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Introduction: FEAST

A huge number of studies are published in journals everyday. Most are read with interest by people involved in the area in which they are published but few every reach the attention of the world’s media. The FEAST study is an exception to this; it attracted a huge amount of attention, the headline from the BBC news story – “Africa trial questions shock treatment for children” was typical of coverage of this trial.

 The use of fluid boluses for shock is an international standard, the American College of Critical Care Medicine recommend the use of 60mls per kg of fluid for a child with a fever who has shock. However, in resource-poor countries these boluses are simply not available.

FEAST – Fluid Expansion as Supportive Therapy – was published in June 2011 in the New England Journal of Medicine with the aim of evaluating the effect of fluid boluses and early fluid resuscitation for shock in febrile children in Sub-Saharan Africa. This was a randomised controlled trial carried out in 6 hospitals inKenya,Tanzania and Uganda. The trial assessed the effects of giving a fluid bolus to children with a febrile illness and impaired perfusion (i.e. children with hypovolaemic shock). Children were randomised into two groups:

  • Stratum A – children without severe hypotension – randomised to receive either a saline bolus (20mls per kg), an albumin bolus (20mls per kg) or no bolus (control group)
  • Stratum B – children with severe hypotension – randomised to receive saline bolus (40mls per kg) or albumin bolus (40mls per kg)

 The protocol was changed in June 2010 and initial boluses were increased to 40ml per kg in stratum A and 60mls per kg in stratum B. Children from the age of 60 days to 12 years were included and the exclusion criteria were children with severe malnutrition, diarrhoea, burns, surgery and trauma. All children received appropriate treatment for their condition as well as being involved in the trial.

 The primary endpoint was mortality at 48 hours after randomisation.

 The study was stopped in January 2011 after the independent data and safety monitoring committee reviewed the 5th interim analysis from the study and recommended stopping owing to safety concerns in both fluid bolus groups.

 The headline finding – 48 hour mortality:

  • 10.6% in the albumin bolus group
  • 10.5% in the saline bolus group
  • 7.3% in the control group

 The relative risk for any bolus vs control was remarkable – 1.44 (P=0.003). The results were found to be consistent across the trial sites and across the subgroups even in respect to the underlying conditions (malaria, coma, sepsis, acidosis and severe anaemia).

The authors of the paper concluded:

The results of this study challenge the importance of fluid resuscitation as a lifesaving intervention in resource limited setting for children with shock who do not have hypotension and raise questions regarding fluid-resuscitation guidelines in other settings as well

 This week I emailed Professor Kathryn Maitland for her thoughts ahead of our discussion and I thank her for taking the time to email me back. Her response:

The major take home message is that we were all surprised by the result. There was no ‘signal’ from the SAE’s and the clinicians involved in the trial — said they all saw children ‘improve’ on boluses and believed that boluses were good. This is why trials are important. 

 Overall, mortality was lower than they had previously experienced– which was probably due to training of all staff involved in paediatric care.

 Professor Maitland also highlights the FEAST study trial video which in her words “takes you to the bedside and puts the trial into context”.

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Tomorrow I will be posting the discussion points for Sunday evening’s journal club meeting and I look forward to critiquing this fascinating paper.

Thank you to @welsh_gas_doctor for his help with this summary.

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Percutaneous Coronary Intervention (PCI) is a surgery in which obstruction in a stenotic coronary artery is cleared either by balloon angioplasty or stenting. It is a very common procedure, with a 2006 American Heart Association report estimating 1.2 million procedures in 2003 in the US.

PCI is not generally effective in reducing numbers of myocardial infarctions (MI) or mortality in patients with chronic stable angina, but rather only improves quality of life. (This is according to a number of randomised trials and meta-analyses, most notably the highly-publicised COURAGE trial.) Conversely, PCI can be effective in reducing morbidity and mortality in unstable angina.

This study looked at 153 patients who were undergoing diagnostic cardiac catheterisation, but who had also signed consent form for PCI to be performed if it was deemed to be necessary by the interventional cardiologist. They were asked about demographic characteristics, history of angina, whether they felt they were adequately informed about the procedure, and what their expectations of its benefits were.

