- Antibiotics for acute otitis media: Cates plots from 2015 update of the Cochrane review
- Vitamin D for people with asthma (Cochrane review 2016)
- How to make sense of a Cochrane systematic review (BREATHE 2014)
- Ear infections with discharge benefit more from antibiotics (Lancet 2006)
- Diabetes and Statins: Cates plots from the HPS study (Lancet 2003)
- Clopidogrel in addition to aspirin in unstable angina (NEJM 2001)
- Warfarin or Aspirin to prevent stroke in Atrial Fibrillation? (BMJ 2001)
- NICE 2000 guidance on the use of zanamivir for influenza
- A 2000 paper that changed our contraceptive practice
The 2015 update of the Cochrane review includes new studies, but the message remains the same. For every 100 children given antibiotics there will be five extra children free from pain at 2-3 days compared to seven extra who develop diarrhoea, vomiting or rash. For more details click here.
Vitamin D reduced the risk of emergency department visits or hospitalisation for asthma from 6% to 3% over six to twelve months, and also reduced the risk of less serious asthma attacks from 29% to 18%. These results are illustrated in the Cates plots shown below:
People with an asthma attacks leading to ED visit or hospitalisation
In the control group 6 out of 100 people had a visit to ED or hospitalisation over 8 months, compared to 3 (95% CI 1 to 5) out of 100 on vitamin D (mostly evidence from trials on 658 adults).
People with one or more asthma attacks (as defined in each trial)
In the control group 29 out of 100 people had a study-defined exacerbation over 7 months, compared to 18 (95% CI 10 to 29) out of 100 on Vitamin D (from trials in 658 adults and 341 children).
For full details of the review please follow this link. The evidence from children is still rather limited and we do not know for sure what dose of Vitamin D is needed or what blood level of Vitamin D determines whether people benefit. Vitamin D is not a substitute for normal preventer treatment.
This free access 2014 article in BREATHE unpacks what goes into Systematic reviews and gives pointers about how to appraise them. We use an example of the Cochrane systematic review comparing spacers with nebulisers to deliver salbutamol in acute asthma in adults and children.
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.
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.
Two articles were published over the same weekend in August 2001 reporting the results of the CURE study investigating the use of clopidogrel in addition to aspirin in patients with unstable angina (1,2). The Lancet published the results from a sub-group of 2658 patients who were treated with percutaneous coronary intervention, in other words they had coronary angioplasty or stents (1). The full study of 12,562 patients was reported in the New England Journal of Medicine, so this article will concentrate on the NEJM paper (2).
Let us first notice how the newspapers reported the results of this trial. One of the Medical Newspapers for General Practitioners in the UK reported that “Treating unstable angina and non-Q wave MI with clopidogrel and aspirin resulted in a 20% reduction in the risk of MI stroke and vascular death. The risk of major bleeding increased by 1% using both anti-platelet drugs”. Similarly Medical Monitor reported that “Clopidogrel cuts MI deaths by 23% and that for every 1000 patients treated with clopidogrel, six will require a blood transfusion.”
These reports are quite misleading because they have used the Relative Risk Reduction to report benefit but the absolute difference for the adverse effects (using percentages to report the outcome in each case). The NEJM paper itself is much more balanced and gives the proportion of patients who have cardiovascular death, MI or stroke as 9.3% in the clopidogrel group and 11.4% in the placebo group. This is illustrated below using Visual Rx (4) to display these results as a picture of 100 patients at risk:
Figure 1: Cates plot showing two people out of 100 on clopidogrel are prevented from having a stroke, MI or vascular death over nine months in comparison to placebo
Over the course of 9 months, treating 100 patients with clopidogrel will prevent 2 cardiovascular deaths, MI or strokes, which gives a Number Needed to Treat of 48. This is shown above as two yellow faces for those who are saved by clopidogrel, whilst the nine red faces are for those who suffer these events on clopidogrel or placebo. In practice we do not know which two will benefit so all 100 patients need to be given the clopidogrel.
In the same way 2.7% of patients suffered a major bleed on placebo compared to 3.7% on Clopidogrel, a Number Needed to Harm of 100. This is illustrated below, where the 3 red faces are the 2.7% who bleed given placebo or clopidogrel, and the single crossed-out green face is the extra patient who bleeds due to the clopidogrel who would not have done so on placebo.
Figure 2: Cates plot showing one additional person out of 100 has a major bleed on clopidogrel over nine months in comparison to placebo
So overall after 9 months of clopidogrel treatment there is one patient suffering a major bleed for two patients saved from strokes, heart attack or cardiovascular death for each 100 patients treated. This strikes me as a more balanced summary of the benefits and risks of treatment, using the SAME statistic to describe both outcomes.This example also illustrates the importance of reporting the rates of events in both groups (as shown on the pictures), and using the differences not the relative risks. In fact the relative risk of death, MI and Stroke is 0.80 (a drop of 20%) whilst the relative risk of major bleeding is 1.38 (a rise of 38%)! These relative risks by themselves are meaningless unless the event rates on placebo are also presented. The 20% reduction reported is from a baseline rate of 11.4% in the placebo group, so the absolute difference is only around 2% of all those treated with clopidogrel. Likewise the 38% increase in bleeding is from a baseline rate of 2.7% on placebo and translates into 1% of all the patients given clopidogrel.
