RESEARCH NEWS
“How many subjects do you need in a randomised trial? Statisticians groan over this silly piece-of-string question every day, but the answer is simple: just so many as will All you need to read in the other general medical journals prove that your intervention does or doesn’t work” Kristina Fišter, associate editor, BMJ [email protected] Richard Lehman’s blog at www.bmj.com/blogs
Breast cancer screening: one at the end of the study period. Overdiagnosis Cancer drug shows promise was assessed from the population perspective, for multiple sclerosis life saved at a cost of three as the proportion of all cancers ever diagnosed overdiagnoses in women invited to screening who are over- Two manufacturer sponsored phase III tri- diagnosed. It was also assessed from the per- als suggest that alemtuzumab, an anti-CD52 Overdiagnosis in women invited for screening spective of a woman invited for screening, as the monoclonal antibody that is licensed to treat From the population Percentage perspective (% CI) probability that a cancer diagnosed during the leukaemia, may help control multiple sclero- Malmö (– years) . (. to .) screening period represents overdiagnosis. sis. Both trials lasted two years and compared Canada I . (. to .) Many observational studies were also consid- alemtuzumab with interferon beta-1a, which is Canada II . (. to .) ered, but results varied greatly and contributed considered first line treatment. One trial looked Overall . (. to .) little to the panel’s final estimates. at 563 patients who had not yet undergone From the perspective Lancet 2012; doi:10.1016/S0140-6736(12)61611-0 treatment for multiple sclerosis, whereas the of a woman invited for screening Cite this as: BMJ 2012;345:e7460 other trial looked at 840 people, some of whom Malmö (– years) . (. to . ) had not responded to previous treatment with Canada I . (. to .) interferon beta-1a or glatiramer. The second Canada II . (. to .) Single application of ivermectin trial tested 12 mg and 24 mg doses of alemtu- Overall . (. to .) lotion helps get rid of head lice zumab against interferon. In the first trial, 22% (82/376) of patients Overdiagnosis (%) Oral ivermectin is often used to treat infection who received alemtuzumab relapsed within Adapted from Lancet ; doi :. /S - () - with roundworms, but its topical preparation two years, compared with 40% (75/187) of might also help combat head lice. New prepara- those who received interferon beta-1a. In An independent expert panel estimated the tions are needed for this condition because of the second trial, 35% (147/426) of patients risks and benefits of screening for breast cancer increased resistance to existing first line agents, who received 12 mg alemtuzumab relapsed in the UK, where women aged 50-70 years are such as permethrin and pyrethrins. compared with 51% (104/202) of those who invited for mammography every three years. It Two trials tested home application of 0.5% received interferon beta-1a. No difference was seems that for every 235 women who are invited ivermectin lotion against vehicle only in nearly seen in the first trial in sustained accumula- for screening, or every 180 women who are 300 children aged 6 months or older. All chil- tion of disability (an increase of at least one screened, one life is saved, but three women are dren were the youngest affected household point on the expanded disability status scale diagnosed and treated for a cancer that would members (three or more head lice) and were con- over six months). In the second trial, however, not otherwise have become apparent in their sidered index patients. In addition, all house- this outcome also improved with alemtuzumab lifetime (overdiagnosis). hold members were checked for head lice, and Eect of treatment on primary endpoints Nearly a fifth of women who receive a diag- those with three or more were also enrolled. nosis at screening are overdiagnosed, but it Both the active and control lotion were Interferon beta-a Alemtuzumab is impossible to know which ones. However, a applied once, on dry hair, left for 10 minutes, Relapse-free survival woman who attends all invitations to mammog- and rinsed with water. Nit combing wasn’t raphy screening has only a 1% chance of being allowed. The next day, 94.9% (131/138) of diagnosed with a cancer that would never have children who had received the active lotion caused problems if she had not been screened. were free of lice, compared with 31.3% (46/147)