The study also looked at physicians’ responses to a similar survey. Ten interventional cardiologists and 17 referring cardiologists were asked about their beliefs on the benefits of PCI, and expected outcomes for various hypothetical patients. With interventional cardiologists, the authors also asked about beliefs for study patients undergoing surgery. From my perspective, the numbers here are strikingly small, though since this is a single-centre survey, this probably placed limits on the number of cardiologists who could be asked. It does, however, mean that some of the n numbers in the results section are very small.

The key finding of the paper is that, among patients, 88% believed PCI would reduce their risk of MI, and 82% believed it would reduce their risk of fatal MI; however, among physicians, only 17% believed PCI would reduce the risk of MI and 15% believed it would reduce fatal MI. Furthermore, there was little agreement between individual patients’ and their cardiologists’ responses.

Despite this disparity, most patients reported their doctor spending at least 5 minutes explaining the procedure to them, and over half received some written information on the matter. Furthermore, 96% believed they knew why they might undergo PCI, and more than half felt they had been actively involved in decision making. With patients on whom PCI was carried out, physicians were more likely than patients to believe that the patient had been involved in decision making (78% v 94%). Also of note: patients felt they were at greater risk of MI than their cardiologists did (according to a 5 point Likert scale). Perhaps bizarrely, patients who thought they knew why there were getting PCI were more likely to hold the inaccurate belief that PCI prevented MI though this did not reach significance (Odds ratio = 5.3, CI 0.82-34.53).

The physician responses to hypothetical scenarios also generated some interesting results, perhaps most significantly:

In the first 2 scenarios, 70% of cardiologists did not identify any bnefit associated with PCI, yet 43% of these indicated that they would proceed to PCI anyway

I can’t help but question why a doctor would go ahead with a procedure from which they could foresee no benefit. In addition, this recent study also showed that for non-acute indications, 12% of PCIs were classified as inappropriate. The majority of these procedures performed in patients with little to no angina or with low-risk ischemia on stress testing.

Patients overestimating the benefits of drugs is not limited to PCI and cardiology, but why is it that patients perceive benefit when there is none? Given that most patients in this study had a discussion with their cardiologist, why were they not better informed about the potential outcomes of PCI? Is it a failure to adequately distinguish between unstable and stable angina? It does follow logically that alleviating the symptoms of cardiovascular disease would alter some underlying mechanisms to reduce the risk of MI, but shouldn’t cardiologists be making it clear to patients that this is not the case? What can doctors do differently to communicate effectively with their patients?

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If you have any other comments on the paper, please do raise them this evening. As usual, a bit before 8 o’clock this evening (UK time, so 7pm GMT) I’ll post the key points for discussion.

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Beta blockers are widely prescribed for a range of conditions and are now widely used in the management of cardiovascular disease. Patients with chronic obstructive pulmonary disease (COPD) often have concurrent co-morbidities including cardiovascular disease. However there has been concerns regarding the prescription  β-blockers in these patients due to worries about the effect it may have on their respiratory function:

  • evidence that the use of  β-blockers in patients with COPD may lead to a reduction in their lung function (by reducing their FEV1 – Forced expiratory volume in one second)
  • β-blockers may increase airway hyperresponsiveness

One of the mainstays of treatment of COPD is the use of beta-agonists and there have been concerns that  β-blockers may lead to inhibition of the bronchodilator response to these drugs.

As such there has been some reluctance to prescribe  β-blockers in these patients. This paper published in the BMJ looked at the use of  β-blockers in patients with COPD to assess the effect on mortality, hospital admissions and exacerbations when used in combination with established therapy for COPD.

This was a retrospective cohort study which identified cases from a disease-specific database in Tayside which is used by GPs and secondary care respiratory physicians. All patients fulfil the GOLD guidelines for diagnosis of COPD and data on these patients was collected by respiratory nurses at yearly visits. The authors then identified patients who had an admission to hospital due to COPD and also gathered data on the prescription of respiratory and cardiovascular drugs and on deaths from the general register.

The main outcome measures were hazard ratios from all cause mortality, emergency oral corticosteriod use (use to treat exacerbations of COPD) and respiratory related hospital admissions. In these patients 88% of the β-blockers used were cardioselective.

The results – this paper showed a 22% reduction in all cause mortality in patients prescribed  β-blockers. There was a reduction in the adjusted hazard ratio for patients prescribed β-blockers with standard treatment for COPD compared to those who weren’t (0.28 vs 0.43). The paper also showed a reduction in oral corticosteriod use and hospital admission. There was no adverse effect on lung function detected at all stages of the stepwise treatment approach to COPD.

