JOURNAL SNIPPETS November 3

NEJM 25 Nov 2010 Vol 363
2091 Quality improvement is actually, of course, a good thing in itself, and we need better ways of doing it and better ways of studying it. High quality outcomes research, carefully reflected on, is one essential input, and there are two good examples in this week's New England Journal. A general survey of North Carolina hospitals (see below, p.2124) produces a rather gloomy view of overall improvements in patient safety, but this study of mortality from allogeneic haematopoietic-cell transplantation is very much cheerier. The period 2003-7 showed an overall mortality fall of over 40% compared with a decade earlier, driven by significant decreases in the risk of severe GVHD; disease caused by viral, bacterial, and fungal infections; and damage to the liver, kidneys, and lungs. Further details are strictly for the haematologists: but it seems they have much to congratulate themselves about.
http://www.nejm.org/doi/full/10.1056/NEJMoa1004383

BMJ 27 Nov 2010 Vol 341
1144 Thrombolysis for acute occlusive stroke has been shown to be marginally beneficial in several RCTs, but the number of people over 80 in these trials is minuscule, whereas in real life, 30% of strokes occur in this age group. There is a presumption that the hazards of thrombolysis will be greater and the outcome difference less. This European registry study indicates that neither is true: thrombolysis remains beneficial for stroke beyond the age of 80.
http://www.bmj.com/content/341/bmj.c6046.full
1146 Any enthusiastic regular drinker of wine, will be delighted to note the PRIME study which confirms that by doing so you halve your chance of myocardial infarction. I suppose you also increase your chance of pancreatitis, cancers of the GI tract and stroke. Perhaps liver disease too, though the literature is surprisingly obscure at levels of intake below about 100u/week. The thing not to do is binge drink, which is a common pattern in Northern Ireland, and probably increases your baseline risk of MI. I think the further north you travel, the more dysfunctional alcohol use becomes, as warm oblivion becomes ever more desirable. As if to illustrate this point, a review of frostbite on p.1151 finds that nearly half of it is associated with alcohol use. I bet that means vodka or whisky in most cases, and wine alone hardly ever.
http://www.bmj.com/content/341/bmj.c6077.fullhttp://www.bmj.com/content/341/bmj.c5864.extract

Arch Intern Med 22 Nov 2010 Vol 170
1926 In studies of drugs that put people into hospital, warfarin usually comes near the top. This study looks at how combined platelet inhibition with aspirin plus clopidogrel compares in emergency department visits for haemorrhage-related events. The score is 2-1: 2.5 events per 1000 prescriptions of warfarin as compared with 1.2 events for aspirin/clopidogrel.
http://archinte.ama-assn.org/cgi/content/abstract/170/21/1892

JAMA 17 Nov 2010 Vol 304
2129 Like all doctors who survived their hospital jobs in the 1970s, I have some shocking memories. Oddly enough, though, some of them are happy too, as the shocks saved lives. The woman dragged out of a freezing canal with a core temperature of 28ºC who survived intact after 16 defibrillations; the 43-year old man with chest pain who went into VF just as we were putting the leads on his chest: all of us can still remember these kinds of event, while our futile attempts go forgotten days after. Surely an automated defibrillator must beat a sleep-deprived, dishevelled house doctor at achieving survival following in-hospital cardiac arrest? Actually no: another massive US cardiac outcomes study looks at the results of introducing automated defibrillators on to the wards of 204 hospitals and finds that results actually tend to be worse.
http://jama.ama-assn.org/cgi/content/abstract/304/19/2129
2137 The harmful effects of low-dose ionizing radiation are not well understood, but from about 100mSv upwards we are no longer talking about low doses, but the kind of exposures about which we have data from Hiroshima and Nagasaki. Alarmingly, such doses were received by a third of patients in this study of repeated myocardial perfusion scanning. OK, the majority of these people were over 60 and had heart disease, and would escape long-term harm: but it suggests that we are getting too gung-ho about exposing people to high energy photons from X-ray machines and unstable isotopes, and the cumulative damage which they cause.
http://jama.ama-assn.org/cgi/content/abstract/304/19/2137

