Research highlights – 10 December 2010

Research questions “Research highlights” is a weekly round-up of research papers appearing in the print BMJ. We start off with this week’s research questions, before providing more detail on some individual research papers and accompanying articles.

Varenicline and quitting smokeless tobacco
The use of oral smokeless tobacco is increasing in many countries; snus use is well established in Scandinavia, and the largest Western market for such products is the United States. Last year we published a meta-analysis of observational studies from these areas, which reported an increased risk of fatal myocardial infarction and stroke associated with use of smokeless tobacco (BMJ 2009;339:b3060). A recent clinical review notes that it’s also a risk factor for head and neck cancer (BMJ 2010;341:c4684).

Nevertheless, users often view smokeless tobacco as less harmful than smoking—but reports suggest that many would like to quit. There’s evidence that behavioural interventions can help them do so, but pharmacotherapy has so far shown little success.

In a multicentre randomised controlled trial, Karl Fagerström and colleagues investigated whether varenicline, a drug licensed as a smoking cessation aid, could also work for users of smokeless tobacco—mainly Norwegian and Swedish men who used snus. They found that the drug was more effective than placebo at helping users achieve both short and longer term abstinence, and it had an acceptable safety profile. The study was funded by Pfizer, the manufacturer of varenicline.

Safety of carbamazepine in the first trimester
A High Court action in England against Sanofi-Aventis over birth defects in children whose mothers took its anticonvulsant drug sodium valproate (marketed as Epilim) during pregnancy collapsed last month after legal aid was withdrawn (BMJ 2010;341:c6384). Lawyers for the families had argued that even though mothers were informed of this drug’s risks, they would have risked their unborn babies’ health by not taking an anticonvulsant.

So which anticonvulsant should women take? Carbamazepine seems to be the safest option in early pregnancy, but studies so far have lacked the power to detect risks for specific congenital malformations with the various drugs. Now Janneke Jentink and colleagues have analysed data from 19 European population based registers of congenital anomalies in the EUROCAT Antiepileptic Study Database, covering over 3.8 million births. Spina bifida was the only specific major congenital malformation significantly associated with exposure to carbamazepine monotherapy, and the risk was smaller for carbamazepine than for valproic acid. The authors also found, in an extensive literature review, an overall prevalence for a major congenital malformation of 3.3% (95% confidence interval 2.7 to 4.2) after exposure to carbamazepine monotherapy in the first trimester.

Editorialist Irena Nulmnan agrees that carbamazepine is the drug of choice for pregnant women with epilepsy and asserts that seizure control, perinatal counselling, and careful management should produce favourable outcomes in more than 95% of such pregnancies.

Non-specific benefits of measles vaccination in west Africa
Research from Africa, Bangladesh, and Haiti has shown that measles vaccination in infancy is associated with much greater reductions in mortality than would be expected simply from preventing measles. Given this, should the World Health Organization review its advice that measles vaccination should be given to 9 month old babies? Could more lives be saved by vaccinating sooner? 

Two years ago we published an interim analysis of a randomised controlled trial in Guinea-Bissau suggesting that two doses of the Edmonston-Zagreb strain measles vaccine given as early as 4.5 months of age might be warranted in humanitarian emergencies or measles outbreaks (BMJ 2008;337:a661). In that trial the number needed to treat to prevent one case of measles during the epidemic was 7.2 (6.8 to 9.2). The treatment group tended to have lower overall mortality, but this was not significant.

Now Peter Aaby and colleagues’ further analysis of this trial finds that mortality was significantly lower between 4.5 and 36 months of age for vaccinated girls but not boys (intention to treat mortality rate ratio 0.64 (0.42 to 0.98). This trial is just one of many intriguing studies arising from the long term Bandim Health Project on the population effects of vaccines, vitamin A supplementation, distribution of bed nets, and other interventions in Guinea-Bissau, one of the world’s poorest countries (

Research online: For this and other new research articles see

Lifetime cardiovascular risk
Validated risk prediction algorithms such as QRISK2 usually use a 10 year absolute risk of cardiovascular disease of 20% or greater to identify patients at high risk. But applying this threshold may miss people at younger ages who, despite a low absolute 10 year risk, have a high risk relative to their peers.

In a UK cohort study, Julia Hippisley-Cox and colleagues aimed to develop, validate, and evaluate a new QRISK model to estimate lifetime risk of cardiovascular disease. Their approach identified younger people with a high lifetime risk who would not have been identified with 10 year risk estimates—such patients were more likely to be men, to be from non-white ethnic groups, and to have a family history of premature coronary heart disease.

But although lifestyle interventions at an earlier age could help some people at high lifetime risk, it’s unclear whether the benefits of earlier medical treatment would be outweighed by the associated risks and costs, say the authors.