Journal Watch - December 2006

J A M A  6 Dec 2006  Vol 296

2563   A few years ago, our local community mental health team decided on a strategy called “aggressive outreach”, but it didn’t seem to last for long. Now pharmacists seem to be adopting the same philosophy, but I wonder whether they can keep it up. Here is the latest of a very long line of studies where pharmacists review the adherence of elderly patients taking four or more drugs. Half of them were randomised to receive blister packs and get pharmacist advice on the purpose of their medication. Sure enough, they took more of them correctly and their lipids and blood pressures were better than those left to their own devices. I suppose we must get used to the fact that the future of primary care lies in ever more hassle by ever more people to achieve improvement in ever more surrogate outcome markers in ever older patients.

2572   One surrogate outcome marker particularly treasured by the research community is carotid intima-media thickness (CIMT) because progression shows a close association to long-term cardiovascular outcomes, which means that you can publish a study in a couple of years rather than ten or more. Good news also for Takeda, manufacturers of pioglitazone and sponsors of this trial, who can claim benefits for their product well within its patent life. It definitely does better things to CMIT over the first 72 weeks than the sulfonylurea glimepiride: but if you look at the graphs, it seems that the glitazone merely delays rather than prevents increases in CMIT, and whether this is of any clinical significance cannot be known in less than ten or more years’ time.

2582   Do babies drive young Danes to depression? Indeed they do, for several months after they are born. But this only applies to the Danish dames: Danish fathers do not get the baby blues. For a good summary of what we know about the epidemiology of postnatal depression, see the editorial on p. 2616.

2601   Talking of surrogate outcome markers beloved of big pharma, one of the most lucrative is osteopenia. Once you have been told that your bones are thinning, it is difficult to believe that playing golf may do you more good than taking a lot of tablets. But that is the message of this clinical discussion, which provides yet another perspective on this vexed and vexing subject.

N E J M  7 Dec 2006  Vol 355

2395   If you haven’t managed to open up an occluded coronary artery within 3 days of a myocardial infarction, should you go ahead and stent it anyway? Don’t bother, is the message of this multinational study: you may even harm the patient by trying. Or, to look at it a different way, just make sure you do your PCI as soon as possible after MI, as there is no rescue option later.

2409   Famed for its orchestra and a Cream Cheese Spread, the City of Brotherly Love also gives its name to a chromosome which is involved in the pathogenesis of chronic myeloid leukaemia. The Philadelphia chromosome encodes the production of BRC-ABL tyrosine kinase, which is specifically blocked by imatinib. I mention these interesting facts because they may have led to a cure for this nasty condition. Nearly 90% of patients from the initial imatinib study are still alive after five years. And a similar genomic approach may bring cures for other myeloproliferative disorders – see the review on p.2452.

2418   Antibiotic-associated haemorrhagic colitis is of course usually due to Clostridium difficile, however you choose to pronounce the beast. But now it is being joined by a fellow-beast, Klebsiella oxytoca. At least we can agree how to pronounce that. It was detected in 22 patients with post-antibiotic colitis who were negative for C-diff: the klebsiella was then given to rats and duly gave them haemorrhagic colitis, but only if they had been pre-treated with co-amoxiclav. So Koch’s postulates were handsomely satisfied.

2427   We now have three oral drug classes for the routine management of type 2 diabetes, but which one should we ADOPT as our first choice for initial monotherapy? Metformin seems the obvious answer, since it is the only one which has been proved to improve outcomes by helping patients make better use of their own insulin. But it does tend to cause bloating and diarrhoea, so we often end up substituting sulfonylureas like glibenclamide (glyburide) which thrash the islet cells and in all likelihood burn them out faster. Then there are the thiazolidinediones like rosiglitazone which work on insulin sensitivity but can cause weight gain, oedema and even heart failure in the susceptible, and take a long time to kick in. The ADOPT trial, paid for by GlaxoSmithKline, shows that their drug keeps people going on monotherapy a little longer than metformin and a lot longer than glibenclamide. The confidence intervals just manage to part company at five years, ensuring a rosy future for GSK, which in any case hedges its bets by producing combinations of rosiglitazone with metformin or glimepiride.

B M J  9 Dec 2006  Vol 333

1193   ‘Tis the season to be sending in patients with chest infections, known as community acquired pneumonia in today’s parlance. Unless the patient is worryingly ill, we’ve usually tried oral antibiotics for some time before we send them to hospital, but it isn’t clear that whether this was the case in this Dutch trial comparing short and long courses of in-hospital intravenous antibiotics. We tend to ascribe almost magical properties to antibiotics given through a vein, but all this does is ensure high peak concentrations (and low troughs): within three days, the antibiotic can be taken orally without any difference in outcome for hospitalised severe pneumonia.

