Richard Lehman’s journal review—3 December 2012

Richard LehmanJAMA  28 Nov 2012  Vol 308
2097   Heart failure is a common process of dying which mostly affects people over the age of 75. Living with heart failure can be burdensome and unpredictable, and dying from heart failure can be awful, unless you are lucky enough to die suddenly. I thought I’d get those sentences out of the way first, because when we look at the evidence base for treating heart failure it’s easy to regard it as a “disease” rather than a process, and to regard death and hospitalization as the most important aspects of it, and as things that are potentially avoidable. Most people in their late seventies expect to have something wrong with them and to die before too many more years have gone by: their fear is not so much death itself as what they will have to go through before they die. So when I look at a paper about heart failure, I first check out the age of the population and then see if there are any clues about what the patients experienced as a result of the intervention, other than death and hospitalization.

The patients in this study of associations between aldosterone antagonist therapy and risks of mortality and readmission among patients with heart failure and reduced ejection fraction had a mean age of 77: they were the same age as the real patients you and I deal with all the time. And in this observational study, it didn’t make a jot of difference to either end point whether they were taking aldosterone antagonists or not. They died and went to hospital at exactly the same rate, unlike the patients in the original landmark randomized trials of spironolactone and eplerenone, who showed a 30% decrease in both endpoints during these trials, which were both stopped early because of the magnitude of the effect. So why is there such a difference between the benefit in those studies and the lack of benefit we seem to observe here? There could be several reasons. The patients in the RALES trial were younger (mean age 65) and 45% of them had a non-ischaemic cause for their heart failure, whereas in this study it was less than 30%. The same applies to a lesser extent to the eplerenone trials. But I think the main clue in this observational study is that the patients who were taking these drugs were already taking higher doses of ACE inhibitors and ß-blockers than the comparison group. In other words, they were at a later stage of the heart failure process, and that’s why they had been given what most clinicians regard as third-stage treatment. And whether they felt any better on it is a question this study can’t answer: very few studies have ever bothered to ask.

2108   Half of all the elderly patients who have heart failure do not have a reduced systolic ejection fraction, and they live in a diagnostic and therapeutic no-mans land, despite being just as likely to die. Attempts to treat this kind of heart failure with renin-angiotensin system inhibitors have met with no success in randomized trials. But in this Swedish database study of patients with heart failure and preserved ejection fraction (defined as over 40%), the use of RAS antagonists was associated with lower all-cause mortality. A good editorial by James Fang speculates as to why this might be so, and sensibly suggests that rather than trying out RSA antagonists on everyone with this form of HF, we should use them preferentially to treat the large number who have elevated blood pressure.

2118  Travelling south across the straits from Sweden to Denmark, we turn to another registry-based study for cardiovascular enlightenment. “Through a search in the Danish National Patient Registry, 4075 patients were identified who had bioprosthetic aortic valve replacement surgery performed between January 1, 1997, and December 31, 2009. Concomitant comorbidity and medication were retrieved. Poisson regression models were used to determine risk.” The question here is whether warfarin therapy can safely be stopped at three months, as is common practice. But the analysis convincingly demonstrates that discontinuation of warfarin treatment within 6 months after bioprosthetic AVR surgery was associated with increased cardiovascular death. Usual practice may need to change.

NEJM  29 Nov 2012  Vol 367
2075   A cream cheese spread, a smooth orchestral sound, the birthplace of the American constitution, brotherly love, and a chromosome of evil repute: what do they all have in common? Why yes, it is the name Philadelphia. The so-called Philadelphia chromosome results from a reciprocal translocation between chromosome 9 and 22 and is present in 95% of chronic myelogenous leukaemia and also in some cases of acute lymphoblastic leukaemia. This trial recruited Philadelphia chromosome positive patients with both these malignancies whose disease had relapsed after a number of previous treatments and gave them all ponatinib: this was a phase 1, dose-finding trial. Ponatinib is a potent oral tyrosine kinase inhibitor that is different from the rest because it can get past the gatekeeper mutant T315I, which is uniformly resistant to other tyrosine kinase inhibitors. The short-term effects in this trial were little short of spectacular. Despite having been treated previously with at least two other tyrosine kinase inhibitors, the great majority of patients showed complete haematological remission with ponatinib. But we need to be patient: there were many adverse effects and the patients with the poorest prognosis (those with acute or blast-phase disease) responded least. We need phase 2 and 3 trials before declaring a breakthrough.

