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Please see the introduction for a summary of the paper itself.

Beta blockers are widely prescribed for a range of conditions and are now widely used in the management of cardiovascular disease. There has been concerns regarding the prescription  β-blockers in patients with COPD due to worries about the effect it may have on their respiratory function, particularly  inhibition of the bronchodilator response to beta agonists.

This BMJ paper examined 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: it identified cases from a disease-specific database in Tayside which is used by GPs and secondary care respiratory physicians. During the discussion, some concerns were raised over the observational nature of the study, and it was felt that while observational studies can be very useful, we need to be aware of their limitations.

@alasdairforrest also commented on the practicality of such a study versus a prospective study:

The Regional Ethics Committee may have preferred a retrospective study to a therapeutic trial. Or 1/5 paperwork?

The key issue was the balance between simplicity, reduced costs and increased patient numbers usually associated with an observational study, and the difficult with being as “controlled” as a prospective study. @silv24 also added that observational studies take less time to carry out.

The consensus reached was that while observational studies have their limitations, such as the need to consider randomisation problems and confounding factors, they “can also lead to more definitive questions and enable better RCTs in the future” (@mgtmccartney).

As for whether observational studies can be used to change clinical practice, again the responses were mixed. Some agreed that they could be used, but that it was dependent on the strength of the evidence. Alternatively, observational studies could act as a good starting point for other research. Others felt that observational studies alone were inadequate, but that they can add the evidence in favour of a particular practice. As @drgandalf52 pointed out, “to convince the bulk of GPs [we] need to convince NICE”.

An important issue raised with the paper was the lack of information on the patient:

  • “we don’t actually know why any of these patients were on beta blockers for one thing!” (@silv24)
  • “Although database sounds comprehensive, past history of patients is unknown and no record of indication for starting BBs” (@northern_doctor)
  • “the biggest bias might have been that beta blockers were only prescribed to less seriously ill [patients] in [the] first place” (@amcunningham)
The discussion then moved onto whether the end-points used in the study were robust enough to show that beta blockers are safe in COPD in this patient population. @alasdairforrest felt that “hazard ratio for emergency steroids is a good endpoint”, and @northern_doctor pointed out that this shows there was no adverse effect of beta-blockers on airway. Furthermore, @silv24 “found the data on reductions in hospital admissions and emergency oral corticosteroid use very interesting”.
I think @northern_doctor neatly summed the issue up:
I think authors were very thorough with statistical and subgroup analysis to anticipate possible limitations – Couldn’t have done more with data that was available
The paper only considers one geographical area, so did this affect the application of the results to other populations? There was a bit of debate over whether the population studied was representative of the wider population in the UK, but @citylivindundee, first author of the paper, clarified that:
database covers tayside, population >200,000. we believe it to be typical of general population
We discussed the possibility of a nationwide database for patient details, either specific for a study, or as a general NHS database. @northern_doctor pointed out the pre-existing SITS-MOST data for stroke thrombolysis, which perhaps shows the idea would be feasible for a study such as this, although there would need to be a reason for collating this data (for example a study) due to costs.

Some felt that the paper, on its own, did not provide adequate evidence for using beta blockers in COPD patients, and that further studies, such as RCTs, would be necessary to confirm the findings. However others felt that since this paper contributed to a pre-existing body of research into the safety of beta-blockers in COPD (such as this Cochrane Review via @mgtmccartney), it may not be ethical to conduct an RCT.

Overall, it was felt that while this paper has its flaws and needs to be considered in context, it provides further evidence towards the idea that all patients with cardiovascular disease can be prescribed beta-blockers, regardless of co-existing COPD.
~*~
We would like to thank Phil Short (@citylivindundee), first author of the paper, for contributing to the discussion.

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Apologies for the delay in posting the summary of last Sunday’s discussion. A week of nights on call in A&E didn’t leave much time for anything but sleeping.  The summary will be posted as soon as possible and I will tweet a link as soon as I do this. Thank you all for continuing to join in the journal club discussions and I am looking forward to tomorrow night’s discussion already.

