Ann Robinson’s research reviews—29 October 2021

Non-alcoholic fatty livers: is drug treatment on the horizon?

Levels of non-alcoholic steatohepatitis (NASH), which can progress to fibrosis and cirrhosis, are rising in parallel with the increase in obesity and diabetes. Apart from lifestyle measures such as weight loss, there are no specific drug treatments. In this phase IIb trial, patients with non-cirrhotic, highly active NASH were randomised to receive 1200 or 800 mg of lanifibranor (an agonist that modulates key pathways in the pathogenesis of NASH) for 24 weeks or placebo. Those receiving 1200 mg showed significant improvement in a composite score of histological NASH activity (SAF-A score) compared with those on the lower dose or placebo. Lanifibranor at both doses improved resolution of NASH without worsening of fibrosis compared with placebo (49% and 39%, respectively, v 22%). There were more adverse effects such as diarrhoea and nausea with the active drug than with placebo, but no difference in the drop-out rates (around 5% in all groups). A larger, longer phase III study including a more diverse population is now needed.

N Engl J Med doi:10.1056/NEJMoa2036205

Tread carefully with tramadol

This large Spanish retrospective cohort study found that a new prescription (not issued in the previous year) of tramadol was significantly associated with a higher risk of all-cause mortality (hazard ratio 2.31), cardiovascular events (hazard ratio 1.15), and fractures (hazard ratio 1.5) compared with a matched cohort who were prescribed codeine. There was no significant difference in the risk of constipation, delirium, falls, opioid misuse or dependence, or sleep disturbance. Despite the use of propensity score matching (a statistical technique that uses artificial control groups to estimate the impact of an intervention), there was a real risk of residual confounding, so the results need to be interpreted with caution. Tramadol is widely and increasingly prescribed for chronic non-cancer pain and was considered to be a relatively safe alternative to other opioids when it was introduced, but this study suggests that we should tread carefully.

JAMA doi:10.1001/jama.2021.15255

Patchy evidence about smoking cessation treatment

In this flawed trial of 1251 smokers (>5 cigarettes a day), treatment with varenicline (a selective nicotine receptor partial agonist) alone or in combination with a nicotine patch for 12 or 24 weeks made no difference to the quit rate at 52 weeks (around 25% for all groups). All participants received cessation counselling before being randomised to one of the groups. The endpoint of abstinence from smoking at 52 weeks relied on self reported data confirmed by biochemical testing in most but not all participants. There was a high attrition rate (23% of the sample was lost to follow-up, and 9% withdrew) so this study is hardly a game changer. It does mean that bigger, better studies are needed to clarify the optimal type and duration of treatment to encourage smokers to quit forever.

JAMA doi:10.1001/jama.2021.15333

Mirtazapine doesn’t help agitation in dementia

People living with dementia commonly experience agitation, which is distressing for them and their carers. Non-drug strategies are preferable but not always effective, and the sedative antidepressant drug mirtazapine is widely used instead of antipsychotic drugs, which are associated with harm. This small but important multicentre UK trial of 204 participants found that agitation scores at 12 weeks (using the Cohen-Mansfield Agitation Inventory, CMAI) didn’t differ significantly in patients given mirtazapine (titrated up to 45 mg) compared with placebo and raised a warning that there were more deaths in the mirtazapine group compared with placebo (7 v 1). This alarm bell needs to be treated with caution: the study wasn’t powered to investigate a mortality difference, and it could have been due to chance. But in the absence of any evidence of a benefit, it certainly needs to be taken seriously.

The trial was also due to investigate whether carbamazepine is effective, but covid-related difficulties in recruitment led to that line of inquiry being dropped. The authors stress the value of an individualised programme of investigation and management that incorporates social and psychological measures as well as drug treatment if needed.

Lancet doi:10.1016/S0140-6736(21)01210-1

“Onco-exceptionalism”: cancer drugs get fast tracked

A cross-sectional US study of 37 348 patients who received one or more of 44 new oral targeted cancer drugs found that the proportion of patients receiving drugs without documented overall survival benefit increased from 13% in 2011 to 59% in 2018, and accounted for 52% of the $3.5bn estimated cumulative spending on new oral targeted cancer drugs by the end of 2018. Surrogate endpoints are increasingly used instead of clear measures of longer and better quality of life, and methodological sloppiness is rife. “Our findings suggest that cancer drugs with major shortcomings in their evidence base are adopted in the health system and account for substantial spending,” say the authors. This thought provoking study may reflect the regulatory and economic characteristics of the US healthcare system. Yet it also resonates with claims of “onco-exceptionalism,” which sees access to cancer drugs fast tracked despite a lack of strong evidence of benefit to patients or value for money.

JAMA Intern Med doi:10.1001/jamainternmed.2021.5983

Ann Robinson is an NHS GP and health writer and broadcaster