2089  The new blockbuster drugs to follow the statins were going to be high density lipoprotein cholesterol increasing drugs, such as the rapibs—inhibitors of cholesteryl ester transfer protein (CETP). But we are rapibly becoming disillusioned. First torcetrapib bit the dust, and now it is the turn of dalcetrapib. In this trial it increased HDL cholesterol levels but did not reduce the risk of recurrent cardiovascular events in patients who had recently had an acute coronary syndrome. The manufacturers of the last CETP inhibitor standing, anacetrapib, continue to pour money into a massive trial being organised by Oxford’s Clinical Trials Support Unit, which will not REVEAL its results until 2017. I am not holding my breath.

2100   Another great money-spinner was going to be platelet function monitoring at the bedside to individualize treatment with the latest antiplatelet therapies: but this too is proving a dead end. “This study showed no significant improvements in clinical outcomes with platelet-function monitoring and treatment adjustment for coronary stenting, as compared with standard antiplatelet therapy without monitoring” say the investigators of this large French trial. So it’s clopidogrel all round folks, and remember that it is now a very cheap drug.

Lancet  1 Dec 2012  Vol 380
1909   A small but worthy comparative effectiveness trial went to a lot of trouble to randomize patients with severe ulcerative colitis unresponsive to intravenous steroids to receive either infliximab or ciclosporin. It took 27 European centres to collect 115 subjects. There was no significant difference in outcomes between the groups.

1927   A much larger comparative effectiveness trial from the UK examined whether antimicrobial urinary catheters could reduce symptomatic urinary tract infections in hospital patients who required temporary catheterization. As we know, the regulatory mechanisms for medical device licensing here are laughably lenient, and there are a number of such catheters available, with no good evidence that they have any superiority over an ordinary polytetrafluoroethylene (PTFE) urinary catheter. So it needed funding from the UK National Institute for Health Research Health Technology Assessment Programme to support this trial, which contented itself with a 3•3% absolute reduction in catheter related UTI as sufficient benefit to recommend routine use of antimicrobial catheters. But in fact neither a silver-impregnated nor a nitrofurantoin-impregnated catheter could reach this lowly bar when compared with an ordinary PTFE catheter in a trial of 7102 randomly allocated subjects.

This makes me wonder how widely British firms sell dud medical products abroad on the basis of inadequate evidence. I think it’s a question we should put to government, which is desperate to turn the NHS into a mechanism of wealth creation. Richard Horton speaks of this in his Offline this week. And all over England, clusters of academics and NHS trust managers are huddling together to create a network of Academic Health Sciences Networks, which have wealth creation as a core objective. Isn’t it time we exposed the moral and intellectual vacuity of the whole idea? Wouldn’t it be wonderful if when the AHSN delegations appear before the accreditation panel next February, each in turn could ask the following panel members some penetrating questions: Sir John Bell, Regius Professor at Oxford, whether as a board member of Roche he is urging them to disclose complete data from all their trials on human subjects; Peter Ellingworth, Chief Executive of the Association of British Healthcare Industries, whether he supports rigorous comparative trials before the licensing of medical devices; and Stephen Whitehead, Chief Executive of the Association of British Pharmaceutical Industry, whether he supports threats by many in industry to take their business elsewhere if the UK does not relax its regulatory environment? Does the imperative to create wealth override the imperative to test new interventions rigorously and openly? Should not all long term interventions—be they devices, drugs or systems of care—not undergo rigorous evaluation for harms and benefits in proportion to the duration of their use and the size of the population involved? Rather than fast-tracking new gizmos to boost exports, should we not be joining in with the developing world in a process of mutually learning how to deliver simpler and less costly models of health care? If the AHSNs can turn the tables and deliver these arguments, rather than meekly colluding in the latest dishonest rhetoric from government, then I think they should have everyone’s wholehearted support.