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When I was introducing this paper I chose to highlight that one of the reviewer’s thoughts that it was a poor quality study. I don’t know  if that influenced the discussion or even non-participation in last week’s #twitjc, but there were several tweets expressing disappointment with the paper during the discussion. At first glance this appeared to be an accessible paper on medical education which would provoke a lot of discussion. But when you look more closely it contains complex analyses; the results of which many of those reading the paper did not manage to get to grips with. The poor presentation of some of the results in the additional file did not help. And the authors reach conclusions which are hard to justify.

Overall the main finding of the research was that medical schools seemed to have little impact on how students performed in post-graduate examination. The better the intake of students were at passing exams at 18, then the more likely they were to pass exams a decade later. This prompted me to ask if that suggested that rather than a national exit exam we needed a national entrance exam. @twsy suggested that if we wanted to look at the ‘value added’ by the medical school then we would need a national entrance and exit exam.

Some medical schools have graduates who take longer to pass professional exams. Is this an issue that should concern medical schools? And if it is what should we do about it? The correlation demonstrated in this paper suggests that if we wanted to have uniform outcomes for graduates of all medical schools then we should have uniform intake. It is unlikely that it would be socially acceptable to make students complete a national entrance exam and then allocate them to medical students across the UK to ensure an equal mix of academic performance. So we are left with the current situation.

We asked if performance of graduates in post-grad exams was a good indicator of the performance of a medical school. We didn’t think that it was, but we weren’t sure how performance of a medical school should be assessed, or if it should be at all. As an aside there was some discussion about what would make a good doctor at the individual level. Was it ‘head knowledge’ or good communication? It was pointed out that UKFPO was now trialling an assessment of situational judgement as a way of allocating doctors to further training. This is certainly something I would like to learn more about.

Access to the reviewers’ comments was generally lauded. We would like to see this more, as it can help understanding of the paper. In my own opinion it would be interesting to have seen some editorial comment on how two such different reviews were rationalised so that the outcome was that the paper was published.

I know that some people missed out on participating in this discussion, so I hope that you will take the opportunity to leave a comment here.

Should we have discussed this paper? Yes, we should. Many people will have heard of it before, and now they hopefully have a better understanding of it’s findings and linitations. #win!

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This week’s journal club saw a fascinating discussion of CRASH-2 (Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage) and, as before, it has been a struggle to write a summary post that can do the discussion justice. This post will focus on the five main areas of discussion.

Study population

CRASH-2 was conducted in 40 countries world-wide and in an impressive range of healthcare settings. The criteria by which patients were deemed with or at-risk of significant haemorrhage were clinical ones. Patients were deemed to have significant haemorrhage with a systolic blood pressure less than 90 and/or a heart rate greater than 110 beats per minute. However the judgements of which patients were at risk of significant haemorrhage was purely based on clinician judgement. The question was posed by myself, ‘are these criteria robust enough?’.

The inclusion criteria were felt to be one of the strengths of the study as @ welsh_gas_doc commented

The words “at risk of…” are somewhat open to interpretation, but good inclusion criteria.

Many participants commented on the range of health care settings involved in the trial. This was felt to be very impressive as the following tweets show:

@GabrielScally

I think the clinical criteria were fine. There is an amazing range of settings involved – both developed and developing countries.

@PaedsSHO

@GabrielScally Agree, the range of settings was really impressive.

Primary outcome measure

This paper reported all-cause mortality as the primary outcome to be measured. We asked whether this paper was asking the right question.

It was widely agreed that all cause mortality was the right outcome to measure, though @paramedicsa commented that:

with normal Trauma mortality at 60% within first 24hrs, shouldperiod be reduced from 28days?