1196   Another trial from the Netherlands, a mythical land where there are occupational therapists who can spend ten one-hour sessions with demented patients and their carers. This has benefits which, say the investigators, are still detectable after 12 weeks. Marvellous. Where I live it takes ten phone calls to get an OT to spend ten minutes with the patient and carers after a ten-month wait. This gives them time either to die or buy their own stair lift.

1200   I’ve already summarised the management of hyperglycaemia in type 2 diabetes in commenting on the NEJM ADOPT paper, but this review comes up with three more drug classes we may soon be able to use: a-glucosidase inhibitors, meglitinides and dipeptidylpeptidase 4 inhibitors. To test when you have had enough to drink at your next Christmas party, repeat the following sentence aloud:

”Trying the thiazolidinediones in hyperglycaemia may be pipped by dipeptidylpeptidase inhibition imminently”.

Lancet  9 Dec 2006  Vol 368

2053   There is still plenty of room for debate about the usefulness of screening mammography over the age of 50, but after this study, I hope we will hear no more about lowering the starting age to 40. In 55,000 British women aged 39-41 who were randomised to receive it, it failed to show a significant effect on breast cancer mortality after ten years.

2061   In the heyday of the Mad Cow panic, a professor of microbiology from Leeds prophesied that hundreds of thousands would die from variant Creutzfeldt-Jakob disease, and we don’t yet know for certain that he is wrong, since it has an incubation period of up to 50 years. However, a moderate degree of complacency seems in order, since rates are falling rather than rising, and it remains about as common as getting struck dead by lightning. The editorial on p.2037 summarises the situation. It’s certainly a bit disquieting that there is the possibility of an undetectable and untreatable infectious agent lurking in one or two bags of blood somewhere in the UK: but it seems to me that the risk from receiving a transfusion is about the same as taking a short walk in the country.

Ann Intern Med  5 Dec 2006  Vol 145

797   We have a lethal virus carried by 0.2% of the community. It is sexually transmissible and the only preventive measures are behavioural; it is treatable but not curable. Should we screen for it, and if so, how often? No prizes for guessing that this a real question about HIV in the UK. The prevalence statistic is roughly similar to some parts of the USA, where this modelling study was conducted, and the cost-benefit equation is borderline (£15-30K per QALY) however you play the assumptions. The authors plump for screening.

807   I was quite looking forward to taking a close look at this paper, called “The pathogenesis of venous thromboembolism: evidence for multiple interrelated causes”. After all, there’s a lot we don’t understand about VTE. Autopsy studies show that pulmonary embolism is far commoner than we realise and that it can present in many atypical ways. But as soon as I tried to read the abstract I realised that what’s inside the tin does not match the label. This is all about some Dutch families with rare thrombophilias whose relatives were chased up by a team of academics, and I’m afraid my interest in their fate was not sufficient to get me past the first paragraph.

Plant of the Week: Daphne bholua

It’s time again to sing the praises of this most wonderful of winter plants, an evergreen shrub which various plant hunters have rushed to our gardens from below the snow line of the Nepal Himalaya. It is gradually becoming more affordable and more popular, though not nearly as much as it deserves. Plant it by your back door – it doesn’t matter in what aspect or what soil – and it will give you joy all winter. It grows slowly to about three metres high, becoming hardier and more floriferous each year. The flowers are small, waxy and star-shaped, and they fill the winter air with the most amazing fragrance for several months. Most varieties are pink but there is a white-flowered clone too, usually referred to as “Alba”, though botanists demur.

The most famous of the bholua (pronounced “boolah”) stories has Major Spring-Smyth telling his Gurkha to run down to the nearest settlement (200 miles away) and make sure the plant gets on a good boat to England. It did, and the variety is now known as “Gurkha”. Perhaps someone should find out the poor chap’s actual name and commemorate it properly by means of this hardy garden clone.

J A M A  13 Dec 2006  Vol 296

2683   This observational study takes a careful look at 44 630 men diagnosed with localised prostate cancer between the ages of 65 and 80. Over 30,000 of them had radical prostatectomy or radiotherapy, and in this group, mortality was 30% less than in those who were simply observed. Sounds impressive, doesn’t it? But of course this also tells us something about the patients that surgeons and radiotherapists don’t want to treat, since this was not a randomised trial. And to put it in a truer perspective, prostate cancer itself was responsible for 6.8% of deaths in the treatment group and 8% of deaths in the observation group. The old saying that you’re more likely to die with your prostate cancer than from your prostate cancer proved true in more than nine cases out of ten, whatever the treatment.

