Richard Lehman’s journal review—8 December 2014

richard_lehmanNEJM 4 December 2014 Vol 371
2227 “We need to remember that these drugs also have toxic effects, they are enormously and inappropriately expensive, and they haven’t cured anyone yet. It is premature to be opening the victory champagne bottles.” Yes, this editorial refers to a new drug class for cancers—the ALK inhibitors. But it applies across the board for new cancer drugs, as I pointed out over the last month. Their average cost is just short of $10 000 per month and the mean survival gain from them is 2.1 months. The annual production of champagne is 312 million bottles, which at an average wholesale price of say $30 would fetch about $10bn. So, unless I have got a nought wrong, you could buy up the word’s supply of champagne for the equivalent of 100 000 months of new cancer treatment, or enough to treat 10 000 cancer patients to extend their last year of life by two months. When Chekhov lay ill in the south of France, his doctor came up to his room with a bottle of champagne. “It’s a long time since I drank champagne,” said Chekhov, and died. Perhaps patients with metastatic cancer should be given the choice between a year of novel therapy or 4000 bottles of champagne.

2178 When I first read about “functional” mitral regurgitation in echo reports of my heart failure patients in the 1990s, I wondered if anybody had done a trial to see if mitral valve repair might help this. Well, it’s now been done and the answer is no, probably. The trial randomly assigned 301 patients with moderate ischaemic mitral regurgitation to coronary artery bypass alone or CABG plus mitral-valve repair. The mean age of the patients was 64-5, and most of them had New York Heart Association (NYHA) grade 3-4 heart failure, although those in the group randomised to valve surgery were slightly younger and fitter. Despite that, they showed no benefit at one year judged by left ventricular end-systolic volume index (a surrogate for adverse remodelling), and inevitably had longer hospital stays and more neurological complications.

OL Waiting on the website of the NEJM and in JAMA are papers that may alter the management of hyperkalaemia. This may even have an impact on UK general practice, since almost every week when working out of hours I would get a call from the biochemistry lab saying that so and so had a potassium of 6.8 and could I check if they were still alive and get them seen by the medics. Paul Glasziou once told me about such a patient he saw in the depths of Australia, who refused to go to hospital a hundred miles away. He treated her with a salbutamol inhaler, since beta-adrenergic drugs promote immediate potassium excretion. But clever doctors of the future with more time to spare may use sodium zirconium cyclosilicate. Or perhaps patiromer. Never heard of either? Well, let’s start with sodium zirconium cyclosilicate. The very name gives me a buzz, reminding me of the time I was 11 years old and my favourite book in the world was Mellor’s Modern Inorganic Chemistry, which I had on almost continuous loan from Sheffield Public Library. Zirconium! From the Arabic word zargun—meaning golden coloured—atomic number 40, a transition metal, which I think I painted in green on my huge, homemade, periodic table of elements on the back of a piece of wallpaper. I was a spindly pre-adolescent geek then. Now I am a fat ancient geek but I still love chemistry, and it thrills me to learn that sodium zirconium cyclosilicate (ZS-9) is a highly selective cation exchanger that entraps potassium in the intestinal tract in exchange for sodium and hydrogen. I am less thrilled to think that a simple inorganic molecule like this can be patented by ZS Pharma, if indeed that is true. They obviously thought it worth their while running a big trial in 65 sites across three continents. The result was hardly dramatic: mean reductions of 0.5, 0.5, and 0.7 mmol per litre of K at 48 hrs, from a mean level of 5.3. Diarrhoea was the main adverse effect.

OL Patiromer is a silly name. You can bet that people will divide immediately between those who pronounce it to rhyme with Homer and those who rhyme it with polymer. The latter would be correct, for it is indeed a non-absorbable polymer that binds potassium in exchange for calcium. This trial examined its effect on people with stage 3 to 4 kidney disease, who were mildly hyperkalaemic owing to taking inhibitors of the renin-angiotensin-aldosterone pathway. Their mean potassium levels fell and a few of them got constipated. An editorial asks if these agents herald a new era in the treatment of hyperkalaemia, and concludes that such short studies in people so close to normokalaemia don’t tell us very much.

JAMA 3 December 2014 Vol 312
2223 “Effect of Sodium Zirconium Cyclosilicate on Potassium Lowering for 28 Days Among Outpatients With Hyperkalemia:” a trial run on three continents by ZS Pharma. No, you’re not getting diplopia: this is not the same trial. Just awfully similar. And it usefully tells us that this compound lowers potassium in as little as two hours. It is called The HARMONIZE Randomized Clinical Trial. As for the chemical itself, I’m sure that if you had given me a Bunsen burner, some salt, silica, and zirconium oxide in 1961, I could have made you a nice batch of it.