…and there was an interesting discussion of whether 28 days was just an “arbitary” cut-off point, as suggested by @TWSY. @MsPhelps highlighted an interesting point – that looking at the mortality figures in the paper the all-cause mortality would probably been the same had the cut-off point been 14 days. @iamdoctord’s views did seem to reflect that of the majority of participants:

I think 28d appropriately covers the early mortality from the primary insult and secondary complications which were to be evaluated

Adverse events

No matter how effective a treatment is shown to be in any trial, it is important that any adverse effects relating to treatment are identified and reported appropriately. This paper reported no adverse events as serious, unexpected or suspected to be related to the study treatment. However as @TWSY commented the discussion of the paper stated ‘we cannot exclude the possibility of some increase in risk’. Was the reporting of adverse effects in this paper adequate?

Many felt like this issue had not been covered in enough depth in the paper: @Assidens highlighted:

really difficult to judge as all info seems to ‘play down’ possible side effects, would need more data on side effects

The paper did mention the risk of  non-fatal vascular occlusive events but the authors stated that the relative risk  of such events should be unbiased even if possibly under-reported. As @TWSY commented:

Studies are rarely large enough to detect rare events. Yes, a risk of undereporting or not recognising rare events

Tranexamic acid is now being used in clinical practice in trauma patients as a result of this trial. It is vital that there is ongoing research and monitoring of any adverse effects that may be related to this treatment in this population group as highlighted in this interesting discussion.

Mechanism of action of tranxeamic acid in trauma patients

This trial showed that tranexamic acid was effective (the number needed to treat was 67) but the precise mechanism is unknown. The question posed was should research into how this drug works in trauma patients be a major priority or is research like this showing that it does work be enough to allow its widespread use? As @iamdoctord asked:

Is full comprehension a pre-requisite for application to clinical practice

Two of the highlights of the debate surrounding question came from @welsh_gas_doc:

It would be an act of intellectual masturbation to spend money researching HOW Tranexamic Acid works. Fun, but ultimately pointless

It isn’t clear exactly how most anaesthetic drugs work; theories abound, butnobody is 100% sure . . .(I know, but it’s a secret)

The last point was one raised by several people: the precise mechanism of action of many drug treatments is unknown, paracetamol being a widely raised example, yet they are known to be clinically effective. The general consensus seemed to be that since this treatment has been shown to be effective, further research into its mechanism of action would be interesting, but should not delay this treatment’s widespread use in trauma patients with, or at risk of, significant haemorrhage.

Trials in the emergency setting – consent and delays

A subgroup analysis of the CRASH-2 trial showed that early treatment with tranexamic acid was the most effective, with treatment later than three hours actually leading to increased bleeding .One area of delay was in gaining consent for participation in the trial.  @GabrielScally pointed out that consent accounted for a delay of about an hour in administrating treatment in this trial. Roberts et al wrote a very interesting accompanying article in The Lancet about consent in emergency trials, suggesting that seeking consent may actually be unethical if it leads to a delay in the start of trial treatment, such that the effect could be reduced or obscured. The question was asked during the discussion – should consent be necessary in the emergency setting?

This lead to an extremely interesting debate (I have to admit I did play the role of devil’s advocate during this – asking “When we have real clinical uncertainty for a trial treatment should we just treat without consent?!”). @TWSY, an emergency physician, discussed how emergency care research can actually allow for retrospective consent, for example if pre-agreed by the ethics committee before the trial is run.

As with any ethical discussion opinions did vary. @TheNerdse and others felt that consent need not always be sought but this does come with caveats. From @TheNerdse:

consent need not be sought in emergency where the treatment proposed is viable, needed fast, life saving & proven. In my opinion.

But as @amcunningham pointed out this was a trial and it was conducted because the benefits of treatment were not known:

yes, but trial was conducted because benefits not known.. could have done harm… in that case consent needed

@iamdoctord raised the issue of clinical uncertainty regarding trial treatments and consent:

Despite uncertainty, and if patients know such uncertainty exists, we cannot relinquish their right to choose their therapy.