2703   As markers of cardiovascular risk go, C-reactive protein is something of a bit-player, but has aroused a lot of interest as a potential causal link between inflammation and cardiovascular events. This study looks at common polymorphisms of one of the genes that governs CRP production – conveniently called the CRP gene. Over a 13 year period, variation in this gene shows the expected correlation with variation in CRP levels, and at the same time a correlation with cardiovascular risk.

2720   Another circulating chemical associated with cardiovascular risk is homocysteine (HCy), and many people have assumed that this association is causal too. Elevated HCy is a marker for deficiency of folic acid, pyridoxine or cobalamin, and the most popular therapeutic intervention is to increase intake of folic acid. In fact many countries now enrich all bread flour with folate, more to prevent neural tube defects than vascular disease. This meta-analysis of all RCTs shows that it may be vain to hope for the latter: eleven studies show no overall effect.

N E J M  14 Dec 2006  Vol 355

2513   Apart from the threat posed by a new strain of pandemic influenza, there’s the irksome fact of antigenic drift in existing subtypes of influenza A, which means that most circulating viruses are now dissimilar to those included in the vaccines. But this big US study shows that they are nonetheless still protective, the inactivated vaccine a bit more so than the live attenuated vaccine.

2523   Most influenza vaccine is still given to protect at-risk individuals, but there are some who argue that we could do more good by encouraging wider vaccination and so creating herd immunity (see editorial, p.2586). The chosen calves of the herd in this study were children at 28 infant of elementary schools in two American states, and the families of immunised children duly showed a slight reduction in flu-like illnesses. But if you want the idea to work properly, I’d suggest you give intranasal flu vaccine at school, with sneezing powder for use at home.

2533   The advent of screening colonoscopy puts a premium on speed on the part of the colonoscopist, and this is often welcomed by their victims too. In this study, colonoscopists dallied in the bowel for anything between three minutes and seventeen after making their way to the caecum and without removing any polyps. Those who spent less than six minutes were more likely to miss adenomas than those who went a bit more slowly. For more about adenomatous polyps of the colon, see p.2551.

2558   As medical students, we were taught to spot acromegaly by its combination of coarse features, big hands and large shoe sizes. This sometimes caused confusion when we first encountered orthopaedic surgeons. People with growth-hormone secreting adenomas are often only recognised at an advanced stage of their disease, as this useful review points out. The diagnosis is made by measuring circulating levels of growth hormone, and the treatment is still usually transsphenoidal surgery. There are a number of medical treatments too, which you might like to look up if you have a patient with the condition.

B M J  16 Dec 2006  Vol 333

1231   Time was when a new report about the future of medical research in the UK would have had me all agog. But here comes the Cooksey Report written by a “distinguished venture capitalist”, and somehow I can’t get up the energy even to reach for my reading specs. “Something for everybody”, says this editorial; “faith in technology as the principal driver in improvement in people’s health”; no radical changes in funding streams. One could almost imagine that Sir David Cooksey might be telling New Labour what it wants to hear; but he already has a knighthood.

1241   Influenza vaccine given to nursing home residents does not seem to be very protective, according to this paper, which found that despite high resident coverage, a greater protective effect can be obtained by vaccinating the nursing home staff. This is such a good study that its findings deserve to be adopted by everyone who thinks that nursing home residents should be protected against influenza.

1248   Looking at the excellent paper on the management of localised prostate cancer in this week’s JAMA, I highlighted the big difference between the headline message that active management reduces prostate cancer deaths by 30% over 10 years, and the fact that at ten years the vast majority of patients were either still alive or had died of something else. Absolute risk is what you or I or each individual patient needs to know in order to make an informed decision; but this analysis of 222 medical papers shows that such information can be very hard to find.

1251   Another week, another review of osteoporosis – probably the best short pragmatic guide so far for readers in the UK.

Lancet  16 Nov 2006  Vol 368

2117   This week’s Lancet is a bit thin on articles of general interest but here is a superb book review by Michael Marmot about Julian Tudor Hart’s The political economy of health care. Worth getting to celebrate the birth in a stable of the main proponent of the idea that all human beings are of equal value.

2156   “Generalised anxiety disorder is characterised by feelings of threat, restlessness, irritability, sleep disturbance, and tension, and by symptoms such as palpitations, dry mouth, and sweating” begins this rather good review of the subject by two British academics. Old-fashioned general practice used to feel that way to me, and lecturing still does. That’s no doubt because evolution has blessed me with genes for what used to be called “neurosis” – present in about a quarter of the population, and treatable by a variety of means, including SSRIs and cognitive behavioural therapy.