Finally these patients had unstable angina and would have higher cardiovascular risks than patients with stable angina. It may be therefore that in stable angina clopidogrel could cause more bleeding events than heart attacks and strokes prevented.
1. Mehta S, Yusuf S, Peters R et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358(9281):527-33.
2. The clopidogrel in unstable angina to prevent recurrent events trial investigators. Effects of Clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345(7):494-502.
3. Visual Rx. http://www.nntonline.net
A BMJ review in 2001 sought to persuade us that there is little to choose between antiplatelet treatment and anticoagulation in atrial fibrillation except cost. (1) Rather different conclusions were drawn from analysis of a systematic review of a very similar data set published on the Cochrane library in the same year. In the latter case the reviewers concluded that ‘the evidence strongly supports warfarin in AF for patients at average or greater risk of stroke, although clearly there is a risk of haemorrhage. Although not definitively supported by the evidence, aspirin may prove to be useful for stroke prevention in sub-groups with a low risk of stroke, with less risk of haemorrhage than with warfarin.’ (2)
In these reviews it has not been possible to prove beyond reasonable doubt that aspirin is more efficacious than placebo or that aspirin is less efficacious than anticoagulation. The disadvantage of using a 5% significance level to decide if we can be sure about results was highlighted earlier this year in the BMJ (3). Non-significant trends are open to subjective interpretation when results are handled dichotomously in this way. Moreover whilst aspirin is certainly more convenient than anticoagulation, the cost argument employed by Taylor et al is flawed as the costs of caring for stroke sufferers (or those with major bleeds) has not been considered (4).
The directions of the differences found in trials randomising patients to warfarin or aspirin are the same as those found in the placebo-controlled trials. If non-fatal strokes are compared to major bleeds the pooled odds ratios are almost reciprocal from the meta-analysis of the head to head trials. In practice therefore the trade off for an individual patient depends on their assessed risk of having a stroke or a major bleed. In the majority of trials included non-fatal strokes are more than twice as common as bleeds, and therefore since both outcomes are rare the odds ratio behaves like a risk ratio. This means that in comparison with antiplatelet treatment, if 100 such patients are given anticoagulation for three years, roughly two non-fatal strokes will be prevented and one extra major bleed will occur. This is illustrated in the two Cates plots calculated using Visual Rx (version 4) and the point estimates for non fatal stroke and major bleed from Table 3 in the BMJ review with event rates of 7% for stroke and 2% for bleeds over 3 years with aspirin treatment.
In practice therefore the decision to prescribe anticoagulation or antiplatelet treatment needs to be individually assessed and discussed with each patient. Some may well choose aspirin, but this needs to be on the basis of the risks that they face of having a stroke or bleeding, not on whether the pooled results of a meta-analysis reach 5% significance.
Figure 1: Cates plot for warfarin versus aspirin in AF – impact on stroke over 3 years
Figure 2: Cates plot for warfarin versus aspirin in AF – impact on bleeding over 3 years
Taylor FC, Cohen H, Ebrahim S. Systematic review of long term anticoagulation or antiplatelet treatment in patients with non-rheumatic atrial fibrillation. BMJ. 2001;322:321-6.http://www.bmj.com/cgi/content/full/322/7282/321
Segal JB, McNamara RL, Miller MR, Powe NR, Goodman SN, Robinson KA, Bass EB. Anticoagulants or antiplatelet therapy for non-rheumatic atrial fibrillation and flutter (Cochrane Review). In: The Cochrane Library, Issue 1, 2001. Oxford: Update Software.
Sterne JA, Smith GD. Sifting the evidence-what’s wrong with significance tests? BMJ 2001;322(7280):226-231 http://www.bmj.com/cgi/content/full/322/7280/226
Cates CJ. Care is required with cost effectiveness approach. BMJ. 2000;321:449. http://www.bmj.com/cgi/content/full/321/7258/449
Purpose of the NICE guidance: to target zanamivir to at-risk patients with a high likelihood of having influenza. Hence the restriction to use in such patients and only when the level of circulating influenza-like illness has been confirmed to be above 50/100,000. Fever of over 38°C and a clinical picture of flu (sudden onset of illness with muscle pains and dry cough) are also a requirement before treatment with zanamivir is considered as many people think they have flu when they have much milder viral illnesses.
Benefits of the treatment: very modest with only a single day reduction in duration of illness and 7% reduction in complications requiring antibiotics. In other words 14 patients need to be treated with zanamivir for one patient to avoid the need for antibiotics. No proven benefit in terms of reducing hospital admission or mortality. (See picture below.)
Side effects: zanamivir can cause wheezing in asthmatic and COPD patients, so such patients are advised to have their reliever inhaler to hand when they take the treatment! In a study in healthy asthmatics one in 13 developed wheezing.