The authors of this paper concluded that:

 β blockers may reduce mortality and COPD exacerbations when added to established inhaled stepwise therapy for COPD, independently of overt cardiovascular disease and cardiac drugs, and without adverse effects on pulmonary function

A list of discussion points will be posted shortly. Thank you to @amcunningham for suggesting this paper.

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A Surgical Safety Checklist to Reduce Morbidity and Mortality in a Global Population – Haynes et al for the WHO Safe Surgery Saves Lives Study Group

The paper chosen for this week’s journal club has had an impact on patient safety worldwide: As an F1 during my colorectal surgery job (on the rare occasions I went to theatre) I saw how this paper has changed practice with the implementation of the WHO safe surgery checklist.

In the surgical setting it has been estimated that almost half of all complications are unavoidable. This is a huge patient safety issue. In 2008, the WHO published guidelines to ensure the safety of surgical patients. From this, the authors of the NEJM paper designed a 19 item checklist with the with the aim of reducing surgical complications and its subsequent morbidity and mortality.

The surgical safety checklist is a simple intervention, a checklist that is followed at three key points with the whole surgical team present – before the induction of anaesthesia, before skin incision and before the patient leaves the operating theatre. The primary endpoint of the study was the occurrence of any major complication, including death, during a period of postoperative hospitalisation, up to 30 days (complications were defined as outlined in the American College of Surgeons’ National Surgical Quality Improvement Program).

The trial was run at eight sites in a range of healthcare settings worldwide. Before the checklist was implemented at the trial sites, baseline data, including complication rates, were reported for 3,733 patients at all trial sites. The checklist was then implemented, consecutively enrolling patients over the age of 16 years undergoing non-cardiac surgery. During the pre-checklist period the rate of any complication at all sites was 11%. After the implementation of the checklist this fell to 7% (P<0.001). The total in-hospital rate of death fell from 1.5% to 0.8% (P=0.003). The authors of the paper concluded that:

 Applied on a global basis, this checklist program has the potential to prevent large numbers of deaths and disabling complications, although further study is needed to determine the precise mechanism and durability of the effect in specific settings.

According to the WHO over 3000 hospitals worldwide have now implemented the surgical safety checklist, an impressive figure that shows how research can translate into a world-wide change in practice. Tonight night at 8.00pm BST we will be discussing this paper – a list of discussion points will be posted shortly. I look forward to another interesting and lively debate.

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Thank you Fi for asking me to write an introduction and suggest some discussion points for tonight’s Twitter journal club. Having a special interest in medical education I was very happy to see this paper by McManus et al. suggested for Week 4 of the journal club.

Discussion point 1: What factors do you think might explain variation in performance in MRCP between medical schools?

What did authors do? They looked at outcomes in MRCP (Member of the Royal College of Physicians) examination for entrants from all medical schools between 2003 and 2005. They found that in the Part 1 and 2 exams, Cambridge, Oxford, and Newcastle graduates did significantly better than average , and the performance of Liverpool, Aberdeen, Dundee and Belfast students was significantly worse. In the PACES section (a clinical examination based on a modified OSCE) Oxford students performed significantly and Liverpool, Dundee and London students significantly worse.
This first part of the analysis is quite easy to understand but the authors then go on to construct a multi-level model to see if they can explain variation between the medical schools.
Since it is known that ethnicity and gender are correlated with MRCP performance, and they had this as individual level data, they adjusted for this.

Discussion point 2: Is it surprising that the average offer to those applying to a medical school may predict performance of graduates in MRCP?
Two complex analyses were performed in this study: a multilevel model, and a structural equation model. Unfortunately the results of the multilevel model are not produced in an easy to understand format, although there is a figure in an additional file which is downloadable.
The authors looked for correlations between medical school performances in MRCP and a plethora of other factors. This information was pulled from other sources such as the Guardian tables, a survey of the cohort of medical students who started university in 1990/1, and the offers which each medical school made to students in the mid-1990s.
They found correlations between:
– Offers made to students (A level or Scottish higher grades)- the higher the offer the better the performance
– The proportion of final year medical students reporting being interested in a career as a physician, and reporting interesting medical teaching, and better performance in MRCP.
– The higher the percentage of graduates taking MRCP, the better the performance.
However when these factors were analysed together, it was only admission grades that seemed significant.
They also looked at correlations with data from the Guardian tables. In a multiple regression, again only admission criteria were found to be significant.
In the multilevel model, the entrance qualifications of graduates were found to explain 62% of variance, which in this type of study is a large amount. 38% of variance remained unexplained but a commenter has suggested that the contribution of entrance qualifications may be under-estimated because of the ‘ceiling effect’- many entrants may have been offered the highest grades of 3 As.

