduction occurred within the first year of the pioglitazone prescription. This effect remained significant after controlling for age. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: This is the first study of pioglitazone used in a clinical sample focused on alcohol use outcome. The data show that pioglitazone may reduce alcohol use in patients with heavy drinking. Clinical trials of pioglitazone are warranted in patients with AUD.

Identifying barriers to hepatocellular carcinoma surveillance in a national sample of patients with cirrhosis.

Hepatocellular carcinoma (HCC) is a leading cause of morbidity and mortality in cirrhosis patients. This provides an opportunity to target the highest-risk population, yet surveillance rates in the United States and Europe range from 10% to 40%. The goal of this study was to identify barriers to HCC surveillance, using data from the Veterans Health Administration, the largest provider of liver-related health care in the United States. We included all patients 75 years of age or younger who were diagnosed with cirrhosis from January 1, 2008, until December 31, 2010. The primary outcome was a continuous measure of the percentage of time up-to-date with HCC surveillance (PTUDS) based on abdominal ultrasound (secondary outcomes included computed tomography and magnetic resonance imaging). Among 26,577 patients with cirrhosis (median follow-up = 4.7 years), the mean PTUDS was 17.8 ± 21.5% (ultrasounds) and 23.3 ± 24.1% when any liver imaging modality was included. The strongest predictor of increased PTUDS was the number of visits to a specialist (gastroenterologist/hepatologist and/or infectious diseases) in the first year after cirrhosis diagnosis; the association between visits to a primary care physician and increasing surveillance was very small. Increasing distance to the closest Veterans Administration center was associated with decreased PTUDS. There was an inverse association between ultrasound lead time (difference between the date an ultrasound was ordered and requested exam date) and the odds of it being performed: odds ratio = 0.77, 95% confidence interval 0.72-0.82 when ordered > 180 days ahead of time; odds ratio = 0.90, 95% confidence interval 0.85-0.94 if lead time 91-180 days. CONCLUSIONS: The responsibility for suboptimal surveillance rests with patients, providers, and the overall health care system; several measures can be implemented to potentially increase HCC surveillance, including increasing patient-specialist visits and minimizing appointment lead time. (Hepatology 2017;65:864-874).

S100B and Inflammatory Cytokine Levels in Blood as Potential Markers of Blood-Brain Barrier Damage and Psychiatric Impairment in Comorbid Hepatitis C Viral Infection and Alcohol Use Disorder.

BACKGROUND: Hepatitis C virus (HCV) infection and alcohol use disorder (AUD) both adversely affect the immune system resulting in alterations in immune cell signaling and inflammatory processes. The aim of this study was to investigate how comorbid AUD contributes to abnormalities in inflammatory mediators and psychiatric impairments in adults with HCV. METHODS: Alcohol use, mood, and inflammatory factors were evaluated at 3 time points (baseline, week 4, and week 12) in Veterans with HCV, with (n = 42) and without (n = 13) comorbid AUD. Peripheral indices of immune activation, blood-brain barrier (BBB) damage (S100 calcium-binding protein B [S100B]), liver function, and viral load were measured using immunoassays and polymerase chain reaction assays. RESULTS: Comorbid AUD was associated with increased symptoms of depression and anxiety, elevated levels of liver enzymes, and altered expression of inflammatory factors. Alcohol consumption was positively correlated with the severity of psychiatric symptoms. Univariate analysis identified significant group differences in interleukin (IL)-8 (p = 0.006), IL-10 (p = 0.03), and S100B (p = 0.048), with increased levels in participants with AUD, which persisted over time despite reductions in alcohol use and no significant change in HCV viral load. Statistically significant effects of study group or time were not found for the other immune factors assessed. Exploratory receiver operating characteristic curve analysis evaluated the ability of IL-8, IL-10, and S100B to differentiate between levels of alcohol consumption and generated biomarker cutoff values used to identify low risk and unhealthy alcohol use groups. CONCLUSIONS: These results demonstrate that HCV and comorbid AUD are associated with greater psychiatric impairments, potentially resulting from increased inflammation, dysregulated cytokine expression, and compromised BBB function. Alcohol-induced BBB damage may increase the risk of neuropathological consequences within the context of chronic HCV infection.

