Ann Robinson’s journal review—12 June 2019

Ann Robinson reviews the latest research from the top medical journals


Improving exercise tolerance in heart failure

Here is news of a drug that doesn’t work. Neladenoson bialanate (a partial adenosine A1 receptor agonist) failed to improve exercise capacity in patients with heart failure and preserved ejection fraction (HFpEF). This phase 2b randomised clinical trial was designed to confirm clinical efficacy and the therapeutic dose range of this novel drug: 305 patients were randomised to receive different doses of neladenoson or placebo. The authors were looking for an improvement in the six minute walk test, which measures how far you can walk in six minutes, but unfortunately this drug didn’t yield any improvement. “Novel approaches will be needed if further development of neladenoson for the treatment of patients with HFpEF is pursued,” say the authors.

Young stroke survivors—how do they fare?

What is the fate of people who have a stroke at a relatively young age? This large, community based, Dutch cohort study of 15 257 people who had a first stroke aged 18-49 years found that 11.6% of patients died within the first month. The risk of death in the first month was higher after intracerebral haemorrhage than after ischaemic stroke (case fatality 32.3% v 7.4%); possibly because treatment options for intracerebral bleeds remain more limited than for ischaemic stroke and more minor ischaemic strokes are diagnosed as a result of better imaging. Of the survivors, the 15 year mortality was 17%—an excess mortality rate of 19.6/1000 person-years compared with the rest of the population.  Most of the patients had apparently been well before their stroke, with 83.9% having no recorded comorbidity (though a limitation of this study is incomplete data on confounders and risk factors). I was surprised that the single main cause of death was cancer (32.7%) rather than stroke related (15%) or due to other cardiovascular disease (17%). A mix of trauma, infection, and other causes accounted for the other 34.9%. The reason why these young stroke survivors had higher rates of cancer and cardiovascular disease than the general population of the same age cannot be explained by this study, but the authors speculate that “underlying risk factors and causes of stroke continue to expose patients to new events throughout the rest of their lives.”


The fight against malaria: no benefit from adding azithromycin

The antibiotic azithromycin was used to great effect in Ethiopian children with trachoma, leading to a sustained reduction in all-cause mortality. Does adding azithromycin to the seasonal malaria chemoprevention regimen (monthly sulfadoxine-pyrimethamine plus amodiaquine) have a similar impact on mortality and morbidity? A previous trial had suggested that it might, but in this randomised, placebo controlled study undertaken in Burkina Faso and Mali adding azithromycin to antimalarial prophylaxis did not lower mortality or hospital admissions for any reason other than trauma or surgery, although it did reduce the number of clinical visits with gastrointestinal and respiratory illnesses. Malaria remains a major challenge in this area; chemoprevention is effective, but, even among this trial group—who had good access to treated bed nets, chemoprevention, and treatment—the proportion of deaths and hospital admissions due to malaria was high. Adding azithromycin isn’t the answer; let’s hope the malaria vaccine being trialled in Malawi bears fruit.

Is intensive diabetes therapy better than routine?

Intensive glucose lowering for median 5.6 years compared to standard treatment has been shown to lower the risk of major cardiovascular events by 17% after a total of 10 years of combined intervention and observational follow-up in 1791 US military veterans. A new study looks at whether this benefit is sustained after a further 5 years of follow up. During this trial, the glycated haemoglobin levels averaged 1.5 percentage points difference between the intensive and standard treatment groups (target glycated hb 8-9%). Three years after the trial ended, this difference had shrunk to less than 0.3 percentage points. The risks of major cardiovascular events or death were no lower in the intensive-therapy group than in the standard-therapy group after 15 years of follow up (10 years of active treatment and 5 years of follow up). “There was no evidence of a legacy effect or a mortality benefit with intensive glucose control,” say the authors.