Discussion point 3: Are the authors correct to conclude that this analysis suggests that a national exit exam should be introduced?
What do the results of this study mean? To place the study in context it is perhaps useful to start with the last words of the authors in the paper. They believe that this analysis supports the case for the “introduction of a national licensing examination” in the UK.
We don’t have a national exit exam in the UK. Instead the General Medical Council (GMC) regulates medical education through individual medical schools. Quality assurance of medical education and the final exams which must be passed to gain provisional entry to the medical register rests with the GMC and external examiners.
This analysis shows that different medical schools admit students with different school qualifications, and that the higher the entrance requirements, the greater the success may subsequently be in MRCP. McManus et al refer to a study which shows this is also true of performance in MRCGP exams, but I cannot find that publication.

Discussion point 4: How should we judge the performance of medical schools? Is performance of graduates in post-graduate examinations important?
When this study was published it contributed to discussion about whether a national exit exam should be introduced. Ian Noble, a Sheffield medical student, writing in the BMJ, suggested that medical schools should be judged on whether the graduates they produced performed as competent foundation doctors, not on how well graduates performed in subsequent examinations. Since it is rare for graduates to be pulled up for poor clinical performance this suggests that we have no problem for a national exit exam to solve.

Discussion point 5: How helpful is it to read reviewer’s comments on a paper? Is this something that all journals should aim for?
This paper is published in BMC Medicine which also posts the comments of the peer-reviewers. One of the reviewers suggested that this paper should not be published as although it involved a commendable analysis of multiple datasets it did not “help me to understand the problems in medical education better, nor does it help me to improve medical education or to advance medical education as a science”. The authors’ response to this criticism is also published. The reviewers and the main author also had a dispute over another analysis published in BMC Medicine on gender and ethnicity and success in MRCP. But that discussion was pre-submission so is private correspondence between those involved.

Conflict of Interest: I’m a Belfast graduate!

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Introduction: CRASH-2

For the past two weeks Twitter journal club has looked at two fairly old but still very relevant papers. The paper chosen for this week is at the cutting edge of research and recently won the award for Research Paper of the Year at the 2011 BMJ Awards. This award recognises a paper that the judges believe will have an impact on doctors and patients over the next 5 to 10 years.

The results of CRASH-2 (Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage) were published in The Lancet in June 2010. This was a randomised placebo controlled trial which recruited 20,211 trauma patients with, or at risk of significant haemorrhage in 274 hospitals in 40 countries. Patients were randomised into two arms of the study – either to receive placebo or the drug tranexamic acid. Tranexamic acid is an antifibrinolytic, this drug works by blocking sites on an enzyme that causes blood clot breakdown. The trial was designed to assess whether early administration of this treatment (within eight hours) would have an impact on patient deaths due to bleeding.

The headline finding – all-cause mortality was significantly reduced with tranexamic acid (14.5% in the treatment group vs 16.0% in the placebo group – relative risk 0·91, 95% CI 0·85—0·97; p=0·0035). Risk of death due to bleeding was also significantly reduced (4·9% in the treatment group vs 574 5·7% in placebo group ; relative risk 0·85, 95% CI 0·76—0·96; p=0·0077).

The number needed to treat in this trial – 67, an impressive result (from all-cause mortality figures). The findings of this large scale study have the potential to have a huge impact on the management of trauma patients – the authors of the study have called for this drug to be available to doctors treating trauma patients worldwide and that it should be considered for the WHO’s List of Essential Medicines. As the CRASH 2 team said at the BMJ awards:

“Our research showed that giving tranexamic acid to bleeding trauma patients is both effective and cost effective. These findings are of global importance because every year, over 2 million people die from traumatic haemorrhage”

A very simple intervention with a relatively inexpensive drug that could have a global impact on the mortality of trauma victims worldwide – this is why we have chosen to discuss CRASH-2 in this week’s journal club.