All-cause mortality and liver-related outcomes following successful antiviral treatment for chronic hepatitis C.

BACKGROUND: Antiviral therapy for the hepatitis C virus (HCV) reduces all-cause and liver-related morbidity and mortality. Few studies are available from populations with multiple medical and psychiatric comorbidities where the impact of successful antiviral therapy might be limited. AIM: The purpose of this study was to determine the effect of sustained virologic response (SVR) on all-cause and liver-related mortality in a cohort of HCV patients treated in an integrated hepatitis/mental health clinic. METHODS: This was a retrospective review of all patients who initiated antiviral treatment for chronic HCV between January 1, 1997 and December 31, 2009. Cox regression analysis was used to determine factors involved in all-cause mortality, liver-related events and hepatocellular carcinoma. RESULTS: A total of 536 patients were included in the analysis. Median follow-up was 7.5 years. Liver and non-liver-related mortality occurred in 2.7 and 5.0 % of patients with SVR and in 17.8 and 6.4 % of patients without SVR. In a multivariate analysis, SVR was the only factor associated with reduced all-cause mortality (HR 0.47; 95 % CI 0.26-0.85; p = 0.012) and reduced liver-related events (HR 0.23; 95 % CI 0.08-0.66, p = 0.007). Having stage 4 liver fibrosis increased all-cause mortality (HR 2.50; 95 % CI 1.23-5.08; p = 0.011). Thrombocytopenia at baseline (HR 2.66; 95 % CI 1.22-5.79; p = 0.014) and stage 4 liver fibrosis (HR 4.87; 95 % CI 1.62-14.53; p = 0.005) increased liver-related events. CONCLUSIONS: Despite significant medical and psychiatric comorbidities, SVR markedly reduced liver-related outcomes without a significant change in non-liver-related mortality after a median follow-up of 7.5 years.

U.S. multicenter pilot study of daily consensus interferon (CIFN) plus ribavirin for "difficult-to-treat" HCV genotype 1 patients.

BACKGROUND: Patients with chronic hepatitis C genotype 1 (HCV-1) and difficult-to-treat characteristics respond poorly to pegylated interferon alfa and ribavirin (RBV), and could benefit from an interferon with increased activity (consensus interferon or CIFN), favorable viral kinetics from daily dosing, and a longer duration of therapy. The purpose of this pilot study was to determine the efficacy and safety of daily CIFN + RBV for initial treatment of patients with HCV-1 infection. METHODS: Patients with difficult-to-treat characteristics (92% male, 33% African American, 78% Veterans Affairs [VA]; 67% high viral load, 59% stage 3-4 fibrosis, and mean weight of 204 lbs) were enrolled at seven VA and two community medical centers. They were randomized to daily CIFN (15 mcg/day SQ) and RBV (1-1.2 g/d PO) given for either 52 weeks (group A, n = 33) or 52-72 weeks (from time of viral response +48 weeks) (group B, n = 31). RESULTS: Intention to treat analysis for treatment groups A and B demonstrated 33% (11/33) and 32% (10/31) sustained virologic response (SVR), respectively. Only 2/31 patients in group B received more than 52 weeks of treatment. The overall group demonstrated a 31% (20/64) rapid virologic response rate (RVR), 54% (34/64) end of treatment virologic response and a 33% (21/64) SVR. Patients with RVR at 4 weeks, early virologic response from 8-12 weeks, and late virologic response from 16-24 weeks demonstrated SVR of 75% (15/20), 31% (4/13), and 22% (2/9), respectively. Overall early non-protocol discontinuation occurred in 26/64 (40%) patients. CONCLUSION: Daily CIFN and ribavirin for initial treatment of HCV-1 patients has potential for achieving a relatively high RVR rate, but discontinuations are frequent and successful use of this regimen is highly dependent on adequate patient support to maintain adherence.

Significant reductions in drinking following brief alcohol treatment provided in a hepatitis C clinic.

