BMJ  2006;332:536-537 (4 March), doi:10.1136/bmj.332.7540.536

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Popular dietary supplements don't relieve knee pain caused by arthritis

Americans with painful osteoarthritis spend an estimated $700 million a year on glucosamine and chondroitin sulfate, hoping these dietary supplements will help their pain. The latest attempt at rigorous evaluation suggests they don't. In a large randomised trial (n = 1583), patients taking the supplements alone or in combination were no better after 24 weeks than patients taking placebo.

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To measure response, researchers looked for a 20% improvement in pain as measured by the WOMAC (Western Ontario and McMaster Universities osteoarthritis) index. Response rates were 64% (203/317), 65% (208/318), 67% (211/317), and 60% (188/313) among patients taking glucosamine hydrochloride, chondroitin sulfate, both, or placebo, respectively. A fifth group of patients who took celecoxib did significantly better than the placebo group, but only by a disappointing 10% (response rate 70% (223/318); P = 0.008).

There were hints that the combined supplements might work for people with more severe pain (response rate 79% (57/72); P = 0.002). But this finding is not secure, according to a linked editorial (pp 858-60).

Many research dollars have already been spent evaluating these supplements, and the balance of evidence is now against them, at least for the treatment of pain. It's still possible that they modify the underlying disease, however. These authors are due to report on this aspect of treatment later this year.

N Engl J Med 2006;354: 795-808[Abstract/Full Text]

Seasonal influenza A is resistant to adamantanes in the US

More than 90% of influenza A viruses circulating in the US are now resistant to amantadine and rimandatine, according to the latest surveillance figures. The prevalence of resistance among these viruses has jumped from 11% during the 2004-5 influenza season (October to March) to 92% during the first half of the current influenza season (October to December 2005), prompting the US Centers for Disease Control and Prevention to urge doctors not to prescribe adamantanes for the rest of the season. In an editorial (pp 934-6), two infectious diseases experts call for an urgent worldwide response to restore the effectiveness of these critical agents, which are among the very few treatments available. Influenza affects about one in five of the world's population every year, killing half a million people or more.

Inappropriate use of antiviral drugs is widespread globally, especially in countries such as Russia and China where adamantanes are available without prescription in over the counter cold and flu remedies. The editorial blames liberal licensing, coupled with population hysteria over bird flu and inappropriate dosing of chickens and other livestock, for the startling spread of resistance, which has effectively disarmed an entire class of drugs. Adamantanes do not work against bird flu.

JAMA 2006;295: 891-4[Abstract/Full Text]

Helmets protect skiers and snowboarders

More than 3000 skiers and snowboarders were injured in eight Norwegian ski resorts during the 2002 winter season. Five hundred and seventy eight of them (18%) had head injuries severe enough to need attention from the ski patrol. A case-control study comparing this group with 2992 uninjured controls found that wearing a helmet was associated with a 60% reduction in the risk of head injury (adjusted odds ratio 0.4, 95% CI 0.30 to 0.55). Being male, young, a beginner, and a snowboarder were all associated with an increased risk of head injury, but wearing a helmet protected all subgroups to about the same degree. Odds ratios were comparable on and off the piste, and in the snowboard park.

To find out if helmets seemed safer simply because the people who wear them are more cautious and less accident prone, the researchers asked a random sample of 700 uninjured skiers and snowboarders about their attitude to risk. Those describing themselves as risk takers were significantly more likely to wear a helmet (odds ratio 1.48, 1.21 to 1.81), whatever their age or experience.

These researchers found no evidence that the weight of a helmet increases the chance of neck injury. If anything, wearing a helmet seemed to reduce the risk, although this study was too small to be conclusive.

JAMA 2006;295: 919-24[Abstract/Full Text]

Japanese treatment for dyspepsia looks promising

Itopride, a dopamine antagonist, is widely used in Japan as a treatment for functional dyspepsia. Evaluation has been slow outside Japan, although itopride worked well in a recent industry sponsored trial from Germany. Its 523 participants were investigated carefully to rule out gall stones, ulcer disease, or any other structural or biochemical cause for their symptoms, which included persistent or recurrent upper abdominal pain, fullness, bloating, and nausea. Patients with mainly reflux symptoms were excluded.

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Eight weeks of treatment with itopride (50 mg, 100 mg, or 200 mg three times daily) improved symptoms significantly more than placebo, as measured by a validated symptom questionnaire, the patients' own assessment of their pain and fullness, and a global rating of their response (symptom-free, markedly improved, moderately improved, not changed, or deteriorated).

Overall, the percentages of patients symptom-free or much better after eight weeks were 41%, 57%, 59%, and 64% among patients taking placebo, 50 mg, 100 mg, or 200 mg of itopride, respectively (P < 0.05 for all comparisons against placebo). This emphatic result, which surprised even the authors, translates to a number needed to treat of only 6. Although patients taking the drug did not report more side effects than those assigned to placebo, the higher doses were associated with substantial increases in serum concentrations of prolactin (16% at 100 mg and 21% at 200 mg).