Arch Intern Med  11/25 Dec 2006  Vol 166

2437   This study of alcohol intake and total mortality in men and women is written by a team of Italians, and rightly so, because the Italians know how to drink. Tempting sorts of alcohol are cheaply available everywhere and all day long in Italy, but you rarely see a drunk Italian. Regular diners in Tuscan trattorie are brought a 3-litre fiasco of wine to drink with their meal, of which they sip a glassful or two – just so much as to give savour to the dish. It is taken away, still nearly full, at the end of the meal. This paper looks at a million people in 34 studies, and the recommendations are very similar to the BMA’s: 1-2 drinks a day for women and 2-4 for men have a net benefit on survival. A (moderately) merry Christmas to you all.

2455   The first paper on the prognostic importance of B-type natriuretic peptide in patients with coronary heart disease appeared in 1994 and seemed to me of such startling importance that I set up a study based on it. Here is a paper from Germany about the same thing (it’s compared with C-reactive protein and creatinine clearance in the title, and with LV ejection fraction in the text), with the same conclusion, accompanied by an editorial with the title “The Latest and Greatest New Biomarkers” (p.2428). “Latest” and “new” it may hardly be, but BNP is certainly the greatest at telling you which patients are heading for trouble, whether you measure it directly or by means of its N-terminal moiety.

2462   Anyone who tires of repeating prognostic studies using BNP can always do another study showing that vitamin E is useless. The latest in an endless stream is this bit of the Women’s Health Study showing that it does not prevent cognitive decline in healthy women.

2482   Infertility due to ovarian disorder turns out to have an up side in the Nurses’ Health Study II: women who have problems conceiving, and especially those who need to have induced ovulation, are at lower risk of breast cancer.

2502   This study attempts to link the mode of weight loss in obese women with their risk of later osteoporosis. They randomised 48 women to lose weight by caloric restriction only, exercise only, or neither (“healthy lifestyle” only). Sure enough, there was evidence of bone density loss in the first group but not the second.

2525   Beware patients on long-term therapy coming home after elective surgery with some of their medication missing. It happens in Canada, according to this study, and it can certainly happen here.

2533   I think we have evidence to prove that the osteoarthritic knee is highly sensitive to touch. I bet every reader who ever examines creaky knees has had a patient come back following a gentle examination saying that there knee hurt for hours/days/ weeks afterwards. I know that my hands are not alone in possessing this malevolent force, because they say the same – or worse - of orthopaedic surgeons and rheumatologists. On the other hand, anything done to such knees with therapeutic intent – real acupuncture or sham, rubbing in real cream or placebo, or in this case massage – has a beneficial effect which can last for an improbable time.

2539   How do you determine the dose of digoxin for heart failure in the modern era? ask these cardiologists from Chicago.  Why, surely you measure the serum digoxin. If it is zero, the dose is correct.

Plant of the Week: Viburnum farreri

Just a collection of straggling bare branches carrying pom-poms of pink flowers: but what a fragrance! In fact dear Reg Farrer, its discoverer, named it Viburnum fragrans, and the name was only changed to his after he had died. He was a wonderful writer and plantsman who led an extraordinarily busy and tragi-comic life. This ended prematurely in the mountains of Burma where he tried to go plant-hunting alone. Previous expeditions had succeeded due to the calm presence of his trusty companion Bill Purdom, but in the end Farrer’s eccentricity and temper, or perhaps his unrequited love, proved too much for Bill, and he declined another trip. When Farrer expired, possibly from measles, his native bearers threw away his seed collection (and whisky) but brought back his diary and his watercolours.

This plant will often be found in the gardens of the old ladies you visit at this time of year. Sniff it as you go in and as you leave, and your heart will remain warm towards them and towards Reg Farrer. If you want a plant of your own, ask the lady if you can take a cutting. It roots easily, and requests of this sort are rarely refused.

J A M A  27 Dec 2006  Vol 296

2927   While you are reading this, amoeba-like cells are crawling over your bones and eating them away. Unless, that is, you are taking a bisphosphonate to paralyze your osteoclasts and leave your osteoblasts to lay down new bone unhindered. The FIT study, which was published ten years ago, showed that daily alendronate for 3-5 years is safe and prevents osteoporotic fractures; but until this follow-on study (FLEX) we didn’t know what to do after that. Should we stop treatment at five years, knowing that bisphosphonates are highly bound to hydroxyapatite in bone and continue to work for ages after being stopped? Is there a risk of cumulative microfractures if we continue to use them? For the answers, it’s best to go straight to the editorial on p.2968, since the paper itself can be a very confusing read. Essentially, there is no evidence that continuing alendronate after the first five years does any good or any harm.  