BACKGROUND: Although the hepatitis C virus (HCV) alone increases the risk of cirrhosis, alcohol use is thought to act synergistically with HCV to significantly hasten the development of fibrosis. OBJECTIVE: The authors assessed the impact of brief medical counseling or integrated-care approaches to lessen or eliminate alcohol use in these vulnerable patients. METHOD: This retrospective study describes the effect of brief alcohol treatment delivered in a hepatitis clinic on drinking outcomes and antiviral treatment eligibility: 47 heavy-drinking chronic hepatitis C patients received a brief intervention performed by medical clinicians, with follow-up by a psychiatric nurse-specialist. RESULTS: At the last follow-up, 62% of patients reported >50% drinking reduction; these included 36% who achieved abstinence. Only 6% of patients were excluded from antiviral therapy. DISCUSSION: Brief treatment addressing heavy drinking delivered by hepatitis clinicians with psychiatric-specialist follow-up was associated with abstinence or a significant reduction in alcohol consumption in over 50% of patients.

Implementing alcohol use disorder pharmacotherapy in primary care settings: a qualitative analysis of provider-identified barriers and impact on implementation outcomes.

BACKGROUND: Despite the high prevalence of alcohol use disorders (AUDs), in 2016, only 7.8% of individuals meeting diagnostic criteria received any type of AUD treatment. Developing options for treatment within primary care settings is imperative to increase treatment access. As part of a trial to implement AUD pharmacotherapy in primary care settings, this qualitative study analyzed pre-implementation provider interviews using the Consolidated Framework for Implementation Research (CFIR) to identify implementation barriers. METHODS: Three large Veterans Health Administration facilities participated in the implementation intervention. Local providers were trained to serve as implementation/clinical champions and received external facilitation from the project team. Primary care providers received a dashboard of patients with AUD for case identification, educational materials, and access to consultation from clinical champions. Veterans with AUD diagnoses received educational information in the mail. Prior to the start of implementation activities, 24 primary care providers (5-10 per site) participated in semi-structured interviews. Transcripts were analyzed using common coding techniques for qualitative data using the CFIR codebook Innovation/Intervention Characteristics, Outer Setting, Inner Setting, and Characteristics of Individuals domains. Number and type of barriers identified were compared to quantitative changes in AUD pharmacotherapy prescribing rates. RESULTS: Four major barriers emerged across all three sites: complexity of providing AUD pharmacotherapy in primary care, the limited compatibility of AUD treatment with existing primary care processes, providers' limited knowledge and negative beliefs about AUD pharmacotherapy and providers' negative attitudes toward patients with AUD. Site specific barriers included lack of relative advantage of providing AUD pharmacotherapy in primary care over current practice, complaints about the design quality and packaging of implementation intervention materials, limited priority of addressing AUD in primary care and limited available resources to implement AUD pharmacotherapy in primary care. CONCLUSIONS: CFIR constructs were useful for identifying pre-implementation barriers that informed refinements to the implementation intervention. The number and type of pre-implementation barriers identified did not demonstrate a clear relationship to the degree to which sites were able to improve AUD pharmacotherapy prescribing rate. Site-level implementation process factors such as leadership support and provider turn-over likely also interacted with pre-implementation barriers to drive implementation outcomes.

Management of chronic hepatitis C in veterans: the potential of integrated care models.

The prevalence of hepatitis C virus (HCV) infection is higher among veterans than nonveterans, but only about 14% of all identified infected veterans have ever received antiviral therapy. High rates of comorbid psychiatric and substance use disorders are major barriers to receiving antiviral treatment for veterans, and characteristics associated with poor virologic response are more common in this population. However, accumulating evidence indicates that patients with psychiatric and substance use disorders can successfully receive interferon-based antiviral therapies in an integrated or multidisciplinary health-care setting. The broad aims of integrated care models include reducing fragmentation and improving continuity and coordination of care. Although, to date, there are no randomized controlled trials of specific care models for patients with HCV, studies of integrated care for other chronic diseases suggest several strategies for optimizing outcomes for patients with HCV. Components of an HCV clinic incorporating these principles have been tested in a nonrandomized setting and include routine screening of all patients for psychiatric and substance use disorder risk factors, collaboration with mental health providers within the HCV clinic, following a defined integrated medical/psychiatric clinical protocol, provision of ongoing integrated support during antiviral treatment or retreatment, and educating patients on principles of chronic disease self-management.