I will be posting a list of discussion points in advance of the journal club on Sunday at 8pm BST. I am very excited to have the opportunity to critique this paper and look forward to another interesting and informative discussion.

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A few people have enquired about why I have chosen a 30 year old paper as my favourite paper to be discussed this week. Is it relevant? Surely it’s out of date? Aren’t we meant to be discussing papers that affect current clinical practice?

Despite being 30 years old, I still believe Rose’s BMJ paper is of great importance, perhaps more now than ever with widespread prescription of preventive drugs such as statins and the like. It addresses the issues of preventive medicine, presentation of risk to patients, and what strategies we can employ to best reduce the incidence of disease.

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I wrote a blog in January about informed consent and preventive medicine at Occam’s Typewriter. In it, I discussed the issues of prescribing preventive medications to patients who only have a small chance of benefiting from that treatment, and how presentation of risk affects this.

Since the absolute risk reduction (and therefore likelihood of benefit from treatment) is equal to absolute risk multiplied by relative risk reduction, individuals with a low starting risk stand a smaller chance of benefiting. Consequently, when prescribing preventive medications, perhaps we should be targetting high-risk individuals who will be most likely to benefit from treatment. (I briefly explain the terms Absolute Risk Reduction (ARR), Relative Risk Reduction (RRR), and Number Needed to Treat (NNT), but a slightly more detailed explanation can be found here or here.)

The Rose paper effectively shows I am wrong. His argument is based on the fact that the number of adverse events occurring in a  group of individuals is the product of both the probability of the event occurring in a person, and the number of people in that group. Or in other words (and to quote the paper):

A large number of people exposed to a low risk is likely to produce more cases than a small number of people exposed to a high risk.

For example, while older mothers are more likely to give birth to babies with Downs syndrome, the majority of babies with Downs syndrome are born to younger mothers, simply because there are more younger mothers giving birth. Similarly, while we could restrict statin prescriptions to those with very high cholesterol, the majority of cases will arises from those with only slightly elevated cholesterol levels.

Fundamentally, the argument is between treating only those individuals at high risk, providing maximum benefit to the patient, and treating even those individuals with a much lower risk, providing the greatest benefit to the population as a whole.

Rose argues that the best way to reduce incidence of adverse events is to treat the population as a whole. Concentrating efforts on high risk individuals may be most appropriate for the patient, but its ability to reduce incidence of disease is limited.

Conversely, while treating people at lower risk levels may not benefit individuals greatly, it is the best way to reduce the occurrence of disease and illness in a population. However, Rose also argues that safety is paramount, and for individuals who stand to benefit very little from a preventive treatment, the risk of side effects may to be too great for long-term mass prevention to be acceptable.

To ameliorate this, Rose concludes with creating a distinction between “normalising behaviours”, such as healthy lifestyle choices, which can be assumed to be safe, and interventions that increase biological abnormality, such as medications. He then argues that the former may be presumed to be safe and, I assume, appropriate to promote in the population as a whole.

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Another issue raised in this paper is the emphasis that is placed upon relative risk reductions. This particular sentence from the paper really stands out to me:

To express the results of trials only in terms of percentage effectiveness is to conceal what the user really needs to know.

I think this is particularly true of media reports on new drugs, both when talking about efficacy of drugs, but also risk increases as side effects associated with treatments.

For example, this paper shows that five years’ treatment with oral bisphosphonates is associated with a doubled risk of oesophageal cancer in 60-79 year olds. In fact, the risk rises from 1 in 1000 to 2 in 1000, meaning that there’s a 0.1% chance that the drug will cause you to develop one of these cancers. A risk, no doubt, but small compared to the benefits of bisphosphonates, which have been shown to reduce the risk of fractures by 30-50%. (This is particularly important for hip fractures – A meta-analysis by Haentjens et al reported a hazard ratio for all-cause deaths of 5.75 for women and 7.95 for men in the 3 months following hip fracture.)

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There will no doubt be issues I have missed in this post, so please do raise them this evening. A bit before 8 o’clock (UK time, so 7pm GMT) I’ll post the key points for discussion. We are trying a different format this week, with 5 key points pertaining to the paper that we can discuss. The focus will be on how the issues raised in the paper can be applied to current clinical practice.

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