Alex Nowbar’s weekly journal review—24 January 2020

Alex Nowbar reviews the latest research from the top medical journals.

Annals of Internal Medicine

SGLT2 inhibitors and gout protection

Fralick et al conducted a cohort study of almost 300 000 patients in the US with type 2 diabetes looking at rates of gout. To assess the risk of gout in users of sodium-glucose cotransporter 2 (SGLT2) inhibitors, they chose a comparator group of users of glucagon-like peptide-1 (GLP-1) agonists. This isn’t unreasonable as both drugs are in a similar standing in the pathway of treatment escalation. However, there will be differences in characteristics between the users of one drug and the users of the other drug because this isn’t randomised data. Propensity score matching counteracts this but never completely resolves the issue of confounding. Fralick et al found that SGLT2 inhibitors were associated with lower rates of gout than GLP-1 agonists. The theory is that SGLT2 inhibitors reduce serum uric acid levels. While this protective effect is a positive finding, it is slightly misleading to consider gout in isolation. Both drugs, and indeed diabetes itself, carry various risks and benefits that can’t easily be weighed up. 

Rage against the machine

Overhage et al (who have declared financial ties to electronic health record provider Cerner) analysed time spent on Cerner covering 100 million patient encounters by 155 000 physicians from 417 health systems. They report that “physicians spent an average of 16 minutes and 14 seconds per encounter using [electronic health records], with chart review (33%), documentation (24%), and ordering (17%) functions accounting for most of the time.” This is a lot of time but not surprising. We have no measure of how we used to spend time on these tasks before electronic systems were implemented. Naturally it would be desirable to reduce time spent on the electronic health record. If you were looking to solve this, you might focus on the chart review time, but this is also clinician thinking time. This is when the clinician is processing information and even planning the consultation. This is not necessarily modifiable. The paper does a good job in laying the groundwork for Cerner to present us with some solutions or improvements, but I won’t be holding my breath.

JAMA Internal Medicine

More antiplatelet drama

I don’t quite know how ticagrelor wriggled into a leading position in treating acute coronary syndrome, but it did well to hang onto this given its bad press on bleeding rates compared with clopidogrel. This Canadian cohort study of patients with acute coronary syndrome who underwent percutaneous coronary intervention questions the position of ticagrelor. No observational data can negate the results of the randomised controlled trials that placed ticagrelor above clopidogrel, but there are few points from this study worth noting. Turgeon et al found that ticagrelor did not reduce major adverse cardiovascular events more than clopidogrel, but ticagrelor had higher rates of major bleeding and more emergency department visits for dyspnoea. I am sure many will call for a return to clopidogrel, but I’m not sure these observational data warrant this although the sample size (over 11,000 patients) does carry some weight. 

Treating overactive bladder in men

This US trial randomised 204 men to behavioural therapy, drug therapy or both for six weeks followed by six weeks of both for all groups. The participants completed bladder diaries looking particularly at urinary frequency. Combined therapy was better than drug therapy alone, but not better than behavioural therapy alone. This finding is fascinating, but slightly limited by the open-label nature of the study. While these data clearly support starting with behavioural therapy, the longevity of the benefits of behavioural therapy versus drug therapy hasn’t been explored. The other issue is that randomised participants will differ from the true population with the condition in many ways. By providing consent to participate, the participants demonstrate that they are perhaps more willing to undertake and adhere to behavioural therapy than those that did not consent. However, only 12 people were listed as declining to participate. That’s a 95% acceptance rate. Sorry for my cynicism but that seems implausible. Presumably they didn’t approach people who had already given some indication of lack of interest or they didn’t record that they approached more people than this. 


Lupus outcomes in the limelight

Systemic lupus erythematosus has very varied clinical manifestations, making assessment of therapeutic success challenging. The TULIP-2 trial is a lesson in endpoint selection. The TULIP-2 trial randomised 365 people with lupus to anifrolumab or placebo in a double-blind fashion. The primary endpoint was the BICLA, which is a composite of seemingly patient-centred outcomes. You either “responded” as measured by BICLA or you didn’t: 47.8% of patients in the anifrolumab group responded compared with 31.5% in the placebo group. This could be good news for patients. The new drug comes with an added risk of herpes zoster, but otherwise appeared safe in this sample. The benefit seen here contrasts with a previous anifrolumab study (TULIP-1), in which the drug showed no benefit as measured by Systemic Lupus Erythematosus Responder Index (another composite of patient-centred outcomes). So do we believe the anifrolumab is a useful drug? I’m going to go out on a limb to say, yes, I believe. That should save another fairy.


Real world prostate cancer outcomes

People like the idea of real world data for its tangibility even though it tells us next to nothing about the comparative efficacy of an intervention. Of course there aren’t randomised controlled trials for everything. Hoffman et al performed a prospective and comprehensive cohort study of 1386 men with prostate cancer. They looked at patient-reported function at 5 years, in particular sexual function and urinary and bowel symptoms. The focus was on how different treatment options (e.g. prostatectomy or brachytherapy or active surveillance) related to subsequent function. The obvious limitation of this study is confounding because whatever features led men to receive a particular treatment could be the same factors that contribute to the functional outcome rather than the treatment itself making the difference. But since a proper trial in this space is lacking, some feel there is value in the observational data. The clearest finding was that prostatectomy was associated with worse incontinence at 5 years, but they also found no difference in general in functional outcomes depending on treatment option as any differences had attenuated by the end of 5 years. The authors hope these data will better inform risk discussions between clinicians and patients, but I would be reluctant to base the decision of whether or not to have a prostatectomy on this study.

New thromboprophylactic after knee arthroplasty

The phase II FOXTROT trial randomised over 800 people undergoing knee arthroplasty to osocimab, enoxaparin, or apixaban in an open-label fashion and measured incidence of venous thromboembolism. Bilateral venography was compulsory at 10-13 days after surgery, thereby allowing the detection of subclinical venous thromboembolism. Osocimab is a monoclonal antibody against factor XIa. The main finding of the trial was that osocimab was non-inferior to enoxaparin. An interesting aspect of this trial, however, was not only the testing of various doses, but also the testing of preoperative and postoperative administration of the new drug. Bleeding rates were not negligible in the highest dose, particularly in the preoperative dosing regimen, leaving a few attractive dosing options, but further work is required.


Trial reporting not up to scratch

DeVito et al used the database to assess compliance with the FDA regulation to report results within a year of trial completion in the US. Only 40.9% reported results within one year, and 63.8% of trials posted results at any time. Interesting findings included better reporting rates for industry sponsors and for sponsors running large numbers of trials. I applaud the authors for their rigorous analysis and spotlight on a critical deficiency in clinical research, but I object to them throwing the book at regulators. The roots of failure to report clinical trials run deep in academia. Enforcement of regulation doesn’t actually help overcome the barriers to reporting. While this study reports factors associated with better reporting rates, data on why the unreported trials remain unreported are not available. There needs to be a carrot to incentivise good practice rather than the stick of public shaming.

Alex Nowbar is a clinical research fellow at Imperial College London

Competing interests: None declared