In 2007 our local maternity unit was advising pregnant mothers who have reached term to come and have their membranes swept in an attempt to start labour with needing a formal induction. This matters to many mothers as they cannot attend the low risk unit and use the birthing pool if they have labour induced with prostaglandins and an intravenous infusion.
I recall one mother who was given conflicting advice by different midwives. The patient attended to have a sweep only to be told by a different midwife that that sweeping was either a waste of time and she would not countenance it. This sort of discrepancy is a good reason to look for evidence of benefit and this is now available in the form of a Cochrane review in Issue 3 (2007) of the Cochrane Database of systematic reviews.
The authors found that one induction of labour could be avoided for every eight women who had a sweep (NNT of 8), and that “Sweeping of the membranes, performed as a general policy in women at term, was associated with reduced duration of pregnancy and reduced frequency of pregnancy continuing beyond 41 weeks (RR 0.59, 95% CI 0.46 to 0.74) and 42 weeks (RR 0.28, 95% CI 0.15 to 0.50).”
Were there any adverse events? Yes but they were not too serious “There was no evidence of a difference in the risk of maternal or neonatal infection. Discomfort during vaginal examination and other adverse effects (bleeding, irregular contractions) were more frequently reported by women allocated to sweeping.”
These results were found in women who had a sweep compared to no treatment, but there was not enough data to draw conclusions on the comparative effect of sweeping and prostaglandins.
Next time I am asked about the pros and cons of having a sweep I will be able to give a more informed answer!
This is the title of a commentary in the Lancet in 2007. Stephanie Dancer reflected on a randomised trial from Belgium .
She writes: “Malhotra-Kumar and co-workers undertook a randomised, double-blind, placebo-controlled study designed to satisfy scientists and persuade even the most disengaged of clinical readers. The effect of two macrolide antibiotics, azithromycin (500 mg once daily for 3 days) and clarithromycin (500 mg twice daily for 7 days), was measured against placebo in four groups of volunteers by use of oral streptococci as model organisms. The researchers recorded a clearly defined effect on commensal pharyngeal streptococci, with both drugs selecting for macrolide resistance.”
A previous paper from this group showed a clear correlation on a national level between antibiotic use and the prevalence of resistant organisms , but now there is evidence from a randomised trial on the individual level. We can say be more sure of something my patients have expressed for a long time, the worry that the individual who takes lots of antibiotics may be at personal risk of becoming colonised with resistant organisms.
The commentary ends: “We now have strengthened evidence for the links between antibiotic use and resistance. Our only response to the delay in proving this association should be to get on and do something about it before the antibiotic era finally grinds to its apocalyptic halt.”
In my experience there are two useful tactics in Primary Care to reduce antibiotic prescribing where it is not essential. The first is to ask directly whether the patient is expecting an antibiotic (as they may well not be), and then suggesting that the antibiotics could at least be deferred in patients who are not toxic, as many upper respiratory infections will clear by themselves.
This link also gives some further information to guide which children with acute otitis media benefit most from antibiotics.
 Dancer S. Attention prescribers: be careful with antibiotics. Lancet. 2007;369:442-3.
 Malhotra-Kumar S, Lammens C, Coenen S, Van Herk K, Goossens H. Effect of azithromycin and clarythromycin therapy on pharyngeal carriage of macrolide-resistant streptococci in healthy volunteers: a randomised, doubleblind, placebo-controlled study. 369: 482-490. Lancet. 2007;369:482-90.
 Goossens H, Ferech M, Vander Stichele R, Elseviers M. Outpatient antibiotic use in Europe and association with resistance: a cross-national database study. Lancet. 2005 Feb 12;365(9459):579-87.
 Mangione-Smith R, McGlynn EA, Elliott MN, Krogstad P, Brook RH. The relationship between perceived parental expectations and pediatrician antimicrobial prescribing behavior. Pediatrics. 1999 Apr;103(4 Pt 1):711-8.
 Cates C. Reducing antibiotic use in children with acute otitis media. BMJ. 1999 July 10, 1999;319(7202):124.
A useful meta-analysis of antibiotics for acute otitis media using individual patient data was published in the Lancet in October 2006. The abstract is at the bottom of this page.
