Asthma researchers wrangle over safety of inhalers

William Brown

A study which led to warnings that the most popular asthma drugs increase the risk of a fatal attack was strongly criticised by leading researchers this week after the full details of the study were published.

The study by Canadian researchers identified a link between asthma deaths and the beta-2 agonist drugs in common inhalers used to relieve attacks of asthma. But researchers in New Zealand, who first raised the questions about safety of the drugs, say the Canadians have drawn the wrong conclusions and that "questionable findings on beta-2 agonists in general are being over emphasised".

The study carried out in Saskatchewan between 1978 and 1987 concluded that an asthmatic’s risk of dying more than doubled with each extra can of beta-2 agonist used per month in the previous year. Its results seemed so strong that the drugs company Boehringer Ingelheim sent a warning letter to regulatory authorities around the world before the full results were published. When details of the letter emerged last July, front page headlines in North America and Australasia prompted the Victoria state government in Australia to mount an inquiry into the inhalers.

The full results have now been published in the New England Journal of Medicine (20 February) by Walter Spitzer and Samy Suissa of McGill University in Montreal. In New Zealand, Richard Beasley and his colleagues at the Wellington School of Medicine, say the Canadian’s methods cannot support the conclusions which they have drawn.

The Canadians believe they have found an effect which is common to all beta-2 agonist, fenoterol, is more risky than another - salbutamol, which is marketed as Ventolin.

Until recently fenoterol, made by Boehringer Ingelheim, was the leading asthma drug in New Zealand, Germany and the Far East. But on the basis of the new results Beasley now advises doctors to avoid it altogether. An editorial in the New England Journal of Medicine does the same.

The dispute hinges on differing interpretations of the statistical methods used by the Canadians. In the course of the study, 44 people died from asthma. Each case was compared with a control group of up to eight people who did not die. Those who died used more cans of inhaler than those in the control group, leading the Canadians to conclude that there was an association between asthma death and the use of large amounts of beta-2 agonists. However, it is clear from the paper that the people in the control groups had less severe asthma than the people who died.

Suissa says he "adjusted" the statistics to take account of the difference. He says that researchers allowed for factors such as the amount of other asthma drugs used and the number of previous admissions to hospital.

But, since this part of the study does not compare like with like, Beasley says it is wrong for the Canadians to draw any conclusions from it. "No amount of adjusting can clear that," he says.

Beasley believes the study shows instead that fenoterol is more risky than salbutamol. For each extra can of fenoterol used each month over a year, the likelihood of a fatal attack rose five times. For salbutamol it doubled.

However, Suissa points out that the fenoterol inhalers on sale in Saskatchewan dispensed twice as much drug in each puff as the salbutamol inhalers. When the two drugs were compared on a weight for weight basis, the risks were similar. And Boehringer has since halved the dosage in its inhalers.

For this reason, Suissa believes Beasley and the New England Journal of Medicine have gone too far in criticising fenoterol. Since fenoterol is no more risky than salbutamol, doctors should not be told to avoid prescribing it, he says. "I think it is unfair to say something like this."

Peter Burney, a leading British asthma epidemiologist, sided with the Canadians this week. "This is a fallible method, but it is not necessarily wrong," he said. "The final paper is fairly balanced."

New Scientist 7 March 1992