These are best estimates from inadequate who received the control lotion. A week and two Hazard ratio . (% CI .–. ); P<. data, the panel emphasised. They reviewed the weeks later, these figures were 85.2% versus Relapse-free survival (%) evidence available from the literature and heard 20.8% and 73.8% versus 17.6%, respectively. testimonies from leading experts. Trial evidence There were no serious adverse events. Pruri- was considered most valid, although only three tus, excoriation, and erythema were more com- Sustained accumulation of disability of 10 available trials had been randomised prop- mon with the control lotion than with ivermectin Hazard ratio . (% CI . –.); P=. erly. Together, the trials looked at nearly 700 000 (1.5% v 0.8%, 1.2% v 0.3%, and 1.2% v 0.5%, women and were done between 1963 and 1991. respectively). It was thought that only eye irrita- Have improvements in treatment over the years tion and skin burning sensations were related to made these findings irrelevant? The panel found the study drug, but these were rare. no data to support this and thought that relative The authors of a linked editorial (p 1750) Patients with sustained
risk reductions achieved in the trials (20%, 95% write that ivermectin could be the last choice accumulation of disability (% ) CI 11% to 27%) should still hold today. in treating head lice, after all the other options The best evidence on overdiagnosis came had failed. Follow-up (months) from three trials in which women randomised N Engl J Med 2012:367:1687-93 Adapted from Lancet ; doi :. /S - () - to the control group weren’t offered screening Cite this as: BMJ 2012;345:e7472
12 BMJ | 10 NOVEMBER 2012 | VOLUME 345 RESEARCH NEWS
(40 patients (20%) with interferon beta-1a v 54 age categories 8-54, 55-64, 65-74, and 75 CI 0.16 to 0.70). Similar results were seen for (13%) with alemtuzumab; hazard ratio 0.58, years or more were 3.50, 2.21, 1.59, and 1.35, the secondary outcome—one or more new mor- 95% CI 0.38 to 0.87). respectively. Absolute risk differences for these phometric vertebral fractures over 12 months Potential adverse events are serious but comparisons, however, were higher at older (2.8% v 0.9% for placebo and the tested drug, treatable. People taking the drug need to be age: 9.0, 12.2, 13.3, and 27.2 excess deaths respectively; 0.32, 0.12 to 0.88). carefully monitored for thyroid disorders, per 1000 person years, respectively. At two years, zoledronic acid reduced the which were seen in 16-19% of patients, as In people with chronic kidney disease, age risk of moderate to severe morphometric ver- well as immune thrombocytopenia, seen in 1%. didn’t modify the association between markers tebral fractures by 63% (P=0.03); prevented Nearly all patients had reactions associated of kidney function and death. changes in height (−2.2 v −4.5 mm with pla- with infusion, most commonly headache, rash, A linked editorial says that we therefore cebo; P=0.002); and improved surrogate mark- nausea, and fever. Two thirds of patients had need to diagnose and treat chronic kidney ers such as bone mineral density at the lumbar infections, which were deemed serious in up to disease in elderly people (doi:10.1001/ spine, total hip, and femoral neck (P<0.05 for 2% of those taking the tested drug. Between 1% jama.2012.30761), although the best way to all). Clinically evident fractures were also less and 4% of participants taking alemtuzumab do this is not entirely clear. We need new treat- common with zoledronic acid, but this wasn’t stopped taking it because of adverse events. ments, as well as testing of existing treatments significant (1%v 1.8% of men taking placebo; The drug has been used off label for a while, in this population, which is likely to be most hazard ratio 0.6, 0.2 to 1.5). but recently the manufacturer withdrew susceptible to the adverse effects of many drugs. Adverse events were seen in nine tenths of it from EU and US markets and is seeking JAMA 2012;308: doi:10.1001/jama.2012.16817 men given zoledronic acid and three quarters of approval for treatment of relapsing multiple Cite this as: BMJ 2012;345:e7478 men given placebo, most commonly fever, pain sclerosis. A linked editorial voices concern in joints and muscles, and headache. Nine men that when the drug reappears on the market it (1.5%) allocated zoledronic acid had a heart may be more expensive (doi:10.1016/S0140- Zoledronic acid prevents fractures attack, compared with two men (0.3%) given 6736(12)61776-0). in men with osteoporosis placebo (P<0.05); the researchers deemed these Lancet 2012; doi:10.1016/S0140-6736(12)61769-3 events unrelated to the study drug. Lancet 2012; doi:10.1016/S0140-6736(12)61768-1 Risk of one or more morphometric vertebral N Engl J Med 2012;367:1714-23 Cite this as: BMJ 2012;345:e7469 fracture Cite this as: BMJ 2012;345:e7471