The aim of the paper was to try identify which children would be most likely to benefit from antibiotics, and data was available from 1643 children aged six months to 12 years. They concluded that an observational policy (in other words not using antibiotics straight away) was justified in most children with mild disease, but they did find a greater benefit from antibiotics in children under 2 years of age who had bilateral acute otitis media, and in children over 2 years with bilateral otitis media.
A discharging ear was also a marker of persistent pain or fever at 3-7 days, and more benefit was seen from antibiotics when discharge was present. The NNT for antibiotic treatment in children with a discharging ear was three (since 36 children benefit for every 100 given antibiotics):
In contrast the NNT for those without discharge was eight (as only 14 children now benefit for every 100 given antibiotics):
Rovers MM, Glasziou P, Appelman CL, et al. Antibiotics for acute otitis media: a meta-analysis with individual patient data. Lancet 2006; 368: 1429-1435
Individual trials to test effectiveness of antibiotics in children with acute otitis media have been too small for valid subgroup analyses. We aimed to identify subgroups of children who would and would not benefit more than others from treatment with antibiotics.
We did a meta-analysis of data from six randomised trials of the effects of antibiotics in children with acute otitis media. Individual patient data from 1643 children aged from 6 months to 12 years were validated and re-analysed. We defined the primary outcome as an extended course of acute otitis media, consisting of pain, fever, or both at 3 to 7 days.
Significant effect modifications were noted for otorrhoea, and for age and bilateral acute otitis media. In children younger than 2 years of age with bilateral acute otitis media, 55% of controls and 30% on antibiotics still had pain, fever, or both at 3 to 7 days, with a rate difference between these groups of −25% (95% CI −36% to −14%), resulting in a number-needed-to-treat (NNT) of four children. We identified no significant differences for age alone. In children with otorrhoea the rate difference and NNT, respectively, were −36% (−53% to −19%) and three, whereas in children without otorrhoea the equivalent values were −14% (−23% to −5%) and eight.
Antibiotics seem to be most beneficial in children younger than 2 years of age with bilateral acute otitis media, and in children with both acute otitis media and otorrhoea. For most other children with mild disease an observational policy seems justified.
I am always interested to read the results of Randomised Controlled Trials which include an arm with delayed antibiotics, and in 2006 Paul Little’s group in Southampton published results of three different approaches to acute infectious conjunctivitis. (A randomised controlled trial of management strategies for acute conjunctivitis in general practice. Hazel A Everitt, Paul S Little, and Peter W F Smith. BMJ 2006 333: 321)
Just over 300 children and adults with acute conjunctivitis were randomised to immediate antibiotics, no antibiotics or delayed antibiotics. In addition the patients were also randomised to receive a patient information leaflet or not, and to have an eye swab or not (in a factorial design). Information was collected on severity and duration of symptoms, and the patients’ belief in the effectiveness of antibiotics. “Participants completed diaries on concerns about their eye problem, how well their doctor dealt with their concerns, how satisfied they were with the consultation, the importance of seeing the doctor or nurse so that they could continue work or schooling, and satisfaction with the information they were given.”
Immediate antibiotics did not make a significant difference to symptom severity, but reduced the mean duration of symptoms from 4.9 days to 3.3 days and delayed antibiotics to 3.9 days, both reductions were statistically significant. Interestingly the percentage using antibiotics was 99% in the immediate group, 53% used in the delayed antibiotic group and 30% in those who were not given antibiotics at the initial consultation (presumably because the patients returned for review and were given antibiotics later).
Those who had no antibiotics or delayed antibiotics were less likely to report that they were “extremely or very likely to re-attend for future eye infections” in comparison to those given immediate antibiotics. Satisfaction with the consultation was not altered by the use of antibiotics, but satisfaction with the information given was higher with a patient leaflet and taking an eye swab increased patient concerns and worries about conjunctivitis.
The authors conclude “The delayed prescribing approach may be the best approach. Compared with no initial offer of antibiotics delayed prescribing had the advantage of reduced antibiotic use (almost 50%), no evidence of medicalisation, similar symptom control to immediate prescribing, and reduced re-attendance for eye infections.”
What is a Number Needed to Treat?
Some time ago in a discussion about possible future projects Iain Chalmers mentioned to me that he would like to see more work done around the question of whether new treatments were better than older established ones. It seems that the general impression conveyed by the marketers and advertisers is that new is better than old (which may have more than a little to do with the fact that manufacturers make much of their profit when new products are protected by patent).
