NEJM 10 Apr 2014 Vol 370
OL A deadly virus has been conquered. Hepatitis C genotype 1 can be cleared with a simple oral combination treatment, and compared to that, the rest of this week’s medical news seems minor. So I will start by running through the hepatitis C papers which have just appeared on the NEJM website. It you want to read them all, they are free, but as most of you are not virologists or hepatologists, you may just want the bottom line. The names to conjure with are: ledipasvir and sofosbuvir on the one hand, and ABT-450, ritonavir, and ombitasvir on the other hand. Now that you have memorized these, I shall continue. The first of these combinations underwent three trials funded by Gilead Sciences, all of them outstandingly successful. Cure rates of 94-99% were achieved within 12-24 weeks with or without the addition of ribavirin, whether or not patients had received previous treatment or had hepatic cirrhosis.
The second combination, which was given together with ribavirin, was tested in three similar trials funded by AbbVie: the overall success rate was similar, at around 95%.
This amazing triumph of medical science almost justifies the singing of an Easter hymn a week early:
AURORA lucis rutilat, A dawn of light shines,
caelum laudibus intonat, Heaven sounds with praises,
mundus exultans iubilat, Earth rejoices in exaltation,
gemens infernus ululat. Groaning Hell wails.
However, the last line doesn’t quite apply, because these drugs are still hellishly expensive. Two free editorials cover the issue of cost, which is currently estimated at $90,000.
For health systems in developed countries, this is just about affordable, and also timely, because HCV has just overtaken HIV as a cause of death in the USA. But it is estimated that 3% of the world’s population carries HCV, and most of these people have little hope of ever accessing these drugs at current prices. The development of effective antivirals comes just 25 years after the discovery of the virus itself and it’s absolutely right to hail them as a triumph of science. But in the broader scheme of things, the coming of an effective, affordable vaccine will be an even greater cause for celebration.
1382 Human beings are programmed to die. One very common mode of dying is called heart failure. About half of people dying from heart failure do not show any diminution in the percentage of their left ventricular volume that they expel during systole, and in the clumsy jargon of the present, they are said to have HFPEF, heart failure with preserved ejection fraction. This is often referred to as “diastolic” HF, but in reality the mechanisms behind it are not confined to diastolic filling patterns but are far more complex. Let’s leave it at that, and consider what you might want to happen if you had a stiff, failing old heart. My main wishes would be to be looked after compassionately, not to be a burden on my loved ones, to get symptomatic relief for my breathlessness, and to avoid having to go into hospital. Knowing that this was how I would probably die, I might reach the point where I wanted it to happen quickly. These may not be everybody’s aims: some might wish to hang on to life as long as possible, but this seems a very odd assumption to turn into a primary outcome for trials in heart failure, as it invariably is. The median age in the TOPCAT trial was 68, at least a decade younger than most patients with HFPEF. This was essentially a rerun of the trials of spironolactone in systolic heart failure done over the last 20 years. In heart failure with an ejection fraction of 45% or more, spironolactone did not reduce the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. My plea would be for researchers to start looking at other end-points, centred on the quality of dying.
1402 Ever had a pulmonary embolus? Don’t answer no, because in truth you have no idea. Thousands of tiny clots could have passed through your pulmonary circulation without you being any the wiser. The lung is a sieve, and pulmonary embolism is a matter of degree. For lesser degrees of PE, we generally use long-term anticoagulation, but if there is a threat to life, it becomes urgent to remove the clot physically or by fibrinolysis. And then there is a middle category: “normotensive patients with intermediate-risk pulmonary embolism” who have evidence of cardiac strain but are haemodynamically stable. A large French trial randomized them to receive either tenecteplase plus heparin or placebo plus heparin. There was a non-significant reduction in death in the fibrinolytic group but a significant increase in major bleeds including stroke.
1412 Colloid or crystalloid for people with septic shock? I can remember my registrar pontificating on this question forty years ago. Here is another trial showing it doesn’t matter. “In patients with severe sepsis, albumin replacement in addition to crystalloids, as compared with crystalloids alone, did not improve the rate of survival at 28 and 90 days.”