Placebo Zoledronic acid Low eGFR and high albuminuria Denosumab may reduce predict end stage kidney disease hypercalcaemia after and death at all ages transplantation for osteopetrosis
It has been proposed that low estimated glomer- In osteopetrosis, defective osteoclasts impair Proportion of patients (%) ular filtration rate (eGFR) and albuminuria in bone resorption and excessive bone is formed. older people may be signs of ageing rather months months Haematopoietic stem cell transplantation is the than disease worth treating. The literature is Primary endpoint Secondary endpoint only cure for this rare inherited disorder, but it equivocal on this, in part because analytical is often followed by severe hypercalcaemia. A Adapted from N Engl J Med ;: - approaches differ across studies. A consortium report of two cases, in children 3 and 12 years conducted a meta-analysis of individual patient old, suggests that denosumab can help. data for more than 2 million people to help Zoledronic acid, a bisphosphonate given intra- Both children developed hypercalcaemia achieve consensus and aid the implementation venously at a dose of 5 mg once a year, may within 12 days of transplantation, had low of the recently revised classification of chronic reduce the risk of morphometric vertebral serum concentrations of parathyroid hormone, kidney disease. fractures in men by 67% compared with pla- and had calcinoses on kidney ultrasound. Alka- Data from 33 cohort studies done in the cebo. Morphometric fractures are identified by line diuresis and treatment with calcitonin, cor- general population or people at high risk were a change in shape of a bone, rather than from ticosteroids, and pamidronate failed to improve included, as well as 13 cohort studies of peo- pain or other symptoms. About 40% of oste- hypercalcaemia in both patients before deno- ple with chronic kidney disease. The studies oporotic fractures in people over 50 years occur sumab was given a chance. Serum concentra- spanned four continents and ages 18-108 years, in men, yet until now trials that have included tions of calcium returned to normal in both and were carried out over four decades. Patients men have lacked clinical outcomes and only patients within two days, and normal kidney were followed up for up to 31 years (mean 5.8 examined surrogates such as bone mineral function followed suit. years). density. The younger patient died of pulmonary Overall, low glomerular filtration rates and The two year placebo controlled trial looked hypertension—a known risk of transplanta- high albuminuria were associated with an at 1199 men aged 50-85 years, of whom three tion—a month and a half later. Two years after increased risk of dying and of end stage kidney had hypogonadism and the rest had primary surgery, the other patient still receives 5 mg of disease, regardless of age. osteoporosis. All were given daily calcium and denosumab every four to seven weeks, which In people without chronic kidney disease, vitamin D supplements. continues to normalise serum concentrations the relative risk of dying with impaired eGFR The primary outcome—one or more new of calcium and kidney function. decreased with age, but the absolute risk morphometric vertebral fracture over 24 Denosumab is normally used to treat oste- increased. For example, if eGFR of 45 mL/ months—was seen in 4.9% (28/574) of men oporosis and bone metastases. min/1.73 m2 was compared with that of 80 who took placebo versus 1.6% (9/553) of men N Engl J Med 2012; doi:10.1056/NEJMc1206193 2 mL/min/1.73 m , adjusted hazard ratios for given zoledronic acid (relative risk 0.33, 95% Cite this as: BMJ 2012;345:e7477
BMJ | 10 NOVEMBER 2012 | VOLUME 345 13