Whilst I was in Canada at the 12th Annual Cochrane Colloquium the news broke that rofecoxib (Vioxx) had been withdrawn by the manufacturers and on my return I discovered that this was due to the results from a large long-term study on Vioxx to see what effect it had on polyps in the large bowel. The absolute increase in serious thromboembolic events was about 1% over 18 months, which was a doubling of the risk in the placebo group.
The problem is that these events are not very common and short-term trials looking at how well Vioxx performs as an anti-inflammatory agent would not have sufficient power to detect differences of this magnitude.
So in 2004 we had to decide what to do with patients who had been taking Vioxx? The crucial question is whether this is a class effect (which represents an increased thromboembolic risk in all Cox-2 inhibitors) or whether it is a particular problem with Vioxx. Two different questions could be asked:
1.Have other Cox-2 drugs been shown to increase thromboembolic risk?
2.Have other Cox-2 drugs been shown to be better than Vioxx for thromboembolic risk?
We did not know the answer to either question, but my guess it that those with a vested interest in the other Cox-2 inhibitors will major on the fact that we do not know the answer to question one, and those who are more concerned about safety will focus on the second question. The latter will also remember the issues related to delayed publication of adverse effects from SSRIs in adolescents mentioned in my last newsletter.
One alternative to Vioxx is Bextra (valdecoxib) and I was interested to read in today’s BMJ that concern has been voiced about delay in releasing information about Bextra following the withdrawal of Vioxx. Guess what one of the members of the FDA’s Safety and Risk Management committee has found?
“The first of the two trials was published but in a manner that obscured the risks, according to Dr Furberg. He said,’ They listed each [adverse] event individually and said the numbers were too small to analyse. But I added up heart attacks, strokes, and deaths and found a statistically significant fourfold increase over placebo.’” ‘http://bmj.bmjjournals.com/cgi/content/full/329/7472/935-a?ehom .
So do you think a class effect is likely? If you do then changing patients from Vioxx to another Cox-2 inhibitor may not be the right thing to do. This may be an instance where new is not better after all.
Which diabetic patients benefit from statin treatment?
This is the question that the HPS study (1) sought to answer in 5963 adults with diabetes (aged 40 to 80 years). Previous studies on statins have included small numbers of diabetic patients, and showed results that were in keeping with the overall benefit of statins in other groups of patients. However, the wrong conclusion can be drawn if the results from a small subgroup of patients do not show a significant effect (as the confidence interval will be wide when fewer patients are included).
The HPS study was powered to reliably detect a reduction in risk of a quarter by including about 3000 diabetic patients in each arm of the study (one group receiving simvastatin 40mg daily and the other a placebo tablet). When all the patients having a first vascular event were measured over the five-year study period, the rate in the placebo group was 25.1% and in the statin group was 20.2%. This represents a relative risk of 0.76 (95% confidence interval 0.72 to 0.81) and is most unlikely to represent a chance finding (p< 0.0001).
We now have the results from a large enough study to show that statins are effective at preventing vascular events in diabetes, which supports the previous evidence that diabetics seem to derive similar benefit to other risk groups.
An advantage of the large size of the study is that sub-group analysis can be carried out. This showed that the proportional reduction in risk is largely independent of the type of diabetes, the degree of glycaemic control when the statin was started and also was not detectably altered by the lipid concentrations. The benefit with statins was similar whether the patients had a cholesterol level of greater or less than 5 mmol/L when they started on the statin. Patients derived significant benefit whether their initial cholesterol level was raised or not, and the test for difference between groups (or heterogeneity) was negative (p value of 0.7).
Relative Risk and Absolute Difference
Once the study has shown that the relative risk is similar in all diabetics studied the issue for implementation is how much absolute benefit the patients will obtain from being given the statin treatment. This will be determined by the baseline risk of the diabetics being considered, and the rate of major vascular events over 5 years was 36% in patients with arterial disease and diabetes, and 13% in those with diabetes and no previous arterial disease. Therefore when the diabetics without pre-existing arterial disease are considered, although the relative risk is very similar the event rates are lower. In the placebo group 13.5% suffered a vascular event over 5 years, whilst 9.3% of those on simvastatin suffered a similar event. The figures for the diabetics whose pre-treatment LDL cholesterol was under 3.0 with no known occlusive arterial disease were 11.1% in the placebo group and 8.0% in the simvastatin group.
