alcohol meds decrease liver disease progression

 A recent data-mining study found that medical therapy for alcohol use disorder (AUD) was associated with both reduced incidence and progression of alcohol-associated liver disease (see alcohol rx dec progression ALD JAMA2022 in dropbox, or doi:10.1001/jamanetworkopen.2022.13014 )

Details:

-- cohort study from the MassGeneralBrigham Biobank, which had recruited 127,480 patients from 2010 until 2021, assessing the use of medical addiction therapy for AUD (disulfiram, acamprosate, naltrexone, gabapentin, topiramate, or baclofen)

-- 9638 patients had AUD: 60% male, mean age 55, 83% white/5% Black, BMI 29, viral hepatitis 13%, history of homelessness 10%, receipt of psychotherapy 39%, history of psychiatric disorder 85%, nicotine dependence 44%, non-alcoholic substance use disorder 37%

    -- 1135 patients (11.8%) had alcohol-associated liver disease (ALD), and 3906 patients (40.8%) were treated with medical addiction therapy (MAT)

-- the definition of ALD included the usual ICD-10 culprits; they did not include alcoholic fatty liver, since its clinical significance regarding liver-related morbidity and mortality is unclear (eg, see https://pubmed.ncbi.nlm.nih.gov/32073504/ )

-- the results below were statistically adjusted for demographics (age, sex, race/ethnicity), history of homelessness, individual psychiatric disorders, nonalcohol substance use disorders, psychotherapy, concurrent liver diseases (hepatitis B or C, nonalcoholic steatohepatitis, obesity, primary sclerosing cholangitis, primary biliary cholangitis, autoimmune hepatitis, chronic passive liver congestion, alpha-1 antitrypsin deficiency, or hemochromatosis)

-- patients were included if they had at least three prescriptions of a MAT for AUD

-- median follow-up from AUD diagnosis was 9.2 years (9.8 years in those treated with medications and 8.8 years in the untreated group); and for those with a diagnosis of cirrhosis, 7.8 years in those on treatment and 8.6 for the untreated group

-- mean duration of therapy was 4.1 years

-- main outcomes measure: the adjusted odds ratios (aOR) for the development of alcohol-associated liver disease (ALD), and hepatic decompensation

Results:

-- odds of developing ALD after MAT, in multivariate analysis:

    -- any pharmacotherapy: adjusted OR 0.37 (0.31- 0.43), p<0.001 for MAT benefit

    -- naltrexone: aOR 0.67 (0.46-0.95), p=0.03 for benefit

    -- disulfiram: aOR 0.86 (0.43-1.61), nonsignificant

    -- acamprosate: aOR 2.59 (1.84-3.61), p<0.001 for harm

    -- gabapentin: aOR 0.36 (0.30-0.43), p<0.001 for benefit

    -- topiramate, aOR 0.47 (0.32-0.66), p<0.001 for benefit

    -- baclofen, aOR 0.57 (0.36-0.88), p=0.01 for benefit

-- and there was a dose-response curve: each year of treatment was associated with reduced likelihood of developing ALD, with hazard ratio 0.97 (0.95-0.99), p=0.04

-- odds of developing hepatic decompensation after MAT:

    -- any pharmacotherapy: aOR 0.35 (0.23-0.53), p<0.001 for benefit

    -- naltrexone: aOR 0.27 (0.10-0.64), p=0.005 for benefit

    -- disulfiram: aOR 2.59 (0.54-13.26), nonsignificant

    -- acamprosate: aOR 1.99 (0.99-4.06), strong but statistically nonsignificant trend for harm

    -- gabapentin: aOR 0.36 (0.23-0.56), p<0.001 for benefit

    -- Topiramate: aOR 0.43 (0.17-0.99), p=0.05 for benefit

    -- baclofen, aOR 1.06 (0.39-2.69), nonsignificant

-- in those who had cirrhosis and were treated with medications, the first decompensation occurred a median of 5.1 years after beginning the therapy

--Odds of hepatic decompensation in patients with established cirrhosis:

    -- similar to results for overall hepatic decompensation after MAT,  aOR 0.41 (0.23- 0.71), p=0.002

the above graphs show that the effect of MAT persisted over 10 years of follow-up, and that the mean time to decompensated liver disease was much longer with treatment

Commentary:

-- as a background, alcohol-associated severe liver disease has a three-month mortality of 30%

-- the relevance of this study is increased during our Covid pandemic, with the attendant increased alcohol consumption

-- one baseline very major concern is that medications are prescribed quite infrequently for those with AUD: a study in 2019 found that among 14.5 million people age 12 and older, only 7.6% (1.1 million people) receive treatment for their alcohol use and 1.6% (228,000) received medication-assisted treatment, See https://www.samhsa.gov/data/sites/default/files/reports/rpt29393/2019NSDUHFFRPDFWHTML/2019NSDUHFFR090120.htm#tx5

-- the FDA has approved disulfiram, acamprosate, and naltrexone for the treatment of AUD, though there has been reasonably wide use of gabapentin, topiramate, and baclofen off-label. and, this study notably found that the latter 3 drugs actually did better....

