NEJM 6 Oct 2016 Vol 375
MI: better care counts in long term
Forty years ago, it was generally safer to stay at home with a myocardial infarction. Archie Cochrane demonstrated this in a talk where he deliberately switched his slides round. The cardiologists present declared that the figures mandated the immediate adoption of coronary care units, until Archie told them the improved survival figure applied to those who avoided them. There were cries of “foul,” but he had made his point. The science of outcomes research has improved beyond recognition since then, and nobody has done more to bring that about than Harlan Krumholz at Yale. In a big survey of hospital quality rating and MI outcomes, he and his team show that prompt optimal management not only improves immediate survival, but has life extending benefits for 17 and more years after. The management of myocardial infarction has also undergone five revolutions since the 1970s: the de-adoption of lidocaine, the adoption of aspirin, the introduction of thrombolysis, the diagnostic use of troponins, and the arrival of immediate percutaneous coronary intervention. Plus the early use of β-blockers and the long term use of statins. These things work: medicine does achieve progress: evidence counts: putting it into practice even more so.

Semaglutide: a drug that improves real outcomes?
Drugs for type 2 diabetes reduce blood sugar. In fact, the first oral drug to do that was discovered in the 1860s, but was forgotten. There have been lots since, but reducing sugar doesn’t equate with reducing the risks of T2DM, particularly at the low end of the HbA1c range. Semaglutide is a me-too, glucagon-like peptide 1 (GLP-1) analogue, which NovoNordisk was obliged by FDA rules to test on high risk patients to assess its effect on cardiovascular outcomes. It was added on to existing treatments for 3297 patients with HbA1c levels above 7%.
Most of them had known cardiovascular and/or renal disease, and some were on insulin. Overall, the new drug just about showed an improvement in the composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, at the border of statistical significance. Of greater statistical significance was an increase in sight threatening complications, though numbers were small. The drug will get its licence, but clinicians will still be left wondering how to share decisions about using it. In what way is it better than other drugs? Does an HbA1c under 8.5 need extra drugs at all?

Romosozumab for osteoporosis
Osteoporosis is the kind of condition that drug manufacturers love. It is primarily an asymptomatic, long term condition and a risk factor rather than a disease. The market numbers are colossal. Amgen first produced denosumab, a monoclonal antibody that suppresses RANKL and thus stops osteoclasts from working. Now it has produced romosozumab, a monoclonal antibody that binds sclerostin, increases bone formation, and decreases bone resorption. Free to test its own drugs, it came up with a 12 month trial of romosozumab versus placebo, after which all the patients (women aged 55 to 90) were given denosumab. At 12 months, new vertebral fractures had occurred in 16 of 3321 patients (0.5%) in the romosozumab group, as compared with 59 of 3322 (1.8%) in the placebo group (representing a 73% lower risk with romosozumab; P<0.001). Clinical fractures had occurred in 58 of 3589 patients (1.6%) in the romosozumab group, as compared with 90 of 3591 (2.5%) in the placebo group (a 36% lower risk with romosozumab; P=0.008). So what does this tell us? The stuff works: yes. There are harms: one atypical femoral fracture and two cases of osteonecrosis of the jaw. Can we extrapolate these figures over the remaining lifetimes of these patients? Why were they then all given denosumab? Again, I can’t see how this trial can be used to inform decisions with patients who have many alternatives and different perceptions of risk. And then there is cost . . .

Dupilumab for eczema
With the new monoclonal antibody for eczema, things look a bit more straightforward. Dupilumab inhibits the actions of interleukin-4 and interleukin-13, which are important mediators of inflammation in atopic diseases. The SOLO 1 and SOLO 2 trials 
tested weekly or fortnightly dupilumab in adults with moderate to severe atopic dermatitis whose disease was inadequately controlled by topical treatment or for whom topical treatment was medically inadvisable. In both trials, 30% more of patients responded to the active drug given every two weeks than to placebo injections. Judging from the Kaplan-Meier charts, you could tell who would respond by about eight weeks, but this needs checking from individual participant data. When will these be available, please? Can the newly enlightened NEJM help with this?

JAMA  4 Oct 2016  Vol 316
Underperforming big ideas
Genomics and big data will transform medicine in ways we can scarcely imagine. That’s the story we have all come to believe in one way or another, however reluctantly. In the research community, believers get big grants while unbelievers get shunned as Luddites. In the clinical community, most people are too busy worrying about the challenges and absurdities of daily practice to unpick the issues that might or might not arise from the melding of data sources, which are far too massive for anyone but experts to process and understand. I’ve been trying, and my brain hurts. How I welcome this pot of soothing balm from the Ioannidis team:
“For several decades now the biomedical research community has pursued a narrative positing that a combination of ever deeper knowledge of subcellular biology, especially genetics, coupled with information technology will lead to transformative improvements in health care and human health. In this Viewpoint, we provide evidence for the extraordinary dominance of this narrative in biomedical funding and journal publications; discuss several prominent themes embedded in the narrative to show that this approach has largely failed; and propose a wholesale reevaluation of the way forward in biomedical research.” What a pity that a paywall will stop most people being able to read on.

Cold comfort for in-hospital arrest
Whole body freezing is for preserving dead people until science learns how to revive them, while whole body cooling is for preserving half-dead people. Decades ago, ideas like this would have been called “boyish.” Suffice to say that this observational study looks at the effect of induced hypothermia on patients with in-hospital cardiac arrest. Apparently, it’s become quite popular in some places, though there have been no randomised trials within hospitals. “Use of therapeutic hypothermia compared with usual care was associated with a lower likelihood of survival to hospital discharge and a lower likelihood of favorable neurological survival. These observational findings warrant a randomised clinical trial to assess efficacy of therapeutic hypothermia for in-hospital cardiac arrest.” Or just dropping the whole idea?