Lancet 20 Nov 2010 Vol 376
1741 Many doctors in the 1990s went through a phase of taking low dose aspirin and recommending it to many of their patients with high blood pressure and/or type 2 diabetes. Then came a series of trials which showed that it doesn't work for primary prevention of cardiovascular events, even in groups who are at increased risk. But it does prevent about 25% of bowel cancer, according to this long-term follow up study of participants in 5 large aspirin trials, matched at a median of 18.3 years with mortality registers. The results suggest that you need to take about 75mg of aspirin for at least 5 years to achieve such protection, and the effect may be specific to the proximal colon. Thus in theory universal aspirin consumption, combined with a universal programme of screening sigmoidoscopy, could prevent most bowel cancer. However, an analysis like this can tell us little about adverse events, and we will only know for certain after a prospective trial lasting at least ten years.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)61543-7/abstract

JOURNAL SNIPPETS November 2

JAMA 11 Nov 2010 Vol 304
2028 It's not often that you see a paper in JAMA written by a real working British GP - so congratulations to Louis Levene from Leicester for an excellent study that seeks to inform US practice by showing what happens to coronary heart disease mortality in relation to the recorded characteristics of individual primary care trusts. This was quite a statistical feat in itself, but would have been even more useful had it been done on an individual practice basis - after all, the data are out there, literally for all to see. Anyway, rejoice: CHD in the UK has fallen by nearly a half in the last decade, and although there are regional variations, these are not due to variations in the quality of general practice, except in the detection of high blood pressure, which could easily be remedied.
http://jama.ama-assn.org/cgi/content/abstract/304/18/2028

2059 A neat Commentary piece discusses the dilemmas of interventional cardiology in the light of the COURAGE and SYNTAX studies which show that medical treatment is as effective as percutaneous coronary intervention for stable coronary artery disease. When the first study appeared in 2007, interventional cardiologists were asked if they would now have the conviction of their COURAGE and stop putting stents into every stenosis they happened to see at angiography - what has been described as the "oculo-stenotic reflex". All immediate stenting is lumped together as "ad hoc PCI" and accounts for more than 80% of PCI in the USA; done for acute syndromes, it is generally appropriate, but in other situations, often not. This is a thoughtful, balanced discussion which however tactfully bypasses one factor which may keep ad hoc PCI going in the USA - money. There may be a double incentive - patients and HMOs may want to save the cost of a second angiography; and cardiologists and their institutions may just want the extra dollars they get for putting in a stent there and then. This piece argues that there where there is clinical doubt there should always be informed patient decision-making, even if this means taking a two-week pause between the diagnostic angiogram and the procedure.
http://jama.ama-assn.org/cgi/content/extract/304/18/2059

Lancet 13 Nov 2010 Vol 376

1658 A huge trial called SEARCH was set up in Oxford in 1998 in the hope of demonstrating that 80mg of simvastatin would be better than 20mg at preventing further coronary events in survivors of MI, and that additional benefit would result from lowering homocysteine. In fact it has shown neither. The high dose simvastatin group showed a 26-fold increase in significant myopathy, an expected fall in lipid cholesterol (LDL-C), but no significant difference in vascular events at a mean of 6.7 years. Yet in the summary this is taken to mean that high dose simvastatin is preferable, since that fits into a general meta-analysis of statin trials on p.1670. Although medicine has been taught alongside logic in Oxford for 850 years there is still room for improvement. Consider the following three statements:
- there is a continuous association between the observed level of LDL-C and coronary heart disease (CHD)
- all statin drugs lower LDL-C
- all statin drugs lower CHD in the same proportion that they lower LDL-C.

Does it therefore follow that:
(1)statin drugs lower CHD entirely by means of lowering LDL-C
(2) all drugs that lower LDL-C will lower CHD to the same degree as statins?
It would be good to think that any canny medieval Oxford schoolman would immediately answer no to both deductions, or rather "quod non erat demonstrandum".

In the case of (1), the best we can say is that this is a reasonable hypothesis, but a hard one to test. In the case of (2) we can say that this is a weak hypothesis, since every drug class has a mixture of actions, and so far no LDL-C lowering drugs other than statins have been shown to lower CHD. Nor should we prescribe them until they have. But the writing committees of these two studies, sharing a number of Oxford notables, behave more like theologians than logicians. LDL-cholesterol to them is an infallible surrogate, and anything that lowers it must be good, even though they have only studied statins. It's enough to make you want to burn your gown. As for The Lancet: this is the second time in two weeks that they've let triallists write a summary which misrepresents the result of trial which was negative for its primary end-point (SEARCH this week, VITAL last) - not good enough.