Integrating hepatitis prevention services into a substance use disorder clinic.

The Healthy Liver Program, established at the Minneapolis Veterans Affairs Medical Center Substance Use Disorder Clinic, provides screening for exposure to hepatitis infections, a group education class, and an individual nursing appointment to review screening results, give vaccinations for hepatitis A and hepatitis B, and make referrals to the hepatitis clinic as appropriate. A patient chart audit was completed 11 months after the establishment of the Healthy Liver Program. The attendance rate for the educational group and individual feedback sessions was 66.9%, with 94.1% of attendees accepting recommended hepatitis A and/or hepatitis B vaccinations. All patients with chronic hepatitis C who attended the Healthy Liver Program received a referral for evaluation in the hepatitis clinic, as compared with only 50% of patients with chronic hepatitis C who were identified before the establishment of the program. The importance of providing comprehensive educational sessions and recommendations for how patients with substance use disorders can access hepatitis screening, vaccination, and treatment resources are stressed.

Rapid evidence review of the comparative effectiveness, harms, and cost-effectiveness of pharmacogenomics-guided antidepressant treatment versus usual care for major depressive disorder.

OBJECTIVE: This study aims to conduct an evidence review of the effectiveness, harms, and cost-effectiveness of pharmacogenomics-guided antidepressant treatment for major depressive disorder. METHODS: We searched MEDLINE®, the Cochrane Central Registry of Controlled Trials, and PsycINFO through February 2017. We used prespecified criteria to select studies, abstract data, and rate internal validity and strength of the evidence (PROSPERO number CRD42016036358). RESULTS: We included two randomized trials (RCT), five controlled cohort studies, and six modeling studies of mostly women in their mid-40s with few comorbidities. CNSDose (ABCB1, ABCC1, CYP2C19, CYP2D6, UGT1A1) is the only pharmacogenomics test that significantly improved remission (one additional remitting patient in 12 weeks per three genotyped, 95% CI 1.7 to 3.5) and reduced intolerability in an RCT. ABCB1 genotyping leads to one additional remitting patient in 5 weeks per three genotyped (95% CI 3 to 20), but tolerability was not reported. In an RCT, GeneSight (CYP2D6, CYPC19, CYP1A2, SLC6A4, HTR2A) did not statistically significantly improve remission, and evidence is inconclusive about its tolerability. Evidence is generally low strength because RCTs were few and underpowered. Cost-effectiveness is unclear due to lack of directly observed cost-effectiveness outcomes. We found no studies that evaluated whether pharmacogenomics shortens time to optimal treatment, whether improvements were due to switches to genetically congruent medication, or whether effectiveness varies based on test and patient characteristics. CONCLUSIONS: Certain pharmacogenomics tools show promise of improving short-term remission rates in women in their mid-40s with few comorbidities. But, important evidence limitations preclude recommending their widespread use and indicate a need for further research.

The safety and efficacy of baclofen to reduce alcohol use in veterans with chronic hepatitis C: a randomized controlled trial.