1432 The female of the species is more deadly than the male, wrote Kipling of bears and cobras. This is also true of bees and wasps, whose stinging apparatus is an adaptation of the egg-layer (ovipositor), and thus absent in the male. This only one of many things I learnt by reading this review about hymenoptera hypersensitivity, which buzzes with useful information. “Acute systemic allergic reactions typically occur very rapidly after a hymenoptera sting but may be delayed for several hours or be biphasic… Subcutaneous immunotherapy should be considered routinely in patients who have had a systemic allergic reaction to an insect sting and who have a positive test result for venom-specific IgE… Infections at the site of stings are very rare (especially in the first 2 days).”
JAMA Intern Med April 2014
OL Every screening test comes with a no-man’s land between benefit from early diagnosis and harm from overdiagnosis. In the case of screening for lung cancer by CT scanning, harm is likely to result from the mismanagement of so-called pulmonary nodules. Two great investigators of the harms of screening, Lisa Schwartz and Steven Woloshin, are on the authorship of a study which examines how these nodules are followed up in the US Veterans system. Sometimes they seem to be ignored, sometimes overinvestigated. This needs to be sorted out before any mass screening of at-risk individuals.
JAMA 9 Apr 2014 Vol 311
1397 For some time now, I’ve been wondering what JAMA is for. Fifteen years ago it was one of the top journals for publishing major interventional trials, but these now all seem to go elsewhere. It continues to set new standards for awfulness in poetry. There is quite a lot of health servicey observational research. As in every main journal, there are too few qualitative papers reminding us of what actually matters to people. But this week, JAMA emphatically justifies its existence by running this viewpoint on The Imperative of Overcoming Barriers to the Conduct of Large, Simple Trials, plus the outstanding editorial below. Just consider how many times a day you and your patients are forced to choose between treatment alternatives for which the evidence is uncertain or finely balanced. What if you could agree just to press a button and enter a trial between these alternatives? Iain Chalmers has been advocating this for years, and Ben Goldacre is yearning to do the same thing. Let me just quote Iain from a recent e-mail exchange about “ethics approval” as a barrier to making research an intrinsic part of medical practice:
“When two treatments are already in use within usual care, and there is continuing uncertainty about which is better, why is a distinction drawn between the quality of consent to receive one of the two treatments selected ‘haphazardly’ in usual clinical practice and consent to receive one of the two treatments selected ‘at random’ within the context of an effort to assess which is better? Failure to recognise this illogical double standard penalises the minority of clinicians who wish to assess how the interests of their patients can best be served, and allows the majority of clinicians to continue acquiescing in ignorance about the relative merits of treatments already in widespread use.”
1403 Harlan Krumholz, who is on sabbatical leave, has only two important editorials in the top journals this week. His reflection on the new US Cholesterol and Blood Pressure Guidelines is a classic and needs to be downloaded by anyone interested in the future of medical practice. The radical importance of these latest guidelines is that they refocus attention on what guidelines are really for. Here is the conclusion: “While it is important to advocate for health and promote healthy environments and behaviors on the broader scale, for medical decision making, it is even more important to ensure informed choice with the full participation of the person who will incur the risks and benefits of the decision. When viewed through this lens, the controversies about the guidelines become less contentious and the focus shifts to refining the evidence and producing better ways to communicate what is known for decision-making purposes. By directing attention to that message, already firmly embedded in these guidelines with their bold recommendations and deference to patient preference, they may have accomplished more than they ever envisioned.”
Lancet 12 Apr 2014 Vol 383
1297 The geocarpous bean from Paraguay known as the peanut has an iconic place in American life and is widely consumed elsewhere as a cheap source of protein. This is its only virtue. Its main vice is to produce allergic reactions, even in trace amounts. But make the amounts small enough, and you can cure the allergy, according to this phase 2 trial of oral immunotherapy for the desensitisation of peanut allergy in children (STOP II). After the first phase, 84% of the active group were able to eat five peanuts. Which is about five more than is necessary under most circumstances.