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60310-8/abstracthttp://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)61350-5/abstract

BMJ 13 Nov 2010 Vol 341
1034 Do you like PROMs? When I was 16, I didn't mind queuing for tickets outside the Albert Hall and standing in the top gallery, but now being older, if you buy tickets on-line you can sit down and actually hear the players. This abbreviation also applies to patient-reported outcome measures, of the kind looked at in the context of heart failure. Suddenly these kinds of PROMs have become fashionable politically and get repeated mention in the White Paper "Liberating the NHS" - although they were never designed for service development but as end-points for clinical trials. Their quality and relevance varies widely, as you learn rapidly. This ground-breaking study devised an instrument with a high degree of inter-observer agreement to allow the assessment of PROMs in cardiovascular trials. Suffice to say that in many of the trials where they appear, they are used badly or irrelevantly, while in 70% of trials where they should appear, they don't.
http://www.bmj.com/content/341/bmj.c5707.full

Arch Intern Med 8 Nov 2010 Vol 170
1834 Delay From Symptom Onset to Hospital Presentation for Patients With Non–ST-Segment Elevation Myocardial Infarction. If you're a veteran scanner of titles in the US cardiovascular outcomes literature, the next thing you'll look for is the name of Harlan Krumholz in the authors list - ah yes, there it is, and so too is the name of Brahmajee Nallamothu, co-author of the thoughtful commentary piece on PCI in this week's JAMA. As a result of their work, and that of Henry Ting and John Spertus, who also appear in the credits, we know a huge amount in great detail about the workings of acute cardiology in the USA, despite the great variety of institutional arrangements. As a result of this exercise, for example, we know the exact time delay and clinical characteristics of 104 622 patients admitted to 568 US hospitals with NSTEMI - and realise that there has been no reduction in the delay time between 2001 and 2006. http://archinte.ama-assn.org/cgi/content/abstract/170/20/1834

1842 Now the interventional trials for ST-Elevation MI tell us that time means myocardium, so great efforts have been made in the US as in the UK to ensure that door-to-balloon time should be as short as possible. But what have we here? A study of 8771 patients admitted to a Michigan hospitals group between 2003 and 2008 which shows that although door-to-balloon time improved dramatically, outcomes remained the same. More data from UK studies quickly please: and since we do not have 568 acute hospitals and they all belong to one organisation, this should be a piece of cake compared with Harlan's work.
http://archinte.ama-assn.org/cgi/content/abstract/170/20/1842

1858 From time to time, serious medical journals like to publish pieces about chocolate, which are sure to get them a mention in the global news media. This research letter also involves women, thus allowing journalists to trot out their very funny jokes about the dear ladies and their chocolate. A group from Perth, Australia followed up a female cohort for 10 years to examine the effect of calcium supplements, and happened to ask about chocolate intake in their questionnaire. Here they report that chocolate consumption seems to have a dose-related protective effect against vascular disease in women. Ooh, come on girls, have another. http://archinte.ama-assn.org/cgi/content/extract/170/20/1857

SNIPPETS FROM JOURNAL WATCH

NEJM 15 July 2010 Vol 363
245 If anything can cause a company's profits to BLOOM, it's a new obesity drug. The BLOOM (Behavioural Modification and Lorcaserin for Overweight and Obesity Management) trial was funded by Arena Pharmaceuticals, who will be hoping for vast returns on the latest drug to target the serotonin receptor. Those with supernaturally good memories and profound knowledge of clinical pharmacology (OK, you can put your hand down, Jeff Aronson) will remember that there are actually three such receptors and that previous anti-obesity drugs such as fenfluramine and dexfenfluramine targeted them non-specifically. They worked fairly well for appetite suppression but were withdrawn because they could cause valvular heart defects and pulmonary hypertension. This is because cells around the heart valves and in the pulmonary vasculature contain 5HT2B receptors whereas the receptor you need to hit for appetite suppression is 5HT2C. Lorcaserin is powerfully specific for this receptor and Arena went out of their way to check their trial subjects regularly with echocardiograms which prove that it doesn't cause heart valve problems in the first two years. Whereas it certainly does help people lose weight and will be advertised as blooming wonderful if and when it gets it licence. http://content.nejm.org/cgi/content/abstract/363/3/245

