NEJM 29 Oct 2015 Vol 373
Noddy meets oncology
1679 PARP stands for poly(adenosine diphosphate [ADP]–ribose) polymerase. For every child who grew up in England since the 1950s, it is also the noise that Noddy’s car makes. Now there is a PARP inhibitor called olaparib which costs about £900 a week for treating metastatic cancers of the ovary and prostate.
Noddy looked in his piggy bank, but all he could find was a silver sixpence and a yellow threepenny bit. “Where on earth can I find the money?” cried Noddy. “If I can’t find it I’m going to die,” he sobbed. “I know.” said Big Ears, “You’ll have to rob a bank.” Noddy waited until it was dark and put on a mask. He stuffed a jemmy under his stripy jumper. Then Noddy got into his car and drove to the bank. But when he arrived, Noddy’s car went PARP PARP!—and who should come round the corner but Mr Plod the policeman! “Hullo hullo hullo” said Mr Plod, “you’d better come along with me, young man.” But just then, Big Ears arrived. “Noddy, it is you, isn’t it? I’ve just met a nice lady and she gave me a HUNDRED THOUSAND POUNDS because she couldn’t bear to think of Toytown without our dear Noddy!” So Noddy went to get his medicine. But when he arrived at the chemist’s shop, Mr Potion told Noddy that he would have to have some special tests. They would cost another ten thousand pounds. So Noddy said, “Sod this, I’m going to die.” Then Noddy died and everyone in Toytown was very sad.
This Cancer UK funded trial used phenomenally complex whole exome sequencing and cancer-line sequencing to identify patients with metastatic prostate cancer who were likely to respond to olaparib as third-line treatment. “‘Milestone’ prostate cancer drug” was the BBC headline. We really will have passed a milestone when tests and drugs like this become affordable for health systems and individuals.
Oops, our stents are inferior
1709 Boston Scientific funded this trial of its paclitaxel-eluting stent versus everolimus-eluting stents in diabetic patients with stable coronary artery disease in the hope of proving non-inferiority. But oh dear, they resulted in higher rates of target-vessel failure, myocardial infarction, stent thrombosis, and target-vessel revascularization at 1 year. I doubt whether the NEJM will be making much money in reprint sales to Boston Scientific.
Can diabetes help you live longer?
1720 Here is a must-read, must-keep paper. Rarely if ever has there been such a wealth of observational information about such a massive population of people with type 2 diabetes. It is derived from patients with type 2 diabetes who were registered in the Swedish National Diabetes Register on or after 1 January 1998—435,369 in all. After a mean follow-up of 4.6 years in the diabetes group and 4.8 in matched controls, the adjusted hazard ratio for mortality was 1.15. But that extra mortality was heavily skewed towards people younger than 55, and especially those with renal impairment. People over the age of 65 with stable diabetes and no renal impairment actually have a mortality advantage over age-matched controls. This is probably because they are much more likely to be taking a statin and to have good blood pressure control using a RAS inhibitor, as well as enjoying the prognostic advantages of overweight in the old. This an amazing study, with several days’ worth of material to look through in the article and its 13 online supplements. In an ideal world, I’d like to have had more analyses relating to time from first diagnosis and variability of control: perhaps two of many spin-off papers we’ll no doubt see in the fullness of time. And a final word of caution: don’t be deceived by the HbA1c correlations with mortality. Trial after trial has shown that these don’t work in reverse: pushing levels down with most drugs does not improve survival. It is more to do with the nature of the metabolic disorder itself.
JAMA 27 Oct 2015 Vol 314
Should “black” asthma be treated differently?
1720 I still get a bit fazed by medical papers with titles like “Anticholinergic vs Long-Acting β-Agonist in Combination With Inhaled Corticosteroids in Black Adults With Asthma.” I guess this is acceptable since most Americans of African descent identify themselves in this way, and they have genetic clusters that are different from the “white” or “Hispanic” populations. This unblinded pragmatic trial belongs somewhere in the spectrum of trials which attempt to sort out which inhalers might benefit people with moderate-to-severe chronic asthma. Here is the conclusion: “Among black adults with asthma treated with inhaled corticosteroid, adding a long-acting beta agonist did not improve time to asthma exacerbation compared with adding tiotropium. These findings were not affected by polymorphisms at the Arg16Gly locus of ADRB2. These findings do not support the superiority of LABA + ICS compared with tiotropium + ICS for black patients with asthma.” I hope you can remember that.
Death in America
1731 Between 1969 and 2013 in the United States, death rates for most conditions have fallen. This includes death from coronary heart disease, cancer, stroke, and unintentional injuries (through a decrease in motor vehicle fatalities). But death attributed to chronic obstructive pulmonary disease has increased. I guess this may be a legacy effect from past smoking, or a recording artefact, or perhaps a continuing effect of air pollution.
JAMA Internal Med Oct 2015 Vol 175
Changing medicine, one article at a time
Ever since it started its “Less is More” themed articles, JAMA Internal Medicine has become a journal with a mission. On its website at the moment is a clutch of papers and research letters which probe the causes of futile treatment, especially of people with a short time to live. For most such people, there is hardly any evidence within “Evidence Based” Medicine which can be a certain guide, and what little there is needs to be matched to the goals of each individual. Here are some examples:
- a study by Vinay Prasad and his colleague Chul Kim, measuring the tiny incremental survival benefit of most cancer drugs which were fast-tracked by the FDA using surrogate end-points.
