Richard Lehman’s journal review 23 August 2010

Richard LehmanJAMA  18 Aug 2010  Vol 304
763    Some time ago I suggested that the best time and place to have a myocardial infarct was at about 10 am on a Thursday morning in October in a large city. That way you would get your primary percutaneous intervention as quickly as possible performed by a team who weren’t new to the job and who weren’t away abroad somewhere. This excellent outcomes analysis from Denmark confirms that time really does equal myocardium, as far as we can measure it. We can never be sure when the infarction really started – that first bout of pain might have been unstable angina, or the shocked patient may not be able to recollect – but we can be sure when the patient first contacted the health system. This is clearly a more meaningful measure than door-to-balloon time, which just measures hospital performance but not total delay. The difference between the two is pre-hospital system delay, and it’s overcoming this that is so difficult for health service planners – not every country is so conveniently small and densely populated as Denmark. The long-term mortality curves in Fig 3 deserve to be included in every lecture on service provision for MI: 10% dead at 6 years after PCI within 60 min, 30% dead at 6 years if the call-to-balloon time was over 180 mins.

Early Danish interventional cardiology, from The Tragicall Historie of HAMLET, Prince of Denmarke. William Shakespeare 1605:
Ger. O Hamlet thou hast cleft my hart in twaine.
Ham. O throwe away the worser part of it,
And leave the purer with the other halfe.

772    You are in your car half-listening to some Mozart on the stereo when all of a sudden the gentle rhythms are drowned out by a deep throbbing noise. Pulling by you at the traffic lights is a red customised boy-racer with a black side window drawn down to help you share the owner’s pulsating bliss. And when you look at the pavement you see young people exhibiting all the clinical features of I-pod chorea: forward flexion of the neck, mumbling motions of the mouth, writhing body movements, jerking of the limbs, and wires leading to the ears. No wonder the youth of today are going deaf. Human ears were not designed for this. The twitter of birds and the crackling of a fire, the chanting of a shaman and the occasional bellow of an auroch, or growl of a sabre-toothed tiger – that’s all we can really cope with. Wilhelm Furtwängler produced the sublimest sounds ever heard from a symphony orchestra, but when he went deaf at 68, he gladly embraced death from pneumonia rather than continue with impaired hearing. Youth of today beware: what is happening to the adolescents of America in this 20-year comparative study is almost certainly happening all over the world.

779    When I become confused, I try to hide it. This is a skill honed by 35 years of clinical practice, and I expect it will stand me in good stead when I develop delirium at some point in the future. “Health care clinicians often fail to recognize delirium”, according to this useful addition to The Rational Clinical Examination series. Unmask it using a bedside delirium instrument – there’s a whole boxful to choose from on p.782. Or you can use the Confusion Assessment Method (CAM) diagnostic algorithm on p.784. “Is the patient’s speech disorganized or incoherent, such as rambling or irrelevant conversation, unclear or illogical flow of ideas, or unpredictable switching from subject to subject.” Sounds awfully similar to these reviews. I must try harder to hide my confusion.

NEJM  19 Aug 2010  Vol 363
    There are two ways of dealing with terminal cancer: the battle-it-at-all-costs model or the accept-and-make-the-best-of-it model. These are perfectly illustrated in this week’s New England Journal. Curative medical treatment for cancer began with the use of poisons such as mustard gas that have profound effects on the body’s protective mechanisms, and this approach continues in the era of monoclonal antibodies, here illustrated by ipilimumab for metastatic melanoma. Ipilimumab is an antibody against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) which is an immune check-point molecule. In other words, CTLA-4 stops inflammation proceeding unchecked, but it also limits the immune system’s fight against metastatic cancer. Block it and the T-cells proceed unchecked. In this trial, 14 patients died as a result of the treatment, but a subgroup of patients showed a dramatic response, yielding a median overall survival of 10.0 months in the ipimilumab-treated group compared with 6.4 in the conventionally treated group.

Studies of drugs like ipilimumab may eventually yield big improvements in survival for some groups of patients, but for the great majority with conditions such as metastatic non-small-cell lung cancer, aggressive treatment just adds to the misery of the condition. For such patients, early palliative care with a lower level of oncology treatment not only provides better quality of life but also increases survival. This randomised comparative study is a landmark in the scanty literature of evidence-based palliative care, and it validates what is already standard practice in the UK. As a nice touch, the NEJM lets you have the full text free.

743    Tai chi and fibromyalgia lie largely beyond the reach of clinical science, and it’s a bit of a shock to see them paired up in the New England Journal. But millions of people have something that makes their muscles hurt and disturbs their sleep and mood, and millions of people use Tai chi. Like acupuncture, it is based on ancient Chinese mumbo-jumbo about vital energy (qi) moving around the body, and like acupuncture it probably doesn’t matter a stuff how you administer it provided you go through the right sort of motions with the right degree of conviction. However, nobody has yet devised a form of sham Tai chi to compare with the sham acupuncture which works so well in all the comparative trials. This single-blinded trial randomised 66 patients to Tai chi or “wellness education and stretching”. Tai chi won, of course.

755   The emergency treatment of asthma remains what it has been for ages, according to this clinical review. Oxygen, a nebulised beta2-adrenergic agent (albuterol is first choice in the USA and salbutamol most other places), a stat dose of oral steroids: and some ipratropium together with β2 agonist may save up to 25% of hospital admissions, though continuing it afterwards has no benefit.

