Richard Lehman’s journal blog, 3 May 2009

Richard LehmanA week of small increments than radical breakthroughs in the medical journal sees Richard break into poetry when faced with some particularly fanciful drug names…
NEJM 30 Apr 2009 Vol 360
I usually avoid discussing HIV in these columns, because the role of a GP in my part of the world is just to make a timely diagnosis and hand the patient over to an expert for treatment. That can be more difficult than it sounds: a number of people have written to suggest that HIV is an essential topic for our “Easily Missed” series in the BMJ, because people still die of it in the UK without the diagnosis ever being made ante mortem. I shall always remember a patient of my own who refused HIV testing until he had florid AIDS and was nearly dead. Thanks to modern antiretroviral treatment, he is perfectly well many years later. So does the timing of antiretroviral therapy really matter? Well, that patient was certainly lucky, and nobody would choose to wait for a person with HIV to become symptomatic before starting treatment, but this quite complex long-term study from Canada tries to establish a CD4+ threshold level for treatment, using that most convincing of end-points, death. I won’t try to describe the results in detail but essentially this large stratified trial shows that earlier is better.

Hepatitis C infection is another bit of complex virology I tend to leave to virologists, though again it brings to mind a memorable patient, this time a former waiter from Barcelona who may have inspired the role of Manuel in Fawlty Towers. His death from hepatocellular carcinoma as a result of hepatitis C infection was awful. That is why successful combined therapy for this indolent and elusive virus would be a great step forward; but it is too early to celebrate, as shown by this paper and the one after it (p.1827). The promising new drug is telaprevir, which is more active against HCV genotype 1 infection than existing agents, and these two trials (PROVE1 and PROVE2) use various regimens with peginterferon, with or without ribavirin. It seems you need all three to get a good response in chronic HCV genotype 1 infection: but you are still lucky if more than two-thirds of patients respond.

The main aim of the JUPITER trial was to show that rosuvastatin can lower arterial events in people with low overall cardiovascular risk but slightly raised C-reactive protein. But a large trial like this was also useful for testing the hypothesis that statins can reduce venous thromboembolism as well. Most data to support this had so far been observational, but this randomised controlled trial proves that rosuvastatin definitely does protect against VTE. In fact taking deep vein thrombosis on its own, the rate was halved (HR 0.45, 95% CI 0.25 to 0.79). Tell me a reason why everyone shouldn’t be on a statin, sooner or later.

Lancet 2 May 2009 Vol 372
This is certainly a week of small increments rather than breakthroughs in the medical journals, but just how small can an increment be and still be worthwhile? Here we are talking about a survival advantage of 4-5 weeks in people who know they are dying of non-small-cell lung cancer. Given that the drug concerned, cetuximab, seems very well tolerated when added to standard platinum-based chemotherapy, it would seem unkind to grudge this small advantage in patients with advanced disease; but in the long term, the real benefit of this study may be in demonstrating that the epidermal growth factor receptor is a useful target for treatment earlier in the disease.

In several situations, such as renal disease, heart failure and cancer, anaemia is associated with an adverse prognosis as well as poorer quality of life. So correcting anaemia using human erythropoiesis-stimulating agents seems a very attractive idea, likely to increase survival as well as make patients feel better. But just like lowering glycated haemoglobin in type 2 diabetes, you can only find out by doing the trials; and then the result may be the opposite of what you expect. This meta-analysis of 53 trials of erythropoietin analogues in cancer patients shows a definite increase in mortality. Remember Galileo: until he came along, everybody knew that heavier objects fell faster than light ones, because they made a bigger bump in the ground. But he actually climbed the leaning tower, did the experiment and proved that common sense can deceive. Every specialty of medicine has its Pope and a conclave of cardinals, telling you what to think on pain of banishment: but medicine progresses by taking no notice of them and looking at the facts instead.

Chances are that whatever kind of medicine you practise, you will come across the occasional patient whose life has been saved from haematological malignancy by haemopoietic cell transplantation. For these triumphs we can thank Peter Medawar and others who worked out the fundamentals of modern immunology in a series of painstaking animal and human experiments in the 1940s and 1950s. But the risk of allotransplantation in this situation is that the graft may attack the host, a process first described by Billingham fifty years ago. We now know that graft versus host disease arises when donor T cells respond to genetically defined proteins on host cells. If you have a patient with this condition, or if you want to spend half an hour with a beautifully clear run through this aspect of modern immunology, then here is the article you need.

Bring out your silly names! There are new drugs in the wings to stimulate platelet production in chronic immune thrombocytopenic purpura. I am afraid I shall have to keep to my custom of breaking into verse at this point:

O Thrombocytopenic Purpura!
No subject ever once was murkier,
Till doctors skilled in blood and bone
Started to use Prednisolone;

Or in their fight ‘gainst this Hobgoblin
Resorted to Immunoglobulin;
Else, growing desperate, were seen
Calling the surgeons to remove the spleen.