BACKGROUND AND AIMS: Alcohol use disorders (AUDs) are common among people with chronic hepatitis C (HCV) and accelerate the development of fibrosis and cirrhosis caused by HCV. Baclofen, a gamma-aminobutyric acid (GABA) beta-receptor agonist, differs from medications for AUDs currently approved by the United States Food and Drug Administration (FDA), as it is metabolized primarily through the kidneys. The primary outcome of this study was to compare baclofen with a placebo in the percentage of days abstinent from alcohol. DESIGN: A double-blind, placebo-controlled randomized trial. SETTING: Hepatology clinics in four separate US Veteran Affairs Medical Centers in the United States. PARTICIPANTS: One hundred and eighty Veteran men and women older than 18 years with chronic HCV, a comorbid AUD and current alcohol use. INTERVENTION AND COMPARATOR: Oral baclofen was given at dosages of 0 (placebo) or 30 mg/day over 12 weeks with concomitant manual-guided counseling. MEASUREMENTS: The primary measurement was percentage of days abstinent during the 12-week study period between the baclofen and placebo groups [measured by time-line follow-back (TLFB)]. Secondary measurements were the percentage of Veterans who achieved complete abstinence, the percentage of Veterans who achieved no heavy drinking between weeks 4 and 12 of the study, alcohol craving, anxiety, depression and post-traumatic stress disorder (PTSD). FINDINGS: Primary outcome: compared with placebo, baclofen did not improve the percentage of days abstinent. For all subjects there were significant reductions from baseline to 12 weeks in percentage of days abstinent from 37.0% [standard error (SE) = 2.7] to 68.6% (SE = 2.8, F(1151.1)  = 66.1, P < 0.001). However, there was no statistically significant difference between groups for change in percentage of days abstinent over the 12-week study period [absolute difference 1.3% (-9.1 to 1.7%), F(1152.6)  = 0.005, P = 0.95]. SECONDARY OUTCOMES: Of subjects who completed the first 4 weeks of the study, 8.9% (15 of 168) achieved complete abstinence; 10.1% (nine of 89) in the placebo group and 7.6% (six of 79) in the baclofen group [χ2(1)  = 0.33, odds ratio (OR) = 0.73 (0.24-2.15)]. The percentage of no heavy drinking for all subjects between weeks 4 and 12 was 20.2% (34 of 168), but no statistically significant differences were found between placebo 15.7% (14 of 89) and baclofen 25.3% (20 of 79) [χ2(1)  = 2.38, OR = 1.82 (0.85-3.90)]. There were significant reductions for all subjects in all other secondary variables over the course of the study, but no differences between groups. Measures of various biomarkers of alcohol use did not change significantly throughout the course of the study for either the baclofen or placebo groups. CONCLUSIONS: Baclofen administered at 30 mg/day does not appear to be superior to placebo in increasing abstinence or in reducing alcohol use, cravings for alcohol or anxiety among people with alcohol use disorder.

Effects of a multifaceted implementation intervention to increase utilization of pharmacological treatments for alcohol use disorders in the US Veterans Health Administration.

Over 16 million Americans meet diagnostic criteria for alcohol use disorder (AUD), but only 7.8% of them receive formal treatment each year. Safe and effective pharmacological treatments for AUD exist; however, they are rarely prescribed. Therefore, we developed and pilot tested a multifaceted implementation intervention to improve consideration and receipt of effective pharmacologic treatments for AUD, focusing on primary care settings where patients have the most frequent contact with healthcare systems. The intervention included training of local providers to serve as champions and a website for primary care providers that included educational materials, a case-finding dashboard, and contact information for local and national clinical experts. We also mailed patients educational material about treatment options. The intervention was implemented at three large facilities of the Veterans Health Administration (VHA). An interrupted time series design, analyzed with segmented logistic regression, was used to evaluate the intervention's effects. The odds of a patient with AUD receiving one of the AUD medications was increasing throughout the pre-implementation period, and the rate of change (slope) increased significantly in the implementation period. Translating these numbers into percentages, at baseline 2.9% of patients filled a prescription for an AUD medication within 30days of a primary care visit. This increased to 3.8% by the end of the pre-implementation period (increasing 0.037% per month), and increased to 5.2% by the end of the implementation period (increasing 0.142% per month). However, the intervention effect was not significant when control sites were added, suggesting that improvement may have been driven by secular trends rather than solely by this intervention. Although the intervention was feasible, it was not effective. Continued analysis of process and implementation data including qualitative interviews with key stakeholders, may elucidate the reasons this intervention was not successful and ways to strengthen its effects.

Organizational change in management of hepatitis C: evaluation of a CME program.