This runs counter to the results in other well designed trials (recently diagnosed type 1 diabetes in the Diabetes Control and Complications Trial [DCCT] and new-onset type 2 diabetes in the United Kingdom Prospective Diabetes Study [UKPDS].)  The participants in this trial were older so may have more advanced cardiovascular disease and may have been more likely to be on statins and antihypertensive medication than those in earlier trials. “It is plausible that the cardiovascular protective effects of tight glycemic control have diminishing returns once other cardiovascular disease risk factors are well controlled by medications that may also have vasoactive properties,” say the authors. This type of post-trial follow-up is observational, didn’t look at microvascular complications such as retinopathy and doesn’t rule out the possibility that an even longer period of intensive therapy may give long-term benefits. But it’s something to think about when considering how far to go in pursuing ever lower glucose levels in our older patients.

Annals of internal medicine

Secret shoppers shop buprenorphine prescribers in the US for poor service

In the US, opioid use disorder has become a national priority and buprenorphine–naloxone (“buprenorphine”) treatment can help managed withdrawal. But with registered prescribers in limited supply and many barriers to accessing treatment,  how easy is it to get hold of? I am not convinced how statistically robust it is, but I like the idea of a “secret shopper” audit in which callers contacted 546 publicly listed buprenorphine prescribers twice, posing as uninsured or Medicaid-covered heroin-users and asking for buprenorphine treatment in six states with high opioid use disorder-related mortality rates. Callers recorded a 78% response rate from clinicians, over half of callers were given an appointment (54% of Medicaid vs 62% of uninsured) with around half of those offered the possibility of buprenorphine at that first visit (27% of Medicaid vs 41% of uninsured). Many callers couldn’t get an appointment at all, although those that were offered were generally within a week, and even fewer could get buprenorphine. The problem of access to healthcare in the US is, yet again, well illustrated in this group although there’s no room for complacency in the UK where opioid use disorder is a growing problem and the availability of buprenorphine was threatened last year by price rises and supply problems.  


Gallstones: does better selection for cholecystectomy improve outcome?

This non-inferiority Dutch study (SECURE) asks whether careful selection of patients with uncomplicated, symptomatic gallstones is any worse than current practice. Most surgical studies compare different operations, but this one asks whether better patient selection can improve outcomes. At present, there is no international consensus on criteria for patient selection and surgeons show great variation in practice between and within countries. High rates of post-cholecystectomy pain in up to 41% of patients, suggest that not everyone benefits from the operation. The trial compared pain reduction in patients who were only offered cholecystectomy if they fulfilled the Rome criteria of biliary colic (restrictive strategy) with those in which the doctor’s experience and patient’s preference guided treatment (usual care.) The restrictive strategy resulted in 7.7% fewer operations, but the issue of post-cholecystectomy pain remained a problem in both groups. Only 63% of both groups were pain free at 12 months. Following specific criteria doesn’t seem to be the answer; perhaps we are over-diagnosing symptomatic gallstones or underestimating the effect that cholecystectomy has on metabolic function? A better algorithm for the management of upper abdominal pain is in development and is sorely needed.


Stress urinary incontinence—what options do women have?

This network meta-analysis looked at the clinical effects and safety of all evidence-based surgical interventions for the treatment of women with stress urinary incontinence.  It allowed comparison of any pair of surgical procedures under consideration, including those that were not directly compared in clinical trials. The authors say that the quality of much of the evidence available is moderate to very poor with inconsistent details of symptom severity, trial methodology, adverse events and standard outcome measures and a high risk of bias. It appears that in the first year after surgery retropubic mid-urethral sling (MUS) using a narrow strip of synthetic mesh, transobturator MUS, traditional sling, and open colposuspension seem to be more effective than other surgical procedures such as anterior vaginal repair. But comparative safety data and long term effectiveness remain unclear and the safety of vaginal mesh for prolapse or incontinence has come under fierce scrutiny, prompting the NHS to “pause” its use since July 2018.  Women may now opt for older procedures like colposuspension which might be less safe and effective and surgeons have become de-skilled in performing in the years that meshes have held sway. Urethral bulking agents are thought to be safe and moderately effective but were not included in this study because there are no randomised controlled trials. So where does this leave women who urgently need a solution to their stress incontinence? It’s a complex minefield to navigate; long term evidence on safety and efficacy of all the options are badly needed.

Ann Robinson is an NHS GP and health writer and broadcaster