BMJ  1 Dec 2012  Vol 345
One panacea for all health systems that is repeatedly proposed by politicians is better self-management. This is largely a delusion. Patients and their families are often already self-reliant to a humbling degree, and the nature of most chronic disease is not such that teaching self-management will make much measurable difference. This Dutch trial looked at the effect of a self-management and monitoring programme in chronic obstructive pulmonary disease. There were no benefits in quality of life or “self efficacy,” though some observable difference in managing exacerbations. Let us face the facts about COPD: it is an irreversible condition, not worth diagnosing early or monitoring because there is no specific intervention, and almost all the drugs we use for it are useless, except for long-term macrolide antibiotics. There are big savings to be made in COPD, but they will not come from self-management but from the abandonment of useless investigation and treatment. Above all, from the restriction of tobacco sales to a registered few dependants—but what would that do to the British balance of payments?

Little Denmark hits the big time again this week with a study of thyroid function and the risk of atrial fibrillation conducted in Copenhagen over ten years. Eventually this netted 586 460 individuals with a mean age of 50, and it showed a pretty neat correlation between inverse correlation between TSH levels and the risk of AF. In other words, the more active your thyroid is, the more likely you are to get a hospital first time diagnosis of atrial fibrillation.

Fungus of the Week: Craterellus cornucopioides

When I retired from regular general practice two years ago, I imagined that I would spend most of the autumn wandering in woods looking for exotic and esculent fungi. It has not turned out like that at all, and in fact I have not had any fungus hunting time at all this autumn, except two short woodland walks with friends in Connecticut. The fungi I most hoped to find there were the American form of the European trumpet fungi, or “horns of plenty.”

When I finally found some, it was in Oxford market under the name of Trompets. These are black to grey and they are indeed trumpet-shaped: in France they are known either as trompettes des morts or trompettes de la mort. This should in no way put you off eating them: they are edible and delicious, as I shall explain. Coming straight out of the ground, they do resemble little trumpets played from the earth by the shrunken dead, which is an explanation for one of their names. The other would be an allusion to the Last Trumpet, to be sounded when the dead are raised and the Last Judgement begins. I guess this is the trompette de la mort, best known from Handel’s Messiah and the hymn Dies Irae which often forms a sequence in the Mass for the Dead (Requiem). But in fact French Requiem settings tend to be consolatory and often omit the Dies Irae, for which I like them the better: especially one of the earliest, probably by Antoine de Févin (or Anthonius Divitis 1475-c1530), stunningly sung by the Ensemble Organum; and also a remarkable Requiem by André Campra (1660-1744) dominated by lilting dance-tunes and the word luceat.

Back to the trumpet of the kitchen: here these fungi are well-named not just for their shape, but because they make a lot of noise in relation to their size. They do this best in cream, as for example in this dish of Quails and Trumpets:

Take four quails and joint them. Put the legs in a pan and simmer them for 4 minutes in best butter. Then add the breasts, and four cloves of garlic. Season with salt and pepper. Turn the legs and then the breasts and cook for about six further minutes. Now add a handful of trompettes, followed soon after by a glass of dry white wine. Turn up the heat and add a cup of thick cream and boil this quickly before serving, with chopped chives to garnish if you wish.

Wine: Vino Inferno, Valtellino 2008
Music: Tuba mirum spargens sonum from Mozart’s Requiem, sung by Alexander Kipnis under Bruno Walter (1938)