INTRODUCTION: Effective treatment regimens exist for the hepatitis C virus (HCV); however, clinicians are often resistant to evaluation or treatment of patients with alcohol or substance abuse problems. We describe a continuing medical education (CME) program for clinicians in a nationwide health care system, with emphasis on current treatment practices, multispecialty collaboration, and organizational change. METHODS: Quantitative measures were used to assess changes in knowledge and treatment confidence, and site-specific organizational changes were qualitatively evaluated. The CME program included a preassessment of current HCV knowledge and care; a 2-day preceptorship; and follow-up with coaching calls at 1, 3, and 6 months. Program attendees included 54 medical and mental health providers from 28 Veterans Affairs Medical Centers. RESULTS: Knowledge following the CME program increased significantly. In 93% of the sites, there were organizational changes such as HCV support group-initiated group education, in-service training, improvement in patient notification or scheduling processes, hiring of new clinical staff, development of a business plans, and discussions about changes with administration. Of all sites, 15 (54%) changed existing antiviral treatment protocols, 18 (64%) established collaborative relationships, and almost half (13/28) established regular use of depression and alcohol use screening tools. Major barriers to change included lack of administrative support or resources (or both) and difficulty collaborating with mental health colleagues. DISCUSSION: This multifaceted CME program with follow-up coaching calls significantly increased individual knowledge and confidence scores and resulted in improved clinic processes and structures. Organizational change was facilitated by the development of an action plan. The major change agent was a nurse; the primary deterrent was an administrator.

Outcomes of Citalopram Dosage Risk Mitigation in a Veteran Population.

OBJECTIVE: A public safety communication issued by the Food and Drug Administration declared that citalopram dosages exceeding 40 mg/day were no longer considered safe because of a newly recognized risk of dosage-dependent QT interval prolongation. The authors compared the incidence of hospitalizations and mortality when higher dosages of citalopram were or were not reduced to ≤40 mg/day. METHOD: National electronic medical records compiled by the Veterans Health Administration were used to conduct a retrospective study of a population filling citalopram prescriptions for more than 40 mg/day when the safety communication was first issued in August 2011. Hospitalizations and mortality after dosages of citalopram were or were not reduced to ≤40 mg/day were compared using multivariable Cox regression. RESULTS: The at-risk cohort of 35,848 veterans (mean age, 58 years [SD=11]; 92% male) had citalopram prescriptions for 64 mg/day (SD=8.3), on average. Within 180 days after the safety communication was issued, 60% had filled prescriptions for ≤40 mg/day. All-cause hospitalizations or deaths were found to significantly increase after dosage reductions (adjusted hazard ratio=4.5, 95% CI=4.1-5.0), as were hospitalizations for depression or all-cause death (adjusted hazard ratio=2.2, 95% CI=1.8-2.6). Mortality did not decline (adjusted hazard ratio=1.0, 95% CI=0.8-1.3), and neither did hospitalizations for arrhythmias or all-cause deaths (adjusted hazard ratio=1.3, 95% CI=1.0-1.7). CONCLUSIONS: Reduction of prescribed citalopram dosages to a new safety limit was associated with a higher rate of hospitalization in a large patient population who had been treated with substantially higher dosages. Stipulating a safety limit for citalopram dosages before the benefits and risks of doing so were firmly established appears to have had unintended clinical consequences.

Enhancing access to alcohol use disorder pharmacotherapy and treatment in primary care settings: ADaPT-PC.

