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March 2010

I have been concerned about the study that appeared in the BMJ recently about the association between industry affiliation and position on cardiovascular risk. Basically there was a clear and strong link between the orientations of authors’ expressed views on roiglitazone and their financial conflicts of interest: a drug that has concerned trusttheevidence previously.

In addition to this, an evaluation of solutions to sponsorship bias of more than 40 primary studies, and three recent systematic reviews and meta-analyses, have shown a clear association between pharmaceutical industry funding of clinical trials and pro-industry results.

What is alarming is that only half of the articles analysed in the BMJ had competing interest statements. However, this is much better that the 3% that was reported in 1998 by Stelfox. Authors at this time who supported the use of calcium-channel antagonists were significantly more likely than neutral or critical authors to have financial relationships with manufacturers of calcium-channel antagonists.

So in pondering this problem I think my solution is for primary studies, conflicts of interest should be disclosed when the article is published. However, for editorials and reviews where there is a direct conflict of interest (viz the researcher has received direct cash payments in the last five years) they should not be published by peer reviewed journals and should be left to those with an impartial viewpoint to publish in order to clear the muddy waters.

Obesity and alcohol-bad for your liver and worse in combination

Ami Banerjee
Last edited 22nd March 2010

After smoking, alcohol is the next public health behavioural challenge of our generation. There have been moves at national and international level to recognise and tackle the problem of alcohol misuse. Its consumption is increasing, particularly among younger adults.

Alcohol consumption increases risk of liver disease. However, levels and patterns of alcohol consumption do not fully explain the rises in liver disease mortality that have occurred in some countries.

A recent Scottish study showed that body mass index(BMI) is related to liver disease, suggesting that the current rise in overweight and obesity may lead to a continuing epidemic of liver disease. Looking in the same cohort of men in Scotland, the same authors found that raised BMI and alcohol consumption are both related to liver disease, with evidence of a supra-additive interaction between the two. This led the study authors to suggest that BMI-specific "safe" limits of alcohol consumption may need to be defined. In the same issue of the BMJ, a study of 1.2 million middle-aged women in the UK showed that 1800 of the women developed or died from liver cirrhosis during follow-up. Increasing BMI was associated with increased liver cirrhosis, with a 28% increase in risk for every 5 unit increase in BMI. In addition to the effect of BMI, the absolute risk of liver cirrhosis increased as alcohol intake increased. The authors estimated that 17% of liver cirrhosis is due to excess body weight, compared to 42% due to alcohol.

An accompanying editorial makes the point that “compared with the risk of cardiovascular events in middle aged people, an absolute risk of one case per 1000 people over five years for liver cirrhosis seems low. However, this absolute risk still represents a substantial burden of illness for the patients concerned and for the health service”. The upshot is that alcohol and obesity in combination cause liver cirrhosis, another negative consequence of unhealthy lifestyle. Reductions in alcohol consumption and obesity are currently the only way we can prevent non-viral liver disease.

Blood pressure-are we measuring it wrong?

Ami Banerjee
Last edited 17th March 2010

High blood pressure, or hypertension, is the most common risk factor for vascular disease, explaining half of the risk of stroke and heart attacks, and affecting half of adults in developed countries. In addition, hypertension is the leading cause of people being on prescribed drugs. So the way we measure and treat blood pressure is crucial.

Most of the Lancet this week is devoted to Professor Peter Rothwell, of Oxford University, who is challenging the way we measure and consider blood pressure. In a series of 3 articles in the Lancet, and one in Lancet Neurology, he argues that the idea of an absolute value of normal blood pressure has shortcomings, and in addition, we should be looking at how much the blood pressure varies.

The most common way of being diagnosed with hypertension is to have a raised reading on examination, which is then repeated after a few weeks/months. If the reading is still high, recommendations are made about lifestyle and if the readings are still raised, anti-hypertensive drugs are started. The problem is that blood pressure varies greatly between visits. This blood pressure variability between visits was measured in patients who had suffered from TIA (transient ischaemic attacks or “mini-strokes”) and found to strongly predict risk of stroke, regardless of the average blood pressure. Importantly, even in people with treated hypertension, blood pressure variability was associated with high risk of stroke. The maximum blood pressure was also a strong predictor of stroke.

In a systematic review of several randomised trials of blood pressure-lowering drugs, the drugs that caused the greatest reduction in this variability in blood pressure, were best at preventing stroke. These drugs were calcium channel blockers (e.g. amlodipine) and diuretics (e.g. furosemide), compared with beta-blockers, which were not as good at reducing variability in blood pressure, and therefore not as good at stopping strokes. When Rothwell and colleagues compared the visit-to-visit variability in blood pressure directly, they found that blood pressure variability decreased with calcium channel blockers, and increased with beta-blockers.