So what does this mean in practice? The writers of the paper suggest that it is time to move away from making decisions about statins for diabetic patients on the basis of their initial cholesterol level and instead look at their overall risks of vascular disease. Stopping smoking, reducing blood pressure and reducing cholesterol are all of benefit in such patients and the challenge to the health care providers is to decide how to tackle all three areas. The threshold for starting statins should be determined by overall cardiovascular risk, and the level set for treatment will need to be determined by the local health economy. I suspect that this may generate a vigorous debate.
Visual Rx pictures (Cates Plots)
I have used the Statin Calculator on this website with an overall risk ratio of 0.75 to generate smiley face plots of 100 patients given statins from two levels of risk and these are shown below. The largest benefit is seen in the patients with both diabetes and arterial disease (five year NNT is 12), and although the relative risk is the same in those diabetics with no arterial disease, the absolute benefit is less (five year NNT is 33). The benefits of treatment may be underestimated as 17% of patients in the placebo group took non-study statins during the course of the study. The inclusion of subsequent vascular events would also make the event rates larger and the NNT smaller.
Diabetics with occlusive arterial disease
The picture shows that the 74 green faces will be free from a vascular event on placebo as well as on simvastatin. The 27 red faces will suffer a vascular event over the five years even if all the patients are given simvastatin, but if all 100 patients are put on simvastatin the 9 patients with yellow faces will avoid a vascular event that they would have suffered on placebo. The NNT is therefore 12 because this is the number that need to be put on simvastatin for five years to prevent one vascular event. The calculation to get the NNT is 100 divided by 9 (100/9 = 11.1) and rounded up to the next whole number, which is 12.
Cates plot showing the impact of simvastatin on vascular events over five years in Diabetics with occlusive arterial disease
Diabetics without occlusive arterial disease
In this case 87 out of 100 patients treated with simvastatin would not have suffered a vascular event anyway (the green faces) and the 10 red faces still suffer an event in spite of the statin, but the 3 yellow faces are saved from having a vascular event. As we do not know who these 3 patients will be, all 100 have to be given the statin, meaning that the NNT is 31. In other words 31 patients from this group need to be treated to prevent one vascular event.
Cates plot showing the impact of simvastatin on vascular events over five years in Diabetics without occlusive arterial disease
You may be wondering why the NNT is not 34, since 100 divided by 3 is 33.3 which would round up to 34. In fact the three yellow faces actually represent a drop in the treatment group risk to 9.75% (a risk difference of 3.25%), as shown in Table 1 below. The 3.25% risk difference is rounded to the three yellow faces in the Cates plot. Have a go yourself using the Statin calculator and you will see what I mean (but remember to enter 13% as the baseline risk). You should obtain a data table in Visual Rx which looks like this:
Table 1. Table of Natural frequencies.
|Treatment with statins to reduce the risk of heart attacks and strokes|
|Outcome: a heart attack, stroke or bypass surgery|
|Duration: 10 years|
|Control group risk||Treatment group risk (95% CI)||NNTB (95% CI)|
|(9.10% to 11.05%)||(NNTB 26 to NNTB 52)|
|In the control group 13 people out of 100 had a heart attack, stroke or bypass surgery over 10 years, compared to 10 (95% CI 9 to 11) out of 100 for the active treatment group.|
- Group HPSC. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003;361:2005-16.
Have the results changed?
Yes and No! The overall difference made by antibiotics remains very similar in terms of the Odds Ratio of being in pain at 2 to 7 days; this is still 0.6 and has not been changed much by the data from the new trial in children under 2 years of age (1). The Odds Ratio from this study is also in keeping with the overall effect at 0.55 but what is strikingly different is the proportion of children in this group who are still in pain on placebo treatment. For all of the other studies combined the proportion still in pain at 2 to 7 days is 14% (145/1005) whilst in the Damoiseaux study the figure is 70% (89/123). When all the studies are combined together the proportion in pain is 21% (234/1128) and combined with the pooled Odds Ratio of 0.6 this means that seven out of every 100 treated will see a benefit, and leads to an overall NNT of 14 as was shown in an article in Prescriber on putting evidence into practice. This overall Cates plot is shown below, but it conceals differences between the Damoiseaux study and the other trials.