Does this apply to placebo-controlled trials where a patient’s consent allows us to allocate them to a treatment or placebo arm when we actually don’t know whether a treatment will be beneficial? This is an ethical minefield and hours could be spent discussing this one point and there would never be a consensus on how to proceed. Ultimately, trials in the emergency setting, such as CRASH-2, are very important to developing practice and can have a huge impact on how we treat future patients. Trials need to be well-planned with a robust protocol, though never forgetting that while the patient may be a participant in a trial, they are still a patient and we have ultimate responsibility for their care.

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For our second paper we discussed Rose’s Prevention Paradox. For an introduction to this paper, please see here. I feel confident saying there was no issue with finding relevance in this paper to current practice. There was initially some concern about the choice of paper and whether the usual criteria for critiquing a paper applied, but the general consensus, both at the beginning and after the session, was that it was an interesting and important paper to discuss. I hope everyone would agree that the discussion raised some very interesting points about the nature of preventing disease, including preventive medication and public health initiatives. As with last week, we’ve picked some key points to focus on:

Impact on Clinical Practice

We began by discussing how the paper might affect clinical practice, with @petermbenglish tweeting:

This was a bright shiny new idea when the paper was published. Has it become tarnished in the  mean time?

A few people commented that this will always be an important paper, and consensus was that this is a paper relevant to many areas of clinical practice. Soon, the issue of balancing individual interests against the population’s interests came to the forefront of the discussion. @silv24 pointed out:

[We] need to examine the risks as well as the benefits when giving preventative treatment, that has to apply to every individual

and later:

Should we be aiming for improvement in the patient sat in front of us or the population as a whole?

Fundamentally, this aspect of the discussion boiled down to balancing the interests of the individual patient against the interests of the population as a whole. Most agreed that there was too much focus on high-risk patients, with @davecurtis314 suggesting this might be because they don’t understand Rose, (although in fact this can end up being in the best interests of the patient). The issue of engaging with patients to promote adherence to any medication regime was raised on a few occasions, with concerns also raised about how to encourage low-risk patients to agree to and adhere to treatment, especially in the context of treating a non-event. However, as @GarethEnticott highlighted, there need not be a dichotomy between addressing the needs of the population versus the individual:

Trouble with rose is people think it is an either/or choice. Rose concludes both strategies have to be used.

We then discussed the difference between “normalising” interventions, such as promoting healthy eating and smoking abstinence, and interventions such as medication, which effectively increase abnormality. Related to this point was the “polypill“, which most people felt would be rejected by Rose on the basis that there currently exists insufficient safety data (since safety data takes longer to obtain than efficacy data). We spoke about the fact that Rose declared long-term mass preventive medication to be unacceptable, while suggested that interventions such as promoting healthier lifestyles would be more ethical since they are “normalising” interventions. (Though @drgrumble pointed out that it may be easier to encourage patients to take a pill every day than give up smoking and change their diet.) However, as @davecurtis314 pointed out, the “problem is that effect on individual [is] tiny, effect on population/NHS huge”.

Risk Presentations

Many people felt this was something that doctors could improve on. The difference between relative and absolute risk reductions was emphasised, and number needed to treat (NNT) was also discussed, although this paper showed that presenting NNT alone to a patient may not be appropriate. This Cochrane review suggests that natural frequencies (“50 out of 1000” rather than “5%”) may be preferable, but does not provide conclusive results. There was also a brief discussion about the teaching of statistics at medical school. The responses were mixed: @silv24 and @DrDLittle reported receiving very little teaching, though I received a lecture series in medical statistics in my first year of medical school.