The take-home message is that measuring the absolute value of blood pressure should be combined with a measure of variability, and the ideal drugs to prevent strokes will both reduce the value and the variability of blood pressure. This has tremendous implications for not only how GPs diagnose and treat hypertension, it also has implications for population-level strategies such as the polypill.

Stenting versus surgery-lessons from the heart to the brain

Ami Banerjee
Last edited 17th March 2010

Atherosclerosis, or clogging up arteries, causes more deaths and more suffering than any other cause worldwide, most commonly in the form of heart attacks and strokes. Blocking of coronary arteries in the heart causes a spectrum of disease from angina to heart attacks, while blockages in cerebral arteries in the brain cause mini-strokes (transient ischaemic attacks or TIAs) and strokes. How best to prevent further strokes and heart attacks (secondary prevention) has occupied medical research for 40 years. There are similarities in the disease process and treatment strategies and lessons from the heart are proving useful in the brain.

Thrombolysis uses clot-busting drugs very soon after the heart attack or stroke to reduce the risk of further events. In both heart attacks and strokes, this treatment is now well-established as long as it is delivered within the narrow time window (12 hours for heart attacks and 4.5 hours for stroke). Evidence from randomised trials was 7 years later in the case of stroke, compared with heart attacks, and the data from meta-analysis has been even slower .

In both heart and brain, surgery is possible to remove or bypass the area of the blood vessel that is worst affected by atherosclerosis.
Coronary artery bypass surgery (CABG) uses a strip of vein or artery to bypass the section of narrowed vessel. An alternative strategy is to insert “stents” to keep the narrowed section patent and allow blood flow. Coronary stents have been adopted across the world for the last 20 years, at the expense of CABG for several reasons, including patient preference, shorter hospital stay, physician preference and stent-company lobbying. Meta-analysis has shown that in the case of multi-vessel disease, CABG is at least as good as stenting, and perhaps even better. Stents had been widely adopted despite inadequate long-term follow-up data, and despite inadequate trial data.

It was not long before stents started to be used in the arteries to the brain as well. However, it seems that the same caution needs to be used with stents in the brain circulation as in the heart. A recent randomised controlled trial of carotid endarterectomy (stripping away the clot from the wall of the artery) versus carotid stents in 1700 patients, concluded that carotid endarterectomy should remain the treatment of choice for patients suitable for surgery. Another analysis from the same trial showed that new lesions on MRI scan (suggesting stroke) were 3 times more likely after carotid stent versus carotid surgery. Data presented at the American Stroke Association last week from a similar North American trial suggests that the two treatments are near equal. Until proper long-term trial data and proper consensus is reached, let us hope that carotid stents are not rolled out with the same zeal as coronary stents.

The 1968 version of Oliver Twist in my mind is a classic. Anyone who has seen the film will remember that classic seen where Oliver asks for more:

The evening arrived; the boys took their places. The master, in his cook's uniform, stationed himself at the copper; his pauper assistants ranged themselves behind him; the gruel was served out; and a long grace was said over the short commons. The gruel disappeared; the boys whispered each other, and winked at Oliver; while his next neighbours nudged him. Child as he was, he was desperate with hunger, and reckless with misery. He rose from the table; and advancing to the master, basin and spoon in hand, said: somewhat alarmed at his own temerity:

'Please, sir, I want some more.'

The master was a fat, healthy man; but he turned very pale. He gazed in stupified astonishment on the small rebel for some seconds, and then clung for support to the copper. The assistants were paralysed with wonder; the boys with fear.

'What!' said the master at length, in a faint voice.

'Please, sir,' replied Oliver, 'I want some more.'

The master aimed a blow at Oliver's head with the ladle; pinioned him in his arm; and shrieked aloud for the beadle.

Condensed from Oliver Twist chapter 2

So, upon reading Susi Kriemler, trial in the BMJ on the Effect of school based physical activity programme (KISS) on fitness and adiposity in primary schoolchildren all I could think of was surely we need more of this type of research in our preventive strategies and less of the poly-pill mentality.

In the study children received a programme that included adding two additional physical activity lessons a week, daily short activity breaks, and physical activity homework. Overall, physical activity and fitness improved and led to reduced adiposity in children.

'Mr. Limbkins, I beg your pardon, sir! Oliver Twist has asked for more!

There was a general start. Horror was depicted on every countenance.

'For MORE!' said Mr. Limbkins. 'Compose yourself, Bumble, and answer me distinctly. Do I understand that he asked for more, after he had eaten the supper allotted by the dietary?'

'He did, sir,' replied Bumble.

'That boy will be hung,' said the gentleman in the white waistcoat. 'I know that boy will be hung.'

Condensed from Oliver Twist chapter 2

What do you think will happen if we ask: physical activity research, please sir can we have some more?

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