Children: zanamivir is not licensed for children under 12
Workload: NICE recognise that there could be a considerable extra workload caused by this guidance (in terms of telephone calls and home visits). Practices may wish to have a plan prepared to deal with this eventuality. A possible scenario would be 2 extra visits per GP per day with an unknown extra number of telephone calls for patients enquiring about their suitability for treatment. A questionnaire has been prepared for nurses to use in triaging telephone queries from patients and presumably this will be used by NHS direct, but could also be implemented at practice level. However issuing of prescriptions for zanamivir without seeing the patient seems unwise, in view of the possibility of complications (such as pneumonia), and the fact that it was a new ‘black triangle’ medication.
Cates plot on preventing complications of flu by using zanamivir
If 100 patients are all given zanamivir for a flu-like illness 74 will not suffer a complication requiring antibiotics anyway (shown as green smiling faces below); 20 will still need antibiotics (shown as red faces) and 6 (shown as yellow faces) will be saved from having antibiotics by the use of zanamivir.
Summary of Nice Guidance on the Use of Zanamivir (Relenza) in the treatment of Influenza
Issue date: November 2000
Review date : June 2002
1.1 For otherwise healthy adults with influenza, the use of zanamivir is not recommended.
1.2 Zanamivir is recommended, when influenza is circulating in the community, for the treatment of at-risk adults, who present within 36 hours of the onset of influenza like illness (ILI) and who are able to commence treatment within 48 hours of the onset of these symptoms.
1.2.1 Based on the evidence from clinical trials, at-risk adults are individuals falling into one or more of the following categories:
age 65 years or over
chronic respiratory disease (including chronic obstructive
pulmonary disease and asthma) requiring regular medication
significant cardiovascular disease (excluding individuals with hypertension)
1.2.2 Community based virological surveillance schemes should be used to indicate when influenza is circulating in the community (see paragraph 5.4).
1.2.3 Effective targeting of zanamivir for the at-risk adult population with a high incidence of true influenza is essential to maximise both the clinical and cost effectiveness of this therapy.
1.3 The guidance does not cover the circumstances of a pandemic or a widespread epidemic of a new strain of influenza to which there is little
or no community resistance. In such circumstances, the Department of Health and the National Assembly for Wales might wish to consult the Institute on the need for supplementary guidance.
In 2000 my senior partner presented the results of a paper published in the Lancet (1)comparing the standard combined oestrogen and progesterone method (Yuzpe) for post-coital contraception with two doses of progesterone (levonorgestrel) only. Until then women to take large numbers of tablets, but a formulation in two single tablets had become available in the UK (Levonelle-2). The comparison was quite clear cut: less vomiting following the progesterone only regimen and also less pregnancies.
I decided to check this out further on the Cochrane Library and found a review covering emergency contraception which was updated in March 1999. The review found two randomised controlled trials which compared levonorgestrel and Yuzpe (including the WHO study in the Lancet). These Pooled results are displayed graphically below as Cates plots using Visual Rx (version 4). In this case Yuzpe and levonorgestrel have been compared and the graphical displays represent 100 patients who are treated.
Figure 1 demonstrates the pregnancy rates; the green faces are patients who do not fall pregnant whichever regimen they receive, and the one red patient will fall pregnant anyway. The single yellow face represents a patient would be pregnant if given Yuzpe but not with levonorgestrel. This represents a Number Needed to treat of 63 (95%CI 45-193) with progesterone only compared to Yuzpe to prevent one extra pregnancy.
Figure 2 looks at the numbers of patients who will vomit; again the green faces will not be sick with either treatment, and the red ones are sick with both. Here the 14 yellow faces will be patients who do not vomit with levonorgestrel but would have done so with Yuzpe. The Number Needed to Treat is 7 (95% CI 7-8) to prevent one patient vomiting.
Although the new treatment was more expensive we estimated that switching to levonorgestrel should save between one and two pregnancies in one hundred patients attending for post-coital contraception. The extra cost of levonorgestrel was about £200 per pregnancy prevented as it was more expensive than Yuzpe in the UK, but in France it was already available to patients directly from the chemist. For us the extra prescribing cost compared well with the alternative cost and inconvenience of terminations of pregnancy!
We abandoned Yuzpe in our practice and switched to levonorgestrel instead. The only unhappy member of the practice team is one of my other partners who had the topic lined up for her own presentation a few weeks later and had to find a new topic to present!
1. Randomised controlled trial of levonorgestrel versus Yuzpe regimen of combined oral contraceptives for emergency contraception. Task Force on Postovulatory Methods of Fertility Regulation. Lancet 1998; 352: 428-33
2. Cheng L, Gülmezoglu AM, Ezcurra E, Van Look PFA. Interventions for emergency contraception. (Cochrane Review). In: The Cochrane Library, Issue 1, 2000. Oxford: Update Software.
Figure 1: Levonorgestrel v Yuzpe – Patients who became pregnant
Figure 2: Levonorgestrel v Yuzpe – Patients who suffered vomiting