-- this current study adds to our information by its very large database, as well as its long-term follow-up. In terms of the off-label medications, it should be noted that many medications are used appropriately off-label. Drug companies may not have particular interest in funding expensive studies to document benefit in medications that already are on the market and FDA-approved for other indications, especially if they are available as generics. but, without rigorous studies and going through the somewhat daunting approval process, the FDA is unlikely to approve the medications for those other indications

--It was curious why acamprosate did so poorly in the above analysis (especially in light of http://gmodestmedblogs.blogspot.com/2021/05/alcohol-meds-for-abstinence.html), but a few thoughts:

    -- acamprosate Is generally used more often in patients with more advanced liver disease, given its hepatic safety profile; naltrexone is contraindicated in those with severe liver disease. and it is quite possible that people felt to be at high risk of developing ALD were less likely to be put on acamprosate by their clinicians

    -- and acamprosate might have been used later in the course of AUD when the patients had more severe disease and a worse prognosis

    -- acamprosate also is a much more complex therapeutic regimen with multiple pills taken three times a day, as opposed to many the other medications being once or twice a day. There is an argument that many people with AUD think about alcohol often during the day and 3 times day medications may actually be better, but this may not have been the case in this overall group of patients. And many patients on more complex regimens may need more intensive support systems/reminders. The above study does not give enough info on that, but perhaps with more phone calls or visits, these patients might have done a lot better: there may need to be just more comprehensive support systems available to people on more complex drug regimens in order for them to work, with more outreach, visits to counselors/nurses/etc

    -- as an example of actual selection bias: acamprosate in the practice of the authors of this study "is reserved for use in patients with more severe AUD"

        --In this light, it was notable that patients with established cirrhosis did quite well on naltrexone, and perhaps naltrexone should be reconsidered for those with more advanced liver disease in future studies

    -- acamprosate Is also used more often in those with an accompanying opioid use disorders since naltrexone is contraindicated for that. And these patients with multiple substance use disorders may be fundamentally different and have different prognoses from those with only AUD (no data in this study on that)

-- and, why did gabapentin do so well (despite my proclivities against it, eg see http://gmodestmedblogs.blogspot.com/2020/01/fda-warning-gabapentinoids-and.html)?

    -- it is anxiolytic, and some people drink to quell anxiety

    -- it can be combined with naltrexone with some evidence of improved effectiveness over naltrexone alone, and it may also help with insomnia (another potential reason to drink): see https://www.ccjm.org/content/86/12/815.long

        -- these issues might show benefit for gabapentin in this study, but perhaps other meds targeting anxiety or insomnia might work even better??

Limitations:

-- this was an observational study based on a large database. There is not a lot of granular information about some important issues, such as why certain individuals received their prescribed medications. Was there something in their history that led to these therapies, and this might bias their results?

-- though they did mathematically control for many demographic variables, the fact that there was a predominance of middle-aged white men might limit generalizability to other groups; also, such a high percentage had reported psychiatric conditions, this might also limit generalizability. as well as the limited geographical/cultural area involved.

-- there is no information on the number of patients in these different MAT subgroups for any of these analyses in either the article or the supplement. This might affect the validity of their conclusions. For example, the analyses cited above with very large confidence intervals may reflect just small numbers of patients and not true effects

-- no information about whether people continued to drink, or if there were different risks associated with those achieving cessation versus continuing to drink. We do know from prior studies that many of these medications do decrease drinking but are less likely to lead to full abstention (see http://gmodestmedblogs.blogspot.com/2014/06/meds-for-alcohol-relapse.html)

so, this very large study provides some important insight into MAT for alcohol use disorder:

-- it is dramatically underused (though used more in this study population than overall in the US)

-- it seems to have a significant benefit in decreasing the incidence of alcohol-associated liver disease

-- and, this seems to be even true in decreasing hepatic decompensation in those with cirrhosis, even if initiated after the diagnosis of cirrhosis

-- bottom line: it is really important for us clinically to find out if a patient has an alcohol use disorder, and if so to engage them in therapy, including counseling, support groups but also medications which really do help

geoff

 

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