N Engl J Med 2006;354: 832-40[Abstract/Full Text]

Statins and blockers may change the presenting features of coronary heart disease

Coronary heart disease can present for the first time as an acute event, such as a heart attack, or in a more stable way, as exertional angina. When researchers compared the characteristics of American adults in these two groups, they found that the 916 who presented with heart attack were less likely to have taken statins recently (adjusted odds ratio 0.45, 95% CI 0.32 to 0.62) or blockers (0.26, 0.19 to 0.35) than the 468 presenting with angina. They were also more likely to be men, to smoke, and to report a history of hypertension or diabetes.

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This could mean that statins and blockers tip the balance in favour of a safer start to symptomatic heart disease, although it's hard to say from these data, which are purely observational. The main problem is that the researchers weren't able to find out how many of their subjects took aspirin. If aspirin was associated with the use of statins or blockers, it could have been the aspirin, not the other drugs, that reduced the odds of presenting with heart attack.

Despite this and other limitations a linked editorial (pp 296-7) says this study's findings are intriguing and potentially important—well worth the effort and expense of a randomised trial to test whether drugs for primary prevention really can alter the way people present with heart disease, and if they do, what mechanism might be behind it.

Ann Intern Med 2006;144: 229-38[Abstract/Full Text]

Trial data on adverse events are untrustworthy

Good trials are a reliable source of information about the clinical effects of drugs and other treatments. They are not so reliable when it comes to side effects. There's no "right" way to ask trial participants about adverse events, and the answers depend very much on the method used. To illustrate this point, researchers compared three methods in 214 men taking a placebo during the run-in period of a trial of saw palmetto for benign prostatic hyperplasia. The men were randomised to answer an open ended question (have you had any significant medical problems?), a more specific open ended question (have you had any medical problems limiting your usual activities for more than a day?), or tick off a checklist of 53 possible symptoms.

Overall, 77% of the men using the checklist reported at least one adverse event, compared with only 13% and 14% of the men asked open ended questions (P < 0.001). Men using the checklist reported about 20 times more adverse events (238) than men in the other two groups (11 and 14).

The research community has made a lot of effort to standardise the practice and reporting of clinical trials. These authors and a linked editorial (pp 298-300) say the effort should be extended urgently to the identification and reporting of adverse events. Otherwise, "reported toxicity rates can be manipulated to the point that they become virtually meaningless."

Ann Intern Med 2006;144: 257-61[Abstract/Full Text]

Patients with Crohn's disease have a weak acute inflammatory response

A series of laboratory experiments in volunteers suggests that Crohn's disease is caused by a constitutionally weak immune system. Volunteers with the disease had an impaired inflammatory response to various insults, including trauma to the bowel (two rectal biopsies in the same place, six hours apart) and skin (dermal abrasion on the volar surface of the forearm). They also responded abnormally to a subcutaneous injection of killed Escherichia coli, with less vasodilation than healthy controls.

The team of researchers from London who did the experiments think defective macrophages are probably to blame. Cultured macrophages from well patients with Crohn's disease seemed defective when challenged with fluid from wounds and a series of inflammatory mediators. Specifically, the macrophages secreted significantly less interleukin 8 than macrophages from controls. Interleukin 8 is a cytokine that attracts neutrophils, an essential early response to injury or infection.

If the lesions of Crohn's disease really are the result of a defective acute response when bacteria and other debris breach the mucosal barrier, immunosuppressants will help the ensuing secondary chronic inflammation but not the primary underlying disease, say the researchers.

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Lancet 2006;367: 668-78[CrossRef][Medline]

Monoclonal antibody improves bone mineral density in preliminary trial

Denosumab, a human monoclonal antibody, is a new and potentially useful treatment for postmenopausal osteoporosis, according to a preliminary trial. The antibody is directed against a receptor essential to the survival and action of osteoclasts. When injected subcutaneously it rapidly reduces bone resorption. A single injection works for up to six months, increasing bone mineral density, particularly at the lumbar spine.

In this trial, which was paid for, designed, and analysed by the manufacturers, 412 postmenopausal women were treated for one year with a low dose of denosumab every three months, a higher dose every six months, a placebo, or alendronate. They all had low bone mineral density at the start of the trial and took calcium and vitamin D in addition to the drugs in the trial.

After 12 months, denosumab had increased the women's bone mineral density by between 3.0% and 6.7% at the lumbar spine, and by 1.9% to 3.6% at the hip. Women taking placebo had a lower bone mineral density in both places at the end of the trial (P < 0.001 for all comparisons between placebo and denosumab). The monoclonal antibody worked about as well as standard weekly treatment with 70 mg alendronate.

N Engl J Med 2006;354: 821-31[Abstract/Full Text]

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