Gingering up treatments for hyperemesis
I have a small advisory job with Cochrane UK, and a few months back we looked at a new review of treatments for hyperemesis gravidarum. I remember we all chuckled about the inclusion of ginger. Here is the conclusion of the Cochrane review: “On the basis of this review, there is little high quality and consistent evidence supporting any one intervention, which should be taken into account when making management decisions . . . The limitations in interpreting the results of the included studies highlights the importance of consistency in the definition of hyperemesis gravidarum, the use of validated outcome measures, and the need for larger placebo-controlled trials.” Here in JAMA comes a very similar systematic review from a different (British) team reaching very similar conclusions, although more positively expressed:
“For mild symptoms of nausea and emesis of pregnancy, ginger, pyridoxine, antihistamines, and metoclopramide were associated with greater benefit than placebo. For moderate symptoms, pyridoxine-doxylamine, promethazine, and metoclopramide were associated with greater benefit than placebo. Ondansetron was associated with improvement for a range of symptom severity. Corticosteroids may be associated with benefit in severe cases. Overall the quality of evidence was low.” Both conclusions are correct, but highlight the problem of whether to make any mention of agents when the evidence for all of them is poor.

Hype, regulation, and affordability
Three authors from the drugs and devices industry begin their Viewpoint by declaring that “Breakthrough advances in the understanding of fundamental biology and the dawn of an era of precision medicine coupled with access to ‘big data’ and research conducted in clinical care settings herald a new age of innovation for drug discovery and devices with the promise of improved health.” Ah, where have we heard this before? But the article moves beyond hype and discusses issues of affordability and patient involvement. It even ends by saying that “priorities include initiatives to enable and facilitate the roles of patients and families in all clinical decision making and to enlist their guidance and involvement in the capture, design, and use of clinical data for new knowledge.” Hmm. Is this the sound of progress? I could almost have written that myself.

JAMA Intern Med  Oct 2016 Vol 175
The surprise question
For over 20 years, Scott Murray has worked to align the values of palliative care and good primary care, and to point out the dangers of “prognostic paralysis” and single condition thinking when dealing with people who may be near the end of life. He came up with the “surprise question” in relation to people with heart failure: “Would you be surprised if this patient were to die within a year?” It was meant to give permission to GPs and cardiologists to move away from “What have we still left to try?” towards “How can we make this person’s process of dying more comfortable?” As the surprise question has become more widely popular, Scott has cautioned that it should not be used in isolation without a broader assessment. Here is a survey from the US to show that it is not a very good prognostic indicator. That’s fine. It was never meant to be. It probably translates badly to the US context, where “hospice” is a distinct sort of care package. The question was meant to be an attitude changer, and still may have its place; attitudes still need a lot of changing.

Alternatives to admission
The UK has one of the lowest numbers of hospital beds per unit of population in the developed world, and levels of bed occupancy that would be considered dangerous by most criteria. Yet politicians and their favoured advisers still talk blithely of moving more acute medical care into the community. Here’s a big systematic review of alternatives to hospital admission for acute medical conditions, which concludes that “for low risk patients with a range of acute medical conditions, evidence suggests that alternative management strategies to inpatient care can achieve comparable clinical outcomes and patient satisfaction at lower costs.” But here, context is everything. It depends on the robustness and capacity of the primary care workforce: I don’t believe that you can generalise across health systems.

Lancet  8 Oct 2016  Vol 388
The Lancet’s global health issue marks the week that Theresa May said that if people think they are citizens of the world, then they are citizens of nowhere. I am such a person. Her vision of England makes me sick. Look instead at the seven articles here about the Global Burden of Disease Study 2015 and think how proud you might feel, as a citizen of the world, to address some of the real issues of illness and deprivation on our planet.

The BMJ  8 Oct 2016  Vol 355
How long between smears?
Screening for cervical “pre-cancer” using smear cytology has always been a costly exercise of uncertain precision. Soon after the introduction of easy tests for human papillomaviruses, the Dutch POBASCAM trial began recruiting 43 339 women aged 29-61 years with a negative HPV and/or negative cytology test. They were randomised to cytology screening alone or in combination with HPV testing. Fourteen years on, it’s clear that the long term incidence of cervical cancer and CIN3+ was low among HPV negative women in this study cohort, and supports an extension of the cervical screening interval beyond five years for women aged 40 years and older. Other clear recommendations for subgroups emerge. POBASCAM. Crazy name, good trial.

Fungus of the Week: Amanita pantherina
I’m currently writing in a motel room on Cape Cod, with the rain lashing down outside. Yesterday the weather was beautiful and we visited towns, woods, beaches, and kettle ponds. Kettle ponds were created by ice blocks from the last glaciation, about 14 000 years ago. So were kettle lakes and pingos. Describe and distinguish their characteristic features, with particular attention to the past and current role of artesian pressure.

By Long Kettle Lake I found several fungi close together, all with similar brown caps emerging from the sandy soil. Superficially, you could hardly tell them apart. One proved to be a russula of crumbly texture. One was a strange earthball with black contents interspersed with strange white seed-like grains. The third was an amanita, with a typical volva and ring around a pure white stem, and a few white flecks on the rather oily looking tan cap.

This was a lesson in never trying to identify an emerging fungus without due care and attention. The amanita may have been deadly. I thought it was Amanita pantherina, a single specimen of which can cause a protracted awful death from liver and renal poisoning. But I learn that this species is not found in North America: my find must have been some similar species, unless the Pilgrim Fathers inadvertently introduced pantherina to this peninsula. In which case I made a mycological discovery of the highest importance, now destroyed by my kicking it over.