2234 Find and cure: identify those at greatest peril and save their lives by early intervention. That’s the great sales pitch for screening but it’s seldom true. To be sure, lots of people with type 1 or 2 diabetes have silent coronary artery disease and many of them will die from it, but it does not follow that picking it up early with CT angiography will work better than giving preventive drugs to everybody. The FACTOR-64 trial shows that “among asymptomatic patients with type 1 or type 2 diabetes, use of CCTA to screen for CAD did not reduce the composite rate of all cause mortality, nonfatal MI, or unstable angina requiring hospitalization at 4 years. These findings do not support CCTA screening in this population.”

Lancet 6 December 2014 Vol 384
2027 The results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up provide a wonderful teaching example of how the same statistical information can convey contrary messages depending on how it is presented. In this trial, men were randomised to have prostate specific antigen screening or none, and those with a PSA of 3 or over were investigated further. After 13 years, the screened group showed a significantly lower mortality from prostate cancer with a rate ratio of 0.79 (0.69—0.91) at 13 years. So a triumph at last for PSA screening? Well, the authors commendably go on to explain what this means in terms of individual likelihood of benefit: “The absolute risk reduction of death from prostate cancer at 13 years was 0.11 per 1000 person years or 1.28 per 1000 men randomised, which is equivalent to one prostate cancer death averted per 781 (95% CI 490—1929) men invited for screening or one per 27 (17—66) additional prostate cancer detected.” The authors also deserve credit for including harms in their discussion section, but only in the disembodied form of QALYs gained per thousand of population, whereas the true weighting of each harm—unnecessary surgery, impotence, incontinence, anxiety about cancer for the rest of one’s life—is entirely personal and individual.

2036 Ponesimod is an oral, selective, reversible modulator of sphingosine 1-phosphate receptor 1.
Your sphingosines are misbehavin’,
Get yersel’ ponesimod,
Ponesimod, ponesimod,
Take it till you feel like ravin’
Bring some swing into your scene,
Counter all that sphingosine,
Swing until you feel like god,
Ponesimod , ponesimod!

But is ponesimod likely to reach number 1 in the psoriasis charts? Impossible to tell from the placebo controlled phase 2 trial run by Actelion Pharmaceuticals, which the Lancet decided to give its space to. For a potentially long term drug, it has some disturbing adverse effects: dyspnoea, liver enzyme rises, and dizziness. Ponesimod. Brought to you by Onesimus Podd and the Swingoscenes.

2046 Patiromer, ponesimod, sphingosines—what next this week from the Ministry of Silly Names? Chikungunya: though you’ve probably heard of this one, as it is foreclosing on the United States and causing enough panic there to lead to the development of a vaccine by government agencies. The name is attached to a mosquito borne alphavirus, which is endemic in Africa and south and southeast Asia, and has recently emerged in the Caribbean. It causes fever and muscle and joint pains, and the latter can persist for years. So as well as being safe and immunogenic, a vaccine must not cause these pains, and so far the one described in this phase 1 trial seems OK in all respects.

The BMJ 6 December 2014 Vol 349
Telomeres tell us how long we’ve got left, right? And they can be shortened by bad behaviour but never lengthened by good? I hope I understand the telomere, since it is the latest vehicle for trying to prove that the Mediterranean diet is a good thing. As I have told you almost every week, the Nurses’ Health Study enrolled 121 700 American nurses in 1976, and not one was male. Many of them kept food diaries and most had lots of blood tests. From these we can assess the “Mediterraneity” of their diets, and also measure how their telomeres changed over time, as the Fates snipped at them with their abhorred shears until the day of their personal doom. It seems that if you eat the necessary amount of whatever diet dweebs deem to be Mediterranean, the Fates will do less snipping. I tell you this because it is in The BMJ.

Giving money to Médecins Sans Frontières will not lengthen your telomeres, but it could save someone else’s life, and it will certainly support a wonderful cause. Have you been watching those pictures of Ebola villages in west Africa and wishing you could do something to help? Well these guys are doing that work for you, at their own risk. Give them some dough.

A Brill Recipe

Unless you buy your brill direct from a fisherman, you cannot know it is perfectly fresh. We bought ours from a fisherman but could not eat it until the following day, as I had made myself ill by eating too many of his excellent winkles. This 20 minute recipe worked well:

Grill the brill, rubbed with good butter and crystalline sea salt.

While it is cooking, prepare the sauce. Melt butter in a heavy pan and add a small handful of chopped chorizo and a single baby leek, chopped quite finely. Fry for a couple of minutes and add half a glass of white wine. When this has bubbled a bit, add a similar amount of double cream and stir, turning off the heat once it has begun to bubble. Add the ferny leaves of a fennel stalk, pulled into small pieces.

Fillet the fish carefully when cooked, serve on heated plates, and add the sauce.

If you don’t grow fennel in your garden—which everybody should, even in a window basket, as the leaves of the bronze variety are so beautiful—then you can buy a bulb from any supermarket and it is bound to have a few short leaves growing from it. You could otherwise use tarragon, very sparingly.