Lancet  21 Aug 2010  Vol 376
    Last week’s opening paper about rimonabant in The Lancet taught us that drugs taken to reduce weight need to be safe as well as effective. These criteria has never been met by any drug so far, and it’s anyone’s guess whether they will be met by the combination of naltrexone plus bupropion advertised – sorry, I mean examined – in this study, funded by Orexigen Therapeutics. The fact is that drugs for obesity can be licensed and bring in vast profits to their manufacturers long before there is sufficient proof of long-term safety, let alone cardiovascular benefit. This combination stands a good chance in a nearly empty market, because both drugs are already licensed for other indications, and they do produce a useful degree of weight loss (about 6%) in most people, sustained for at least a year. A self-evident benefit? Not if it comes at the price of long-term harm, as has been the case with every previous obesity drug except for orlistat, whose main effect is to make people open windows.

606    An oral pentavalent vaccine for rotavirus has halved admissions for diarrhoea in American children, but it is frustratingly less effective for those who need it most – children in sub-Saharan Africa and Asia. By this time tomorrow, 1500 of them will have died from diarrhoeal illness, much of it due to rotaviruses, which behave much more virulently there. The trials here (the other is on p.615) show a reduction in severe rotavirus diarrhoea of 40% – not perfect, but much better than nothing and likely to be greater when mass vaccination produces herd immunity.

624   Several recent surveys have provided gloomy data about the long-term effects of cancer treatment in children, and this one is no exception, except that it is reassuring for men who have had gonadal irradiation. Their children are not more likely to be stillborn or die as neonates, but sadly this is far from the case if the mother has had radiation to the uterus or ovaries. Doses as small as 1-2.5 Gy given before menarche increase the risk, whereas after menarche the dose needs to be higher at 10 Gy to confer a ninefold risk.

631   Over the years I have read at least half a dozen reviews of pre-eclampsia in these journals, with ever-diminishing expectations. People I know, like Chris Redman who taught me as a student, have spent their entire working lifetime trying to unravel this condition. This is the best account I’ve yet seen of the mechanisms and the treatments we currently use, with a much longer list of treatments which have been shown to be futile. There is no break-through in sight.

   If the current treatment of migraine is unsatisfactory, the future treatment may be pants. Telcalgepant is the first of the calcitonin-gene-related peptide (CRGP) receptor blockers, and a whole drawer-full of pants may be on the way, though most of them are still code numbers undergoing phase I and II trials. They seem to be about as effective as triptans and may become a useful alternative. The review also covers topiramate as a treatment for chronic migraine. It has just the sort of adverse effects you want to avoid in young people with frequent disabling migraine, notably general cognitive impairment in 20%. Deeply hidden in the text is mention of a comparison with onabotulinumtoxin A, a three-monthly treatment of at least equal effectiveness and far greater acceptability. I hope it will be available right now from a neurologist somewhere near you.

BMJ  21 Aug 2010  Vol 341
    When I was doing an obstetrics and gynaecology job in London in the 1970s, I remember going to a meeting about treatments for heavy menstrual bleeding attended by an entirely feminist audience. When I put my hand up and suggested hysterectomy, a shocked murmur spread through the room. It was typical of a male to suggest genital mutilation: didn’t I care about the profound effect on women’s self image? Well, actually women prefer hysterectomy, as this study shows. That is because unlike endometrial ablation or the Mirena coil, it works, once and for all. And many studies since the 1970s have shown that it actually improves women’s mood and self-image.

    You have read a lot in these columns about surrogate outcomes in randomised trials, but you ain’t seen nothing yet. In fact if you write to me now you can become a founding member of my new organisation, SASO: Society for the Abolition of Surrogate Outcomes. At the moment, drug companies can market drugs which may lower a surrogate outcome – like glycaemia, or LDL-C, or microalbuminuria – but actually worsen clinical outcomes. This analysis shows that the majority of RCTs that use surrogates do not report on them properly. They fail to give detail on the validity of the surrogate and often confuse surrogate outcomes with real clinical events. The drug licensing authorities allow this to happen and we follow suit, prescribing drugs like rosiglitazone. It needs to stop.

381   Another trick is to use composite outcomes. I hate these too, though Nick Freemantle argues for them in his editorial on this paper. Take the trials of dosage differences of ACE inhibitors in heart failure: three were negative but in two the highest dose improved the composite outcome of death or hospitalisation for heart failure. But actually they didn’t reduce death at all, and had an effect on hospitalisation which is only just significant. On such a basis we build an entire clinical management strategy.

Plant of the Week: Anemopsis californica

There aren’t all that many plants that reach their best at the end of August, but this small perennial from the bogs of the southern USA is one of them. We bought ours last year and it has survived a hard winter and a long summer drought. It is now looking particularly happy flowering in the rain.

The flowers appear as white cones flecked with yellow, and then pure white bracts open at the base, nicely set off by the darkish evergreen leaves. Edible seeds follow, which were pounded into flour by native Americans. They also used the roots of yerba mansa to treat vaginal thrush. So if you’re hungry or itchy, or just need a good front-of-border plant for late summer, this is a handy one to have in your garden.