Richard Lehman reviews the latest research in the top medical journals

NEJM  8 Feb 2018  
Et tu, apalutamide
“In this international, placebo controlled, randomised trial involving men with castration-resistant prostate cancer, the risk of metastasis or death was more than 70% lower with apalutamide than with placebo, and the median metastasis-free survival was more than 2 years longer (40.5 months vs. 16.2 months).” Now this is a really impressive effect size, and if apalutamide was first in a new class of anti-androgen non-steroidal drugs, it would be hailed as a breakthrough. But of course, it isn’t. The first drug in this class was flutamide (1983) and the standard since the late 1990s has been bicalutamide, which costs less than £10 per month in the UK. Apalutamide is a me-too drug and as such needs to prove its superiority over others in the class: but in this manufacturer funded study, it was compared with placebo rather than bicalutamide.

I searched for a justification in the accompanying review article on the management of prostate cancer but I couldn’t find any. But ethics approval was obtained in 26 countries, so I must be missing something.

Prazosin and the pale horse
In the years after 1945, the whole of Europe was in a state of post-traumatic stress disorder (PTSD). For years people would scream in the night but refuse to talk about what they had seen and experienced; and if you watch any recorded recollections about WWII the phrase “I still have nightmares about it” will always come up. In this trial, 304 modern day American service personnel with PTSD were given prazosin or placebo to alleviate disturbed sleep and reduce nightmares. Both were equally ineffective over six months. The “pale horse” I refer to is the night mare herself, as depicted by Fuseli in a series of paintings, which became a sensation in the early Gothic Revival period. (The original was painted in 1781, with later copies and variations, including William Blake’s Death on a Pale Horse).

JAMA  6 Feb 2018
PFOs and preventable flying objects
I recently read that one person in four has a hole between their right and left cardiac atrium with a flap that will open and let clot through if the circumstances are right. But in this cohort study from Massachusetts General Hospital, just 1% of the 150 000 patient cases analysed had a diagnosis of patent foramen ovale (PFO) before undergoing various kinds of non-cardiac surgery. In absolute terms, the incidence of perioperative stroke in patients with known PFO was 3.2% compared with 0.5% in those without a known PFO. But they were older, sicker, and on more medications. As with most things to do with PFOs, it is hard to know what to make of these new data. These people probably represented less than 5% of the total number with PFOs. Do we need better preoperative case finding and observation? Some kind of perioperative intervention? You’ll still be reading about this in 10 years’ time.

Getting the SPIRIT of a real PRO
Saint Paul wrote to the Corinthians that the letter killeth but the spirit giveth life (2 Cor 3.6). Patient reported outcomes contain the letter of what we might ask patients about the effect of care they receive, but it’s the spirit we do it in that matters. In particular, those conducting interventional research (clinical trials) need to put themselves in the shoes of the patients they enrol and find out what really matters to them. I’m delighted to find that myself in the University of Birmingham working with colleagues who really get this—and I hope their special communication in JAMA will reach the wide audience that it so much deserves. “The SPIRIT-PRO guidelines provide recommendations for items that should be addressed and included in clinical trial protocols in which PROs are a primary or key secondary outcome. Improved design of clinical trials including PROs could help ensure high-quality data that may inform patient-centered care.”  

JAMA Intern Med Feb 2018
Avoid ICDs in heart failure with renal impairment
About a third of people with the label of heart failure also carry the label of chronic kidney disease (CKD). These people also tend to be the poorliest and carry the highest risk of sudden cardiac death. Logic dictates that they are the ones who would benefit most from implantation of a cardiac defibrillator (ICD), provided they wish to. But logic is turned on its head by this large, Kaiser Permanente observational study of community based patients with heart failure and CKD. “ICD placement was not significantly associated with improved survival but was associated with increased risk for subsequent hospitalization due to heart failure and all-cause hospitalization. The potential risks and benefits of ICDs should be carefully considered in patients with heart failure and CKD.” I think I would rephrase that to read “Unless there is some compelling reason to believe an ICD might benefit a patient with HF and CKD, the offer should not be made. If it is, it should be carefully discussed with the use of a decision aid including these data.”

Ann Intern Med 6 Feb 2018
Scalding tea, alcohol, and smoking
It comes as no surprise that pouring inflammatory liquids down the gullet is a risk for cancer, or that smoking adds to the risk. Quantifying it is the difficult bit. Based on one time self reporting in 10 regions of China, those who drank burning hot tea and 15g or more of alcohol daily had the greatest risk for oesophageal cancer (hazard ratio 5.00), compared with participants who drank tea less than weekly and consumed fewer than 15g of alcohol daily. The hazard ratio for current smokers who drank burning hot tea daily was 2.03. It would be interesting to do similar surveys around the world, where tastes in hot caffeine drinks and alcohol vary considerably, but I think that the message is already fairly clear.

