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February 2011

The Pubmed Index and lessons from ethnicity and stroke

Ami Banerjee
Last edited 28th February 2011

I have started using what I have termed the “Pubmed index” to show trends on a particular topic in medical research. In essence, after an unrestricted search in Pubmed to find how many articles mention my search terms, I look at how many hits I get by restricting the search to 10, 5 and 1 years, to find out how much of that research has been done recently, and how “hot” the topic is. “Ethnicity” and “stroke” gives 2411 references, of which 1719 hits are in the last 10 years, 1067 in the last 5 years, and 182 in the last year. In other words, most of the work on ethnicity and stroke has been done in the last 10 years, and the topic is still being researched.

This makes sense because 10-15 years ago, data from the UK and North America showed that there were differences between black and white populations in stroke. For example, there was an excess of haemorrhagic stroke in black populations. In America, this ethnic group had reduced access to stroke services and higher mortality rates, leading to the so-called “stroke belt” in the South-eastern region of the US. The research base for racial or ethnic disparities in stroke has increased across ethnic groups, including Hispanics and South Asians. More recently, with epidemiologic transition and rising prevalence of chronic diseases, data is showing differences in stroke subtypes and risk factors between black and white populations in sub-Saharan Africa.

Ethnicity research has faced hurdles, partly because inadequate definitions and partly due to concerns about political correctness, and ethnic minorities are still under-represented in clinical trials in stroke. With increasing migration within and between populations, a greater consensus is required regarding future studies of ethnic disparities. More comparisons need to be made between ethnic groups as “immigrant populations” versus the ethnic groups in “home populations”, to consider what the effects of migration on disease in its own right are.

Prospective studies which follow populations over time, like the REGARDS(REasons for Geographic And Racial Differences in Stroke) Study in the US, are a preferred methodology than retrospective studies. There has been surprisingly little research about ethnicity in relation to other “non-modifiable risk factors”, such as family history or genome-wide scans, which will help in characterising how ethnicity is associated with risk factors, behaviour, treatment and disease outcomes.

This week, the BMJ published a study online showing that black patients and patients from higher socioeconomic groups were more likely to be admitted to stroke units than white patients and poorer patients in an area of London. These results are interesting because historically data about ethnic disparities, regardless of the country or the setting, has invariably shown that ethnic minorities have less access to services. A rapid response to the article, rightly concludes that we need to know more accurately what is happening overall in the population, rather than having isolated studies. As unwarranted variations in population medicine are increasingly studied and linked with changes in health policy, proactive, rather than reactive studies of ethnicity are required. In other words, it is not enough to just describe variations and disparities, we need to move towards explanations and potential actions which can reduce disparities, and need better population-wide surveillance.

Zinc not for colds: heterogeneity, subgroup, toxicology and more

Carl Heneghan
Last edited 21st February 2011

There's no cure for the common cold, but according to a Cochrane Reviews, using zinc supplements may shorten the illness by a few days.

I can see all the hypochondriacs out there, start throwing away their vitamin C, the vitamin for staving off the cold, thanks to Linus Pauling, who said he’d never had a cold in his life. Well, you’ve been wasting your time, because now there is zinc. Wonderful, but is it any good.

Should we just take as fact that a Cochrane review is gospel and get on with sucking the pastels? Just because a reputable journal publishes a paper it doesn’t mean the findings will stand up to scrutiny. Reading the news won't help because there isn’t one critical analysis out there.

What the Cochrane review of Zinc for the common cold found from 13 trials was that the intake of zinc is associated with a significant reduction in the duration and severity of common cold symptoms. What concerns me about the result is the amount of heterogeneity for the main outcome, I squared of 93%.

At this amount of heterogeneity, which is the studies' results differ so much, it is implausible to combine them. Generally anymore than 50% heterogeneity you shouldn’t combine outcomes unless you have a good reason why it makes sense. They don't. The studies differed in terms of variable formulations (zinc gluconate or acetate lozenges, zinc sulphate syrup) and dose range (30 to 160 mg/day) as well as mean duration of symptoms prior to administration of zinc (varying from 24 to 48 hours).

The worst of it is, in the authors' limitations they state ‘the results from all the trials may not be comparable’. Couldn't agree more.

This review also has the added problem of multiple comparisons. Reporting day 3 and 5 results are not significant, and hey presto at day 7 there was a significant difference between the zinc and control group at a p value of 0.05. Doesn’t wash. For those of you who have no idea what I’m on about visit the bonferonni correction.

Oh and by the way, eleven of the studies were funded by pharmaceutical companies. And I didn’t even get the chance to say most trials relied on community-acquired infections in which the infecting agent was not identified. This is what the authors say ‘so it is unclear whether zinc helps those with rhinoviral cold or even cold due to other viruses.’ And one last moan, ‘given its toxicological profile, the potential for zinc to induce adverse effects at the doses participants are required to take also needs to be determined’.

Want my advice, keep taking the vitamin C, it tastes better.

