Monthly Archives: April 2012

Week 19 – Discussion Points

1. How methodologically sound is this study?

2. Are there any unmeasured factors which could influence the choice of procedure and therefore affect the data used?

3. Does this study provide strong enough evidence to recommend CABG over PCI in this population?

4. How much reliance should we put on such non-randomised studies that make use of the available data like ASCERT?

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Week 19 – PCI vs CABG – the ASCERT study

A patient has triple vessel coronary artery disease and something must be done, they need revasularization. The end of their time with medical management only has been reached and now an intervention is needed. But what intervention should we be recommending? Should the patient be referred to the cardiothoracic surgeons for a coronary-artery bypass grafting (CABG) or to the intervention cardiologists for percutaneous coronary intervention (PCI)? Should we be recommending surgery or a minimally invasive procedure? What does the data tell us?

In the past 20 years there have been 12 randomised trials comparing these two interventions, over a time period in which there have been significant advances in both. Of course randomised control trials are one of the best forms of evidence based medicine but the results from trials may not be applicable to the patient sat in front of you, patient groups under study are selected and trials are carried out in selected centres. There is therefore a role for observational data which may reflect real life practice better. The ASCERT study set out to use such date from databases to compare the outcomes of PCI and CABG in two and three vessel disease.

Two different databases were used and over 180,000 patients were included in this study and only the first revascularization record was used for each patient. The primary end-point was all-cause mortality. It is of note that probably the biggest different between the two groups of patients were that patients in the PCI group were more likely to have had two-vessel disease whilst those in the CABG group more often had triple-vessel disease.

The results (patients aged over 65):

  • At 1 year, there was no significant difference in adjusted mortality between the groups (6.2% in the CABG group compared to 6.6% in the PCI group; risk ratio, 0.95; 95% confidence interval, 0.90 to 1.00).
  • However the  adjusted 4-year mortality was 16.4% in the CABG group and 20.8% in the PCI group (risk ratio, 0.79; 95% CI, 0.76 to 0.82).

The 4-year risk ratios showed a benefit of CABG across subgroups studied and in both high and low risk groups (please see the paper for further details).

The author’s conclusion:

In this observational study, we found that, among older patients with multivessel coronary disease that did not require emergency treatment, there was a long-term survival advantage among patients who underwent CABG as compared with patients who underwent PCI.

We will be discussing the interesting paper on Sunday at 8pm

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Week 19 – ASCERT

The paper for this Sunday’s twitjc is the ASCERT study – comparing the effectiveness of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) for the treatment of patients with stable two and three vessel coronary artery disease.

This is a fascinating study – if there are any problem accessing the full paper a link can be found from the excellent Now @ NEJM blog

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Week 18 – Discussion Points

Are there any major design flaws with this study that could impact on it’s results?

Are the outcome measures of this study appropriate?

Should this study have included a no paraenteral nutrition group for comparison?

Should this study widely change clinical practice with regards to the use of parenteral nutrition in critically ill patients?

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Week 18 – Early vs Late Parenteral Nutrition

I have recently finished a four month rotation in ITU which taught me many things, how to put a central line in, how to walk into a cardiac arrest and properly take control of someone’s airway and how to put an NG into a ventilated patient (sometimes with great difficulty).

As soon as patients arrived on our unit we thought about feeding them, within hours of admission suitable patients were started on a NG feeding rota. During the twice daily reviews we would look at how much aspirated was coming back from the NG and was this patient absorbing their feed. And twice daily in the notes the FLATHUG was documented – F for feeding and fluids. When patients weren’t absorbing feed or couldn’t be fed by this route we would get the nutrition team involved very quickly for the inevitable discussion – should we start this patient on parenteral nutrition and when should we do this?

Casaer et al carried out a randomised control trial in seven different intensive care units to address the question of when we should be starting parenteral nutrition in critically ill adult patients. Over 4,000 patients we recruited into this trial and all had a nutritional risk screening score of 3 or more (therefore all patients were deemed nutritionally at risk). Patients were randomised into two groups, early or late parenteral. All patients who were unable to eat by day 2 of their ITU admission received enteral nutrition, however if they failed to meet their nutritional target the group in the early parenteral treatment arm started to receive this within 48 hours.

Those in the late group however did not receive any parenteral nutrition until their 8th ITU day. In both groups continuous insulin infusions were used to maintain normoglycaemia. 

The primary endpoint was the duration of dependency on intensive care, i.e. the number of days spent on intensive care and the time to discharge from intensive care. Secondary endpoints included new infections, duration of antibiotic therapy, time to final weaning from mechanical ventilators support and the rate of acute kidney injury. 

The results were very interesting. The median ITU stay was 1 day shorter in the late-initiation group compared to the early-initiation group, a relative increase in 6.3% in the likelihood of early discharge alive from ITU (hazard ratio 1.06′ 95% CI 1.00 to 1.13 p=0.04).

With regards to secondary outcomes fewer patients in the late initiation group acquired a new infection during their intensive care stay and the duration of renal-replacement therapy and mechanical ventilation were shorter in the late initiation group (see paper for details and for the full list of secondary outcomes.

The author’s conclusions:

In conclusion, the early initiation of parenteral nutrition to supplement insufficient enteral nutrition during the first week after ICU admission in severely ill patients at risk for malnutrition appears to be inferior to the strategy of withholding parenteral nutrition until day 8 while providing vitamins, trace elements, and minerals. Late parenteral nutrition was associated with fewer infections, enhanced recovery, and lower health care costs.