The Lancet 10 Feb 2018
The inhaler’s new particles
Chiesi pharmaceuticals have brought out a new inhaler with extrafine particles of beclometasone dipropionate, formoterol fumarate, and glycopyrronium. At 187 sites across 17 countries, they tested it against an inhaler delivering indacaterol plus glycopyrronium once daily as a dry powder, in people with moderate to severe chronic obstructive pulmonary disease. So they were comparing both the additional steroid and the type of particle delivered. It’s a baffling study design for a paper that has reached the Lancet, since there are too many variables to inform clinical practice. In the first year, moderate to severe exacerbation rates were 0.50 per patient per year for BDP/FF/G and 0.59 per patient per year for IND/GLY. Clinical significance? Your call. Statistical significance: p=0.043. After one year? Your guess.

Non-inferiority: lenvatinib vs sorafenib for liver cancer
“Non-inferiority trials only make sense if the experimental therapy is cheaper, more convenient, less invasive, or less toxic than the active control,“ wrote Vinay Prasad in a terrific editorial last month. Let’s try judging this latest non-inferiority trial by these four basic criteria. Lenvatinib versus sorafenib in first line treatment of patients with unresectable hepatocellular carcinoma.

So what are we trying to achieve here? Basically, an overall survival increase from nine months to something around a year. Now if I had 9-12 months to live I would want them to be as comfortable as possible. If I took sorafenib, I would stand a 50% chance of getting a painful rash on my extremities (palmar-plantar erythrodysaesthesia) and a 40% chance of diarrhoea. If I took lenvatinib, I would stand about an equal chance of getting diarrhoea but would avoid the risk of erythrodysaesthesia. Both drugs carry a risk of “hypertension,” which I would welcome since the kindest way for me to go would be a fatal stroke. So:

• Cheaper? No. Lenvatinib costs 4-5x as much as sorafenib in the UK
• More convenient? No real difference
• Less invasive? Both are oral drugs
• Less toxic? Yes

So this looks like a good starting point to design a shared decision tool. But remember that this should only ever be used if the patient definitely wants to know their prognosis and the treatment options. You must not force this knowledge or put the burden of decision making on them. Before anything else, the patient should be assured of your continued support and that of the palliative care team. And then they must know that the best any current treatment can provide is an average of about three months of extra life, with a near certainty of adverse effects. Think what you would do in this situation: but do not assume it is the same as everybody would. And remember that hepatocellular carcinoma is the third commonest cancer in the world, and that these options (including adequate symptom management) simply don’t exist for most of these 745 000 people dying.

The BMJ 10 Feb 2018
Trimethoprim: UK’s favourite renal toxin?
Here’s a study I’ve long wanted to see, examining the relation between trimethoprim prescribing, hyperkalaemia, acute kidney injury, and sudden death in over 64s, based on the UK Clinical Practice Research Datalink. I think most GPs are, or at least were, unaware of the risk of hyperkalaemia due to trimethoprim. Think of the last time you prescribed trimethoprim over the phone for a dipstick-diagnosed “UTI.” Did it occur to  you to check if she was taking enalapril or losartan or spironolactone? Did it occur to you to check her last potassium level? Well, next time, it should. Because in such patients there is an increased risk of acute kidney injury and hyperkalaemia. There might be for death too, though it was not apparent in this study, perhaps because of the limitations of the database.

Schools fail to curb kids’ obesity
In quite a full week, this strikes me as the best clinical trial in the main journals, and indeed one of the most important that The BMJ has published for a long time. I must declare the same interest as before: this too comes from colleagues in the Institute of Applied Health Research at the University of Birmingham. The subject could hardly be more important. Childhood obesity could become the largest threat to long term health across the world. For once I believe the hype, and I can’t see any simple solution. Nor could the Birmingham investigators, but they put all their energy and imagination into designing and testing a year long school based intervention—with the Aston Villa football club thrown in, for better or for worse. Alas, “the primary analyses suggest that this experiential focused intervention had no statistically significant effect on BMI z score or on preventing childhood obesity. Schools are unlikely to impact on the childhood obesity epidemic by incorporating such interventions without wider support across multiple sectors and environments.”

Plant of the Week: Helleborus foetidus
In days gone by, these handsome late winter plants were ungratefully known as dungworts or stinking hellebores. They are common natives in the woods of Oxfordshire, and indeed their leaves used to be harvested in Wychwood Forest by apothecaries from the great London hospitals, in order to poison patients with their abundant toxic glycosides.

We used to have plenty of them on the road banks around our house, but since we introduced oriental hybrid hellebores, all the stinkers seem to have sulked and disappeared. This is a pity because their pale green flowers, held high above the black-green cut leaves, are a very welcome sight in late winter. Most hellebores need to have their old leaves cut off before they flower, but these are best with them left on until afterwards.

The intrinsic poisons in all hellebore leaves are so powerful that they kill decomposing fungi and bacteria and ruin any compost heap they are put in. I used to burn them, though they produce very acrid smoke. Now I just put them in the brown recycling bin.