2939   O little town of Framingham, how still we see thee produce new data. This week it’s about stroke over the last fifty years, and it’s a mixed story. Lifetime risk of stoke has only declined modestly in that time, since improvements in prevention seem mainly to have postponed rather than eliminated these events; outcome at 30 days has improved in men but not in women.

2947  While you are reading this, cells inside you are pumping out protons and chlorine ions and filling your stomach with hydrochloric acid. Unless, that is, you have gastric atrophy or are taking a proton pump inhibitor, like millions of middle-aged Britons. When these drugs first appeared, we worried that their miraculous symptom-relieving properties might hide serious long-term dangers to the GI tract. These have not materialised, but this study using the UK GP Research Database comes up with worrying evidence of a dose-related increase in risk of hip fracture in people taking PPIs for more than a year.

N E J M  28 Dec 2006  Vol 355

Your Christmas Day came to a blurry end with quantities of port wine and Stilton cheese. You don’t really remember going to bed, but soon afterwards you are aware that you have become a junior doctor working in an intensive care unit, trying to put in a central line. A sharp American voice from behind you snaps, “Doctor, your patient appears to be septicaemic. Are you aware that 20,000 US citizens die every year from catheter-related bloodstream infections?” In your panic, your hand jerks and the line flies out. Blood spurts over you, your patient, and the attending physician.

You wake up, dry-mouthed and sweating.  After groping for a couple of Rennies you turn over and hope for better dreams. But now you are in front of a large audience in the Massachusetts General Hospital. The same sharp American voice asks you “So, doctor, what is your diagnosis?” You see before you the attending physician, with a few remaining traces of blood in his distinguished white hair. A vast audience looks down at you. Every face wears the same expression of earnest disdain. You feel in your pocket for the clinical notes which you must have brought with you, but they are missing: your pocket is full of congealing blood. “Lymphoplasmacytic lymphoma with Waldenström’s macroglobulinaemia and biclonal gammopathy,” barks the attending, “and you missed it! So, doctor, can you tell us how you would go about investigating monoclonal gammopathy of uncertain significance?” You decide to confess humbly that you have never come across a case. The audience sniggers. “Maybe that’s because it’s only present in over 3% of people over the age of 50”, says the attending with an ominous smile, “you may leave the hall, doctor”.

You wake again, with the hooting of the audience in your ears. This time you resolve to wake yourself properly and get up for a glass of water. Settling back groggily, you find that you are in an examination room. A number of solemn inquisitors sit before you, dressed in gowns the colour of blood. The central figure, a white-haired attending physician whom you quickly recognise, begins the interrogation. “If a patient with HER-2 positive breast cancer has disease progression despite a taxane, an anthracycline, and trastuzumab, which chemotherapeutic agents should you use?”

 “Err..

 “No doctor, not err, you will get a better response if you use lapatinib plus capecitabine. Next question: explain why simple mendelian inheritance patterns are not seen in the long-QY syndrome.”

 “Could it be because… actually, I’m sorry I haven’t a clue.” 

“Because survival bias leads to female predominance. OK, a simple one then. Lack of which apolipoprotein predisposes to infection with Trypanosoma evansi?”

“Oh ‘ell…”

“I will allow that. L-1 is the full answer. Now, what can you tell us about the biochemical defect which underlies recessive lethal osteogenesis imperfecta?”

“In all its gristly detail?”

“Hah, you are on the right lines again. Deficiency in cartilage-associated protein. And now, doctor, for which condition might you consider the use of eculizumab?”

At this you break down and shout, “You must be taking the bloody p…!”

“Excellent, doctor”, smiles the attending, “Paroxysmal nocturnal haemoglobinuria!”

You wake up a last time and go to the loo, putting the light on to check the colour…

Then, a couple of days later, the New England Journal arrives and you check the contents:

2725:  IV catheter-related bloodstream infections in the ICU

2733  Lapatinib plus capecitabine for HER-2 positive advanced breast cancer

2744  Female predominance and transmission distortion in the long Q-T syndrome

2752  Trypanosoma evansi infection linked to a lack of apolipoprotein L-1

2757  Deficiency of cartilage-associated protein and recessive lethal osteogenesis imperfecta

2765  Monoclonal gammopathy of undetermined significance

2772  Case Records of the Massachusetts General Hospital: Lymphoplasmacytic lymphoma with Waldenström’s macroglobulinemia and biclonal gammopathy

2786  Correspondence: eculizumab in paroxysmal nocturnal hemoglobinuria.

You had had no ordinary nightmare– you had entered a parallel universe.

 

 

 

 

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