266 In reviews of acute pulmonary embolism I look for two things: mention of it as a common cause of exacerbations in heart failure and COPD, and guidance about which patients need long-term anticoagulation. This article by two Italian authors doesn't fully satisfy either criterion. There's little mention of HF or COPD and although they say that "extended treatment requires a reassessment of the patient's risk-benefit ratio at periodic intervals" they fail to tell us how to calculate these risks and benefits.
http://content.nejm.org/cgi/content/extract/363/3/266

Lancet 17 July 2010 Vol 376
163 Droves of healthy people come to see doctors all year round to have blood pressure checks. If it's off target, their GP sees them every few weeks to make adjustments. Neither the timing, the place nor the health professional involved reflects any real logic. This ground-breaking study (TASMINH2) addresses these realities by passing management to the patient whose blood pressure is monitored at home with a reliable automatic device linked by an automated modem to the GP practice. If it remains high, the patient is given advice and if necessary additional drug treatment to reduce it. The group randomised to this intervention showed usefully better control of systolic BP at the end of a year. If this technology became widespread, we would save many GP appointments and improve control in most of our hypertensive patients.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60964-6/abstract

Lancet 10 July 2010 Vol 376
112 Exercise will also help you avoid a stroke; alcohol alas will not. Most of the other risk factors for stroke identified by the INTERSTROKE study are the ones you might expect, and the ten main ones account for nearly 90% of the risk. The oddest feature is the role of body mass index: when corrected for other factors, a high BMI actually seems protective, whereas a high waist-to-hip ratio is a substantial risk factor.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60834-3/abstract

NEJM 1 Jul 2010 Vol 363
36 Implantable cardioverter-defibrillators often go wrong due to lead failure, and they can lead to shockingly bad ends in heart failure. This trial assesses a new type of ICD which does not rely on venous access but is entirely subcutaneous, delivering shocks to the thorax close to the heart. Its success depended a lot on accurate positioning, and over the ten months of the trial it worked well and appropriately, though it's too soon of course to say anything about long-term reliability, let alone long-term mortality benefit.
http://content.nejm.org/cgi/content/abstract/363/1/36

1037 The well-conceived new Archives series called LESS IS MORE here lives up to its radical credentials: we are giving diabetic patients too many drugs for cardiovascular protection. Again, this flies in the face of what we have been taught over the last few years. It also seems to fly in the face of the calculation done by these authors that treating to targets for LDL-cholesterol and blood pressure results in gains of 1.5 and I.35 quality-adjusted years respectively. But they demonstrate that these overall gains are largely accounted for by the treatment of a small number of very high-risk individuals, and that the more drugs you put in, the more you are likely to achieve minimal benefit or actual harm. A key paper in the continuing debate about targets in type 2 diabetes.
http://archinte.ama-assn.org/cgi/content/abstract/170/12/1037

Arch Intern Med 28 Jun 2010 Vol 170
1024 If in doubt prescribe statins. Among patients with known cardiovascular disease, it is very hard to find any benefit once heart failure has set in. But prescribing statins to high-risk patients for primary prevention may be futile, according to this literature-based meta-analysis. It is a very hard paper to follow, however, with a fairly heterogeneous mix of studies which are not adequately characterised or analysed in these six pages: to do that would require twice the length, or ideally an entire database, which could then be analysed on an individual patient basis...
http://archinte.ama-assn.org/cgi/content/abstract/170/12/1024

1032 The JUPITER trial of rosuvastatin was stopped early and has been a source of controversy ever since. The acronym stands for Justification for the Use of Statins in Primary Prevention, but when JUPITER's data are fed into a meta-analysis like the one we've just seen, there is no such Justification. In fact the data of this trial are internally contradictory in a way that strongly suggests manipulation, according to this critical reappraisal, which suggests that Jove's ire should be directed at the role of commercial sponsors.
http://archinte.ama-assn.org/cgi/content/abstract/170/12/1032