But Hark! What Silly Names are heard
Approaching to the Haemic Ward?
Let us begin, Rituximab:
Thou first the Silly Prize dost grab.

But now appears Eltrombopag;
The Prize is surely in his bag!
But no, there is yet Romiplostim
Which now the Silly Prize hath lost ‘im.

And now our Poet must confess defeat,
For he his Silly Rhyming Match doth meet:
The latest drug is tamatinib fosdium
‘Gainst which all Poetry is lost, dee dum.

So let us praise the Pharmacologists,
Who spend their time devising bolloxes
Like these, in grand cacophony,
To celebrate the cure of ITP.

BMJ 2 May 2009 Vol 338
The name of Venus has inspired much poetry, some (I confess) even finer than my own. But I am not sure that her name has ever previously been connected with the maggot. I have spent a happy hour trawling through the works of Erasmus Darwin on the Gutenberg site, just to make sure, as this wide-dabbling Midlands GP and versifier is the most likely suspect for such a crime. Charles Darwin’s grandfather knew perfectly well that maggots were the larvae of insects but he retained a fondness for the old theory of spontaneous generation:

(For) without parents, by spontaneous birth,
Rise the first specks of animated earth.
From Nature’s womb, the plant or insect swims,
And buds or breathes, with microscopic limbs!
The Temple of Nature 1802

And Venus herself, of course, rose by spontaneous generation from the sea, as you will remember from the Botticelli painting you discovered with awe in your teens, and queued for hours to gawp at in the Uffizi Gallery. However, in this paper the connection is nothing grander than a maggoty pun: VeNUS II investigated larval therapy for venous ulcers. The munching maggots work well for ulcer debridement but do not improve the overall healing rate. The editorial on p.1050 argues that this is a useful contribution, but only if you don’t have enough trained humans to do the job with a knife. So perhaps maggot therapy will never fly. So the buzz goes …

Once a woman has had three negative cervical smears, her chance of developing cervical cancer is about 4 in 10,000. This does not vary significantly with age, according to this prospective observational study from the Netherlands. That seems a fairly straightforward message, easily communicated to most women, but in a national screening programme we seem very averse to giving anyone any choice. A better targeted screening policy is well overdue.

We spend a great deal of time and trouble making sure that patients with chronic systolic heart failure get increasing doses of ACE inhibitors and ß-adrenergic blockers, though the evidence for up-titration of these drugs is extremely weak; but in the UK it is still uncommon to find heart failure patients treated with cardiac resynchronisation therapy or biventricular pacing. I hope this good little clinical review does something to change practice, because this treatment is widely applicable and improves quality of life, reduces hospital admission and reduces mortality. “Identifying suitable patients is straightforward; there is no upper age limit of benefit; the implant technique is of low risk; and the treatment is highly cost effective.” So go on, shock your paymasters: don’t rest content with getting your basic QOF points for heart failure, but while you are about it, go through your HF patients and refer the appropriate ones for pacing.

The Rational Testing series here advises on the appropriate blood tests for investigating hirsutism. The commonest cause in younger women is polycystic ovarian syndrome, for want of a better label: and here is a useful list of the right biochemistry to send off, if your lab will oblige. Ultrasonography of the ovaries is rarely necessary.

Arch Intern Med 27 Apr 2009 Vol 169
Preventing type 2 diabetes is one of the most urgent public health tasks in the developed countries of the world: add the Indian subcontinent to that; then China: and you might as well say the whole world. Unfortunately, this study of lifestyle risk factors and new-onset diabetes looks at an age range where it is no longer so important: an average age of 73 at enrolment, which exceeds the average age at death in many countries. Still, if you are retired in the West and want to know how to avoid diabetes, here are some tips. The dietary score is a mish-mash of fatty factors and glycaemic index, and I make nothing of that; BMI is set at 25, which seems a bit mean; alcohol is beneficial, but only up to 2 units a day; exercise is definitely good; smoking is definitely bad.

Plant of the Week: Magnolia sinensis

This is normally a tree which flowers later in May, but in this year’s peculiar English spring it is out at the same time as a neighbouring Japanese quince and a lilac bush, giving a strange, unplanned-for palette of colours which would normally appear a month apart. Nothing, however, can spoil the absolute beauty of this small tree’s pendent flowers of purest white, surrounding a boss of deep red. If you can, plant it on a bank where passers-by can look up and enjoy it, and catch its pungently sensual scent. There is little to choose between this and the almost identical species wilsoniae, but do not bother with their near relative sieboldii, whose flowers disappoint by never opening to their full beauty.