1313 Chickenpox is going around at present, and the chances are that during a long shift later today I will be called upon to pass judgement on some dubious newly-appearing vesicles. Many rich countries display a wish to reduce or eradicate varicella. If this is to be done, this trial shows that you can only achieve success by giving the vaccine twice, separately from MMR vaccine.
BMJ 12 Apr 2014 Vol 348
Oseltamivir has taken on a new Twitter identity as Scamiflu. The tireless work of Tom Jefferson et al in hunting down every last scrap of trial evidence from Roche has resulted in a Cochrane review which shows that in an influenza epidemic, mass use of oseltamivir would probably have no useful effect, though some would still argue that it might reduce transmission. The fact is that by any reckoning, its mass use was a massive waste of money, and Roche failed to disclose evidence that might have led decision makers to that conclusion at the time of the H1N1 pandemic.
There are several pieces in this week’s BMJ discussing the issues. Harlan Krumholz puts them into context and points out how little we still know about this drug which has been available for 15 years: the main questions could probably be answered definitively within a single flu season. And this of course applies to many drugs we use all the time in daily practice. We certainly need immediate access to all existing information from past trials, but we also need to incorporate ongoing research into our daily practice far more than current models allow. As for Roche, they have made their billions and know that this particular game is up. Their best way forward is to say that it will never happen again, because they are going to be leaders in opening up their clinical trial data—past, present, and future. And they should say that from now on they will fund huge follow-up studies on all their products in primary care.
One night about ten years ago I was doing an overnight primary care shift and became aware of a sharp, deep pain in my left flank. It did not change with position and soon filled my whole side. I started sweating and then retching. Eventually a nice colleague came in from his home at 3 a.m. (although I was based in an acute hospital) and gave me an injection of morphine and I was taken off home myself. It has happened three times since. This is all you need to know about diagnosing ureteric colic. It comes on rapidly. It hurts like hell. It makes you writhe and call out. There is a bit of blood on the urine dipstick. You should know all this already if you are any kind of doctor. You do not need a STONE score.
As usual, the educational content of this BMJ is of high quality and clinical relevance. The only way it could be improved is by involving patients more—in narrative and discussion of the issues that matter most to them. Obsessive-compulsive disorder would have been a good example to use. As it is, the review is comprehensive, but often verges on the paternalistic (“generalists should” is a phrase used several times) and although it shows much insight into what people with OCD may experience and wish to hide, it is more of a third hand account than it needed to be.
Besides little kidney stones, the other painful recurring condition I “suffer from” is migraine. Actually my suffering these days is slight compared with what it was in the past. I get visual auras most weeks, but they seldom turn into the throbbing headache that used to lay me out in days gone by. I well remember the first arrival of sumatriptan injections, a treatment which for the first time actually worked, though boy did it make me feel weird. Since then many other triptans have appeared, most of them more reliably absorbed by mouth and therefore preferable to me and I think most other migraineurs. I find it odd that this review of triptan treatment doesn’t discuss them in detail. Its main message seems to be to take a nonsteroidal anti-inflammatory drug at the same time.
Plant of the Week: Veronica umbrosa “Georgia Blue”
With a little more attention to breeding, our English spring gardens could be full of beautiful soft yellow forsythias and our walls could tumble with aubretias of a pure soft blue. But alas, almost all the forsythias we see are of a shouty butter yellow and the aubretias are various shades of muddy purple or mauve-blue.
There is, however, an aubretia substitute with dark evergreen leaves tending to burnished copper, and flowers of an intense deep blue. This tough and hardy veronica lacks the soft messy tangliness that gives aubretia some of its charm, and you probably couldn’t grow it from right inside a crumbly wall as you can the aubretia. But it certainly provides a good strong presence on the edges of a rocky border, excellent in the company of small white or cream wood anemones and low-growing tulips.