BACKGROUND: Only 7.8 % of individuals meeting diagnostic criteria for alcohol use disorder (AUD) receive treatment in a given year. Most individuals with AUDs are identified in primary care (PC) settings and referred to substance use disorders (SUD) clinics; however, only a minority of those referred attend treatment services. Safe and effective pharmacological treatments for AUD exist, but they are rarely prescribed by PC providers. The objective of this study is to refine, implement, and evaluate an intervention to integrate pharmacological AUD treatment options into PC settings. This paper provides a detailed description of the intervention design and the evaluation components. METHODS/DESIGN: Three large Veterans Health Administration (VHA) facilities are participating in the intervention. The intervention targets stakeholder groups with tailored strategies based on implementation theory and prior research identifying barriers to implementation of AUD pharmacotherapy. Local SUD providers and primary care mental health integration (PCMHI) providers are trained to serve as local implementation/clinical champions and receive external facilitation. PC providers receive access to consultation from local and national clinical champions, educational materials, and a dashboard of patients with AUD on their caseloads for case identification. Veterans with AUD diagnoses receive educational information in the mail just prior to a scheduled PC visit. Effectiveness of the intervention will be evaluated through an interrupted time series with matched controls to monitor change in facility level AUD pharmacotherapy prescribing rates. Following Stetler's four-phase formative evaluation (FE) strategy, FE methods include (1) developmental FE (pre-implementation interviews with champions, PC providers, and Veterans), (2) implementation-focused FE (tracking attendance at facilitation meetings, academic detailing efforts by local champions, and patient dashboard utilization), (3) progress-focused FE (tracking rates of AUD pharmacotherapy prescribing and rates of referral to PCMHI and SUD specialty care), and (4) interpretive FE (post-implementation interviews with champions and PC providers). Analysis of FE data will be guided by the Consolidated Framework for Implementation Research (CFIR). DISCUSSION: If demonstrated to be successful, this implementation strategy will provide a replicable, feasible, and relative low-cost method for integrating AUD treatment services into PC settings, thereby increasing access to AUD treatment.

Suicidal ideation during interferon-alpha2b and ribavirin treatment of patients with chronic hepatitis C.

Psychiatric and substance use disorders affect most patients with chronic hepatitis C and are the most common reasons for exclusion from antiviral therapies. Suicidal ideation (SI) is often cited as a reason to exclude patients from interferon-based treatment or to terminate antiviral treatment that is in progress. This study examines SI in hepatitis C patients untreated and treated with interferon-alpha2b, a medication commonly associated with depression. Fifty-five subjects with chronic hepatitis C were followed for 24 weeks with three measures of depression, each containing one item assessing SI. A total of 15/55 (27%) subjects reported SI while not on interferon therapy. Of the 42 patients treated with interferon, 18 (43%) endorsed SI at some point during antiviral treatment. However, 17/18 (94%) finished at least a 6-month course of interferon therapy. No subjects attempted suicide. Although SI in some form is common in hepatitis C patients, in most cases it is mild in nature. With adequate support most patients can successfully complete a full course of antiviral treatment.

Are selective serotonin reuptake inhibitors associated with hepatocellular carcinoma in patients with hepatitis C?

BACKGROUND AND AIMS: Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for patients with chronic hepatitis C virus (HCV) infection. Research suggests that serotonin promotes the development and growth of hepatocellular carcinoma (HCC). We tested the hypothesis whether exposure to SSRIs is associated with an increased risk of HCC in HCV patients. METHOD: Patients who entered the United States Veterans Affairs (VA) Hepatitis C Clinical Case Registry in 2000 to 2009 were analyzed. During the 8 years of follow-up, 36,192 patients filled at least 1 SSRI prescription. Cases of HCC were identified by diagnosis codes (ICD-9 155.0). Multivariable Cox regression analyses estimated adjusted HCC hazard ratios (HRs) for SSRI-exposed versus SSRI-unexposed subjects and categories of average SSRI doses. RESULTS: The annual incidence of HCC in the VA registry cohort of 109,736 patients was 0.5% and significantly greater in the 8% with cirrhosis at baseline (HR = 5.2; 95% CI, 4.7-5.7). There was no evidence for significant interactions between the effect of SSRI-exposure and cirrhosis. Baseline characteristics of the exposed (n = 36,192) and unexposed (n = 73,544) subjects were similar. The median (interquartile range [IQR]) follow-up period after SSRI-exposure began was 44 (20-74) months with 18 (3-49) months between the first and last prescription. The median average SSRI dose during follow-up expressed as a fraction of initial recommended doses for depression was 0.94 (IQR, 0.5 to 1.3). The risk of HCC was not significantly increased after SSRI exposure (HR = 0.96; 95% CI, 0.87-1.05) or with increasing SSRI doses. CONCLUSIONS: Analysis of a large cohort of HCV patients did not support the hypothesis that SSRIs increase the risk of developing HCC.