Preventive vs Therapeutic: Differences between Specialities

Psychiatry was suggested by @davecurtis314 as a speciality in which prevention and treatment overlap, although prevention is usually of relapse, rather than initial episode of illness. Paediatrics was one area identified as being very pro-active in its use of preventive intervention, in the form of vaccination. A particularly interesting suggestion was made by @danjrharvey, with respect to the use of antivirals during the H1N1 influenza outbreak not only to treat ‘flu, but also to prevent transmission. Rose highlights obstetrics and antenatal care as being largely preventive by nature, both at the individual and population level. In addition, screening is particularly widely used in women’s health, and increasingly in sexual health, which can arguably count as a form of prevention. @adriamarilla also pointed out that in Cuba, doctors are trained with a much stronger population preventive approach, perhaps indicating strong geographical differences.

Most agreed that preventive treatment was more cost-effective than cures; however, as @silv24 pointed out, this raises the issue of commercial interests of pharmaceutical companies, and also the issue of public concerns about medicalisation in light of new medications with lower limits for treatment.

Social Change

The conversation they moved onto sociology: @danjrharvey felt the most powerful way of altering the behaviour of a population was through economics, and socioeconomic factors were identified as being a key predictor of health. @amcunningham tweeted:

Personally I think sociologists [are] at least as important as psychologists when thinking about what determines health behaviour.

It became apparent that social factors and lifestyle were considered very important, and @carotomes pointed out that these were both likely to be cost-effective and sustainable. There was quite a bit of discussion about whether doctors should create social pressure to effect behaviour change – is it effective? is it ethical? Social change, @amcunningham said, arose not from putting pressure on individuals, but on society as a whole, which @petermbenglish pointed out meant engaging mainstream media. No doubt doctors play a role in this too, but most agreed that this was not something they could do on their own. @aj0610, @petermbenglish and @alijmbacon raised the issue of media emphasising things that are either lacking in value, or which are wrong, with sensationalism trumping sensibility in order to appeal to what readers are interested in. However, as @anaestheticdoc pointed out:

This is presuming that society wants to change. Does everybody want good health, and go without some unhealthy lifestyle choices?

What is a Patient?

One concern with preventive treatment is that it make asymptomatic individuals assume the “sick role“. Should individuals receiving preventive treatment be considered patients? @doctorblogs quite emphatically felt “no”, and @Trisha_the_doc added that medicalising healthy people is not a good thing. Some agreed; others, such as @davecurtis314, disagreed, saying that “taking a pill every day makes you a patient”. If true, this medicalises a large proportion of the population, although as @themattmak pointed out, plenty of people take multivitamins or cod liver oil without being designated a patient. Furthermore, would we call women on the contraceptive pill “patients”?

And finally…

After the end of the meeting, the conversation continued into the evening for some time with a discussion about encouraging patients to engage in fewer unhealthy and counterproductive behaviours, such as excessive alcohol consumption and smoking.

Finally, I’d like to conclude with a quote from John Gordon, tweeted by @GabrielScally, as some food for thought:

“No mass disorder afflicting mankind has ever been brought under control or eliminated by attempts at treating the individual”

~*~

Once again, please do leave comments about this second meeting, including anything you think would help improve it. 

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The Sunday before last, Fi tweeted about the possibility of starting a journal club on Twitter to discuss a variety of medical papers. Within a week interest grew, a paper had been chosen, Fi and I had set up a blog, a Twitter account and last Sunday saw the first “meeting” of the Twitter Journal Club. The response was overwhelming – in my wildest dreams I could not have hoped for such a successful first discussion. The paper we had chosen was by no means a simple choice – Rivers et al is a complex paper on critical care but the level of critique more than met the standards of this challenging paper.

The Critical Appraisal Skills Programme (CASP) guidelines were used to give a framework to the discussion (developed and produced by CASP at the Public Health Resource Unit, Oxford). This toolkit gave a clear structured approach to reviewing this randomised control trial and was a fantastic tool.