If we take the pooled Odds Ratio of 0.6 as the best measure of effect and enter this in Visual Rx with the Control event rate of 14% (from all the other trials) this will give an NNT of 19, as five (yellow faces) will benefit for every 100 treated. This is very similar to the original review and is shown in the Figure below:
In contrast the same Odds Ratio of 0.6 applied to the 70% Control Event Rate in the Damoiseaux trial in children under 2 there will be 12 (yellow faces) who benefit for every 100 treated as shown in the Cates plot below, and this will give an NNT of 9 .
This would suggest that in children similar to those studied by Damoiseaux in the younger age group, there is more benefit in using antibiotics than in those from the other trials. Perhaps the age of the child should be taken into consideration, as well as the level of fever and systemic illness (2) in making a decision about deferring antibiotics in children with ear infections.
Please also see the paper on discharging ears to help decide which children may benefit most from antibiotics for their ear infections.
- Damoiseaux RAMJ, van Balen FAM, Hoes AW, Verheij TJM, de Melker RA. Primary care based randomised, double blind trial of amoxicillin versus placebo for acute otitis media in children aged under 2 years. BMJ 2000;320(7231):350-354
- Little P, Gould C, Moore M, Warner G, Dunleavey J, Williamson I, et al. Predictors of poor outcome and benefits from antibiotics in children with acute otitis media: pragmatic randomised trial. BMJ 2002;325(7354):22-8
Selective Beta-blockers for COPD
The (2002, Issue 2) issue of the Cochrane Library contains several reviews that are relevant to Primary Care. I will start with one that I have worked on relating to selective Beta-blockers and Chronic Obstructive Pulmonary Disease (COPD). In general Beta-blockers have been shown to be useful in secondary prevention for patients with ischaemic heart disease, but problems arise because many of these patients have smoked and also have COPD so we may be reluctant to consider a Beta-blocker in case this makes the chest problems worse.
The new review suggests that Cardioselective beta-blockers do not cause important deterioration in COPD and should not be withheld in patients with COPD (1). This is how the abstract puts it:
Eleven studies of single-dose treatment and 8 of treatment for longer durations, ranging from 2 days to 12 weeks, met selection criteria. Cardioselective beta-blockers, given as a single dose or for longer duration, produced no significant change in FEV1 or respiratory symptoms compared to placebo, and did not significantly affect the FEV1 treatment response to beta2-agonists. A subgroup analysis revealed no significant change in results for those participants with severe chronic airways obstruction or for those with a reversible obstructive component.
Cardioselective beta-blockers, given to patients with COPD do not produce adverse respiratory effects. Given their demonstrated benefit in conditions such as heart failure, coronary artery disease and hypertension, cardioselective beta-blockers should not be withheld from patients with COPD.
Treatments for Tennis elbow
A review on tennis elbow (2)has shown topical NSAID treatment to be effective in the short-term relief of pain (although this comes from only 150 patients randomised) and even smaller numbers of patients from 2 trials suggested that patients were more likely to show subjective improvement with symptoms (in the short term) following a steroid injection than oral NSAID. More work is needed to see how topical NSAID treatment compares to oral NSAID and to study the outcomes for longer than 4 weeks.
A note of caution on the comparison between steroid injection and oral NSAID; as the outcome was subjective I would be concerned about bias in trials with no dummy injection. There was only one study (Saartok 1986) that did use a dummy injection and this did not show a significant difference from NSAID, whereas the other study (Hay 1999) with no dummy injection did show a significant benefit. A larger double blind double dummy study with a head to head comparison is therefore needed to confirm whether there is a real difference between these two approaches.
Other new reviews
Other new reviews have found no important differences between carbamezepine and phenytoin as monotherapy for epilepsy, no good evidence to recommend dehumidifiers in asthma, and interestingly only one randomised controlled trial on 22 patients was found comparing surgical with non-surgical treatment of carpal tunnel syndrome. Clearly more research needed here!
1. Salpeter S, Ormiston T, Salpeter E, Poole P, Cates C. Cardioselective beta-blockers for chronic obstructive pulmonary disease (Cochrane Review). In: Cochrane Library. 2 ed: Update Software (Oxford); 2002.
2. Green S, Buchbinder R, Barnsley L, Hall S, White M, Smidt N, et al. Non-steroidal anti-inflammatory drugs (NSAIDs) for treating lateral elbow pain in adults (Cochrane Review). In: The Cochrane Library: Oxford: Update Software; 2002(Issue 2).