- a comparison of people’s own estimates of their life expectancy compared with their recorded survival, demonstrating that it can be difficult to set an accurate context for discussions about the prognostic impact of interventions.
- a survey showing that most primary care clinicians in the US Veterans’ system are at sea over what to do about (de)prescribing for older people with diabetes who are at high risk of hypoglycaemia.
- a full-length paper showing that in real practice, only a quarter of diabetic patients with limited life expectancy have any appropriate reduction in their medication, even when there was clear evidence that it was overshooting its target: “Among older patients whose treatment resulted in very low levels of HbA1c or BP, 27% or fewer underwent deintensification, representing a lost opportunity to reduce overtreatment. Low HbA1c or BP values or low life expectancy had little association with deintensification events.”
Lancet 31 Oct 2015 Vol 386
Take it easy or you’ll have a stroke
1739 An analysis of 25 studies from 24 cohorts in Europe, the USA, and Australia shows a robust association between working long hours and the risk of stroke. There may be an association with coronary heart disease too, but it is weaker. Long hours means >55 hours a week in the main binary model, but there is also evidence of a dose-related connection: the longer you work, the likelier you are to have a stroke. Like most doctors, I really would rather not have a stroke, but I’ve lost the sense of what counts as work and what doesn’t. The authors conclude that “these findings suggest that more attention should be paid to the management of vascular risk factors in individuals who work long hours.” I keep a bottle of low-dose aspirin by my desk and I occasionally take one. I also sometimes take a simvastatin at bed time. I hope that will do. But the editorialist on this paper suggests that working hours are a voluntary choice and should be studied by a randomised trial. I can’t begin to say how unrealistic and confounded I think that would be.
Standing the evidence on its head to cure SVT
1747 A while back I read about a little girl who used to turn up regularly in the emergency department with supraventricular tachycardia. One day she told the doctors she would show them how to treat it: she leapt over, did a handstand, and reverted to sinus rhythm. No more nasty adenosine for her. I don’t know if she inspired the REVERT trial, which compared the standard “stay sitting” Valsalva manouevre with a “lying down with leg lift” Valsalva. In adults with SVT, the success rate was 17% for the first and 43% for the second. It’s simple, it’s free, and patients can be taught how to do it. More trials like this, please.
BMJ 31 Oct 2015 Vol 351
Liraglutide and the sweetness of surrogates
It is very unusual these days to find an industry-funded trial in The BMJ. But here is one that was largely funded Novo Nordisk, testing the effect of adding their drug liraglutide to the regimens of people with type 2 diabetes who were using multiple insulin injections and running an HbA1c of 7.5% or higher. The participants had an average age of 63.5 and had been treated for diabetes for about 17 years. The paper starts off by declaring that “Good glycaemic control is a cornerstone of the prevention of complications among people with type 2 diabetes.” It could equally have started off by pointing out that “There is no evidence that lowering HbA1c below 7.5% has any beneficial effect on any outcome in patients over 60 with longstanding type 2 diabetes,” but that might have been a party-pooper. Like most industry-funded studies, it wants to have a happy ending. And indeed it gets one: “Adding liraglutide to multiple daily insulin injections in people with type 2 diabetes improves glycaemic control without an increased risk of hypoglycaemia, reduces body weight, and enables patients to lower their insulin doses.” Since some of the harms of diabetes may be due to exogenous insulin, that may be a good thing. But without real end-points, we don’t actually know—something that John Yudkin, I and several others have pointed out a number of times, in The BMJ. I seem to remember a particularly good article called “The Idolatry of the Surrogate.”
Prostrate from prostate drugs
The dream of every pharma company must be to run a trial which shows an overall reduction in a process with large natural fluctuations. In that way the drug will be used by huge numbers of people who will never be able to tell whether or not it is working. Most inhalers for COPD are sold on this basis: so are most drugs for benign prostatic hypertrophy. Once they are on the prescription list, the bias is to keep them there in case they might be doing some good. But so called prostate-specific α antagonists can have a lot of non-prostate effects, particularly hypotension in older men. Here’s a registry-based study comparing the rate of falls, fractures, and head trauma in men over 65 taking these drugs in Ontario compared with matched controls. The increase is not large but it’s both statistically and clinically significant.
Plant of the Week: Viburnum farreri
Coming out of our back door over the last two weeks, we noticed a pervasive honey-like scent. This was a mystery: it was certainly not coming from our compost bucket and there is no scented plant flowering anywhere nearby. Eventually we traced it to a viburnum flowering about 10 metres away, round the corner of the house and rather overborne by its neighbours. This is the straggly deciduous shrub which Reginald Farrer brought back from China and named Viburnum fragrans. But the botanical fraternity rightly decided to rename it in his honour.
Fragrant it certainly is, and this is the time of its greatest abundance, though it carries on bearing little pink flower clusters right through the winter. We don’t feel too guilty about relegating it to a rather crowded and tangled spot, because this is a shrub which defies all attempts to make it look tidy. You don’t even need to get very near to it, because its scent comes out to meet you, in lulls between the blasts of autumn and winter wind.