1037 The well-conceived new Archives series called LESS IS MORE here lives up to its radical credentials: we are giving diabetic patients too many drugs for cardiovascular protection. Again, this flies in the face of what we have been taught over the last few years. It also seems to fly in the face of the calculation done by these authors that treating to targets for LDL-cholesterol and blood pressure results in gains of 1.5 and I.35 quality-adjusted years respectively. But they demonstrate that these overall gains are largely accounted for by the treatment of a small number of very high-risk individuals, and that the more drugs you put in, the more you are likely to achieve minimal benefit or actual harm. A key paper in the continuing debate about targets in type 2 diabetes.
http://archinte.ama-assn.org/cgi/content/abstract/170/12/1037

JOURNAL SNIPS

This week includes abstracts from the NEJM and Archives of Internal Medicine

NEJM 1 Jul 2010 Vol 363
36 Implantable cardioverter-defibrillators often go wrong due to lead failure, and they can lead to shockingly bad ends in heart failure. This trial assesses a new type of ICD which does not rely on venous access but is entirely subcutaneous, delivering shocks to the thorax close to the heart. Its success depended a lot on accurate positioning, and over the ten months of the trial it worked well and appropriately, though it's too soon of course to say anything about long-term reliability, let alone long-term mortality benefit.
http://content.nejm.org/cgi/content/abstract/363/1/36

Arch Intern Med 28 Jun 2010 Vol 170
1024 On to statins .... Among patients with known cardiovascular disease, statins are drugs which are very hard to find any benefit once heart failure has set in. But prescribing statins to high-risk patients for primary prevention may be futile, according to this literature-based meta-analysis. It is a very hard paper to follow, however, with a fairly heterogeneous mix of studies which are not adequately characterised or analysed in these six pages: to do that would require twice the length, or ideally an entire database, which could then be analysed on an individual patient basis...
http://archinte.ama-assn.org/cgi/content/abstract/170/12/1024
1032 The JUPITER trial of rosuvastatin was stopped early and has been a source of controversy ever since. The acronym stands for Justification for the Use of Statins in Primary Prevention, but when JUPITER's data are fed into a meta-analysis like the one we've just seen, there is no such Justification. In fact the data of this trial are internally contradictory in a way that strongly suggests manipulation, according to this critical reappraisal, which suggests that Jove's ire should be directed at the role of commercial sponsors. I can hear the distant peal of thunder across the Atlantic: Jupiter tonans.
http://archinte.ama-assn.org/cgi/content/abstract/170/12/1032
1037 The well-conceived new Archives series called LESS IS MORE here lives up to its radical credentials: we are giving diabetic patients too many drugs for cardiovascular protection. Again, this flies in the face of what we have been taught over the last few years. It also seems to fly in the face of the calculation done by these authors that treating to targets for LDL-cholesterol and blood pressure results in gains of 1.5 and I.35 quality-adjusted years respectively. But they demonstrate that these overall gains are largely accounted for by the treatment of a small number of very high-risk individuals, and that the more drugs you put in, the more you are likely to achieve minimal benefit or actual harm. A key paper in the continuing debate about targets in type 2 diabetes.
http://archinte.ama-assn.org/cgi/content/abstract/170/12

Cardiovascular disease

3 articles of interest

Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysisBMJ

Lipid modification : Cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular diseaseNICE

Primary prevention of cardiovascular mortality and events with statin treatments: a network meta-analysis involving more than 65,000 patientsJournal of the American College of Cardiology

National Library for Public Health News

Cardiovascular disease
Effect of high-carbohydrate or high-cis-monounsaturated fat diets on blood pressure: a meta-analysis of intervention trialsCentre for Reviews and Dissemination
Health economic evaluation of controlled and maintained physical exercise in the prevention of cardiovascular and other prosperity diseasesCentre for Reviews and Dissemination
Health Survey for England 2006 : CVD and risk factors adults, obesity and risk factors childrenThe Information Centre
Importance of salt in determining blood pressure in children: meta-analysis of controlled trialsCentre for Reviews and Dissemination
Long-term effects of weight-reducing interventions in hypertensive patients: systematic review and meta-analysisCentre for Reviews and Dissemination
Statins for the primary prevention of cardiovascular events in older adults: a review of the evidenceCentre for Reviews and Dissemination