It is an impossible task to try and summarise the nearly 2 hour discussion into a single blog post, so instead I have decided to pick the five take-home discussion points:

1. Randomised control trials and written informed consent

@ peds_id_doc:

The RCT bit worries me…just how do you get “written informed consent” from someone in SIRS…? Truly no influence…?

When critiquing a paper, and especially a trial, it is easy to overlook the ethical issues in favour of concentrating on methodology and whether the statistics and results stand up to scrutiny. This paper recruited patients with severe sepsis and septic shock and the issue was raised – can we ever really get written informed consent from such acutely unwell patients for involvement in a trial? This trial had approval by an ethics committee although some felt that the issue of consent had not been explored fully enough.

2. Methodology – the issue of blinding

This trial was interesting in that it was partly blinded: clinicians initially treating the patients were unblended; however, once care was transferred to the critical care team, the clinicians who took over care were blinded. This lead to an interesting debate:

@MedEdHelen

Full on double blinded RCT ? no. I can’t think of how they could do better to answer the question & care for patients ethically

The consensus can be summed up by the tweet below:

@themattmak

not having this study as double-blinded doesn’t reduce the quality of its findings

3. Headline result

The reduction in in-hospital mortality was reported in the paper as the primary outcome – this was used to calculate the number needed to treat by several participants:

@fidouglas

If 16% ARR in in-hospital mortality, that’s a NNT of almost exactly 6. (No calculator to hand)

This figure had an impact on several of the participants and highlighted just how effective the interventions in the paper had been shown to be.

@northern_doctor

NNT of 6 is very low!

4. Single Centre Study: Does this reduce the impact of the paper?

The reduction in mortality in the intervention group was a staggering figure; however, many raised the issue that this was a single centre study – did this limit its impact? The issue of resources was also raised: different hospitals in different parts of the world allocate resources in different ways – does this make the Rivers et al paper less relevant?

@amcunningham

Just saying that only studying single centre limits default wider application

@peds_id_doc

@TWSY @twitjournalclub I think resources are a key point – research is useless if can’t be applied.

One point raised, later on in the evening, was the differing nature of A&E / the ER in the USA compared to the UK, with questions raised over how this might affect the relevance of the paper to UK clinicians. Furthermore, while its impact has been huge, is this paper relevant in terms of resource-poor areas?

5. Rivers et al and Surviving Sepsis

This leads onto my final take-home point from the discussion – the impact of this paper. Many comment on how important this paper has been in terms of impact and the way we now manage patients with sepsis, particularly with the Surviving Sepsis Campaign.

@silv24

The Surviving Sepsis Campaign – the impact of care bundles is clearly seen in everyday practice

Time is of the essence when managing septic patients, the importance of the “early” part of “early-goal directed therapy” should never be underestimated:

@northern_doctor

In real life we’re all (or should be) identifying & treating septic patients earlier than used to, and getting them to HDU

~*~

As far as we can tell this is the first journal club to be set up on Twitter and run exclusively through Twitter. While others have “live-tweeted” from real-life journal clubs in the past, one key benefit of hosting a journal club on Twitter is that it allows all sorts of people to participate, from students to consultants. Particularly for students, this can provide a fantastic learning opportunity.

A criticism of our journal club has been that the concept would be difficult to follow. However my experience is of the opposite, there was a huge amount of interaction between all the participants and this lead to a lively and interesting debate.

A static transcript will never be able to show a dynamic process well but as the weeks go on Fi and I aim to improve on this first meeting and on how we present the discussion as a summary on the blog. This is a huge learning curve for both of us and we appreciate any suggestions on how we can improve.

Thank you to all who participated and I cannot wait for the next discussion on Sunday 12th June on Geoffrey Rose’s ‘Prevention Paradox’ officially titled ”Strategy of prevention: lessons from cardiovascular disease”, available here.

Edit: Just a reminder that the transcript from Sunday evening is available here, should you wish to look through it. Also, please do comment on this post and continue the discussion about the paper if you have any other points you’d like to make. 

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