The last couple of weeks have taught me a lot about how clinical research gets published and disseminated. On 1st February, our article, titled, “Familial History of Stroke Is Associated with Acute Coronary Syndromes in Women”, was published online by Circulation Cardiovascular Genetics prior to print. This is one of the subspeciality journals of “Circulation”, a publication aimed at scientists generally interested in cardiovascular medicine and research. Over the last few years, several of the major journals have increasingly multiplied into “sub-speciality journals”. For example, “Lancet” has spawned “Lancet Neurology”, “Lancet Infectious Diseases” and “Lancet Oncology”. Not only are the journals able to publish more specialised research that might have been rejected by the parent, general journal; they can also charge more for subscriptions, reprints and so on.

Interestingly, even as an author, I did not receive a copy of my manuscript and do not have access to the journal article, unless I pay for access or buy a reprint. So I will tell you what the gist of the research is. Basically, within the Oxford Vascular Study, a much studied cohort of 90 000 patients from the Oxfordshire general practice population, we looked at about 1000 patients with stroke and about 1000 patients with heart attacks.

Previous analyses from the same study have shown that women with stroke are twice as likely to have female relatives with stroke as male relatives with stroke. In addition, young women with heart attacks are twice as likely as young men with heart attacks to have mothers with heart attacks. Therefore, mother-to-daughter transmission seems to be important. For this reason we looked at family history of stroke in detail among patients with acute coronary syndromes (heart attacks and “unstable angina”).

Firstly, we found that family history of stroke is as common in heart attack patients as stroke patients. Secondly, women with heart attacks were twice as likely to have history of stroke in their mother as in their father. Thirdly, when we looked at the coronary arteries (which supply the heart) directly using coronary angiography, family history did not predict the location of the coronary artery disease or how severe it was. We concluded that family history of stroke needs to be studied in more detail and may well be important in better identifying women most at risk of heart attack, since women are less likely to be picked up by current risk prediction tools used by doctors. Also family history probably has its effect via influences on clotting rather than on arteries directly, given our lack of correlation with disease on angiography.

I spoke with only 1 freelance American journalist and helped write 2 press releases in the week before the article went online. On 1st February, I received an e-mail from the University that the article had been picked up by news brokering websites from Reuters to Yahoo, newspapers and TV from Canada and the Phillippines to India, South Africa and the UK tabloids. I don’t mind telling you I was surprised by all the interest! Even BBC Radio 4 contacted me to go on Woman’s Hour.

I have taken three lessons from this experience. First, a journal article will probably be read by almost nobody, primarily because it is published in a journal, and secondly because access to that journal requires money. Second, although research is published in journals, the immense speed and penetration of the global media/internet machine (based in this case on 3 interviews or press releases!) have led to the devolution of the dissemination of research findings away from journals, even though journals may be the trusted source of the original research. Third, as scientists, if we want our research to be understood by the broader public, then we need to do more than publish articles in journals, we must engage with the media and with the public. Both doctors and patients are more likely to use internet search engines than journals so we have to make sure that Google is well-informed, otherwise a great opportunity for health communication will be missed.

Statins and drug companies-more than meets the eye?

Ami Banerjee
Last edited 2nd February 2011

We have blogged a lot about statins in the past here at Trusttheevidence.net, partly because they are so commonly used and partly because they are so often in research and in the media. Their role in secondary prevention is not in question and they are arguably one of the greatest advances in cardiovascular disease prevention in modern times in this respect. However, for quite a while, the role of statins in primary prevention has been doubtful, and last week a Cochrane review and a related editorial added to the already strong evidence base that if you are at low risk of coronary heart disease or stroke, you probably should not bother with statins.

The WHO’s Bulletin included research this week which showed that high cholesterol is undertreated even when it is diagnosed. “The proportion of undiagnosed individuals was highest in Thailand (78%) and lowest in the United States (16%). Time series estimates showed improved control of high total serum cholesterol over the past two decades in England and the United States.” One reason for these observations may be the fact that many of these patients with high cholesterol had no history of cardiovascular disease, and so the lack of definitive evidence for statins in primary prevention may have led to their omission. Another reason may be that the most aggressive marketing of statins for primary prevention occurred in US and European health systems. The authors of the study called for increased treatment of high cholesterol to stem the world’s cardiovascular epidemic, despite continued doubts about the role of statins in primary prevention. This research received wide media coverage and adds to the confusion in policy around statins for primary prevention

So I am wondering how come all this data and controversy about primary prevention data for statins has tended to appear so late in the patent life of the drugs. Of course, part of the issue is that it takes time to organize trials, and to gather enough data for meta-analyses. However, the entry about statins on Wikipedia made me think:

“To market statins effectively, Merck had to convince the public about the dangers of high cholesterol, and doctors that statins were safe and would extend lives.”

Did you know that “Lipitor” (aka “atorvastatin”), made by the world’s pharmaceutical giant, Pfizer, is the biggest blockbuster drug of all time? If you look at the list of top-selling drugs of all time, simvastatin, rosuvastatin and pravastatin are all high on the list. The problem for big pharma is that the statins are going off patent. Atorvastatin is already off patent in several countries and most of Pfizer’s patents for this drug expire in 2011. This is a big financial problem for Pfizer and other companies, and only yesterday, the close of Pfizer’s main UK base was announced. Drug companies are being forced to change their old research and development paradigms. They are also not going to be able to get away with withholding data or encouraging “off-label” use of their drugs. It is surely possible to develop safe and effective drugs with more openly available information to both clinicians and patients.

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