I look forward to discussing this paper at 8pm BST on Sunday and discussion points for this will be posted shortly 

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Week 18 – Early versus Late Parenteral Nutrition in Critically Ill Adult Patients

The paper for this week’s #twitjc is Early versus Late Parenteral Nutrition in Critically Ill Adult Patients – a NEJM paper by Caesar et al. This is a very interesting paper and I look forward to discussing it on Sunday 15th at 8.00pm. A summary of the paper will be posted very soon.

If there is any difficulty accessing the full text of the paper please click here and a full link can be found via the NEJM Physicians Now Blog

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Thromboprophylaxis in AF – An Evidence-Based Overview

Thromboprophylaxis in AF – An Evidence-Based Overview

Dr Mark Garside – registrar in elderly care and stroke medicine

The Royal College of Physicians (Edinburgh) recently held a consensus conference about the management of atrial fibrillation (AF), with the aim of producing a set of updated evidence-based guidelines on the management of this commonly-encountered condition. AF carries with it a significant negative implication for mortality and morbidity. In particular, there is an increased risk of stroke in people with AF, and stroke prevention is an important treatment goal. What follows is a brief overview of the evidence surrounding treatment decisions in AF. The aim of this post is not to scrutinise each individual publication, but rather to highlight the most important point from the literature that should inform clinical treatment decisions.

Whilst it has long been accepted that ‘high risk’ patients with AF (ie. patients with other vascular risk factors) benefit from formal anticoagulation with warfarin, there has been less certainty about the best treatment for patients with fewer co-existing risk factors. Until recently, it has been common clinical practice to treat patients with aspirin as a substitute for warfarin if they are either felt to be at lower risk of stroke, or if warfarin was deemed to be unsuitable for some reason.

Risk stratification tools such as CHA2D2S-VASc can be used to quantify patients’ risk of having a stroke, but it is important to note that all but the lowest risk patients (CHA2D2S VASc=0) get a net clinical benefit from anticoagulation treatment.

An important point to make is that the new guidelines from the consensus conference recommend that aspirin should no longer be used for thromboprophylaxis in AF. Not only is this an evidence-based recommendation, but it is also consistent with the pathology of thromboembolic stroke in AF, where the thrombus is mainly fibrin-based, compared to the platelet-rich thrombi that predominate in coronary artery disease.

The evidence for the use of aspirin in AF is actually very weak. Although a meta-analysis by Hart et. al. (1) suggested there may be approximately a 20% relative risk reduction with aspirin compared to placebo, there are some problems with this. Firstly, this reduction did not quite reach statistical significance. Secondly, the methodology in the studies analysed varied widely, not least in the range of different doses of aspirin that were used. Finally, it  appears that the results of a single study, SPAF-1, are skewing the results of the meta analysis to make aspirin appear more effective than it is actually likely to be. SPAF-1, which compared aspirin to placebo in 2 different subgroups (one with patients that would have been suitable to receive warfarin treatment, and one with patients who were though to be unsuitable for warfarin) produced some anomalous results, with only one subgroup (the one with patients who we now know should have been on warfarin) showing a benefit of aspirin (2).

For low-risk patients – ie. those with “lone” AF, who would have a CHA2D2S-VASc score of 0 – an RCT in Japanese patients comparing aspirin to placebo was stopped early due to an increased rate of bleeding in the aspirin arm without any suggestion of a benefit in stroke prevention (3).

Even in the elderly population, who are often not anticoagulated due to a perceived high risk of bleeding, trial data has shown that not only is warfarin significantly more effective  than aspirin in terms of stroke prevention, but also that it is no more dangerous in terms of causing significant bleeding (4).

That is not to say that the risk of bleeding should be ignored, and the HAS-BLED scoring tool has been developed to try and quantify that risk. However, several of the components of the HAS-BLED score also appear in the CHA2D2S-VASc score, reflecting the fact that risk factors for bleeding overlap with risk factors for ischaemic stroke. The HAS-BLED score was not designed to be used as a tool to justify not treating patients with warfarin, but rather to identify high-risk patients so that they could be more closely monitored, and that modifiable risk factors could be addressed.

But warfarin is not without its drawbacks. Although we have many years of experience with it, it dose not have a consistent dose-response, requires careful and regular monitoring, has many drug interactions, is often inconvenient for the patient, and only has a net clinical benefit if over 65% of the time is spent within a therapeutic INR range.

Although they are in their infancy, there are three new oral anticoagulants which may provide a suitable alternative treatment to warfarin, and solve many of the above problems. Dabigatran (a direct thrombin inhibitor), Rivaroxaban and Apixaban (both factor Xa inhibitors) have all been shown to be at least as effective as warfarin for stroke prevention in AF, and at least as safe in terms of bleeding risk (5,6,7). In particular, it’s worth noting that the higher dose of dabigatran has been shown to be significantly more *effective* than warfarin with a similar rate of bleeding, whereas the lower dose is significantly *safer* in terms of bleeding but has similar efficacy to warfarin in terms of stroke prevention. This could prove to be important for clinicians, as the choice of doses allows for extra caution to be taken in patients felt to be at high risk of bleeding.

In addition to comparing itself against warfarin, Apixaban has also been trialled against aspirin in a patient population who were deemed too high-risk for warfarin(8). The results showed it to be significantly more effective than aspirin at stroke prevention, with a similar bleeding profile. So in the near future this may also become a realistic treatment option for patients who are not suitable for warfarin treatment.

Weighed against these advantages though is the fact that there is no specific antidote, which may be problematic in acutely unwell and bleeding patients. However, although there are concerns and as-yet unanswered questions about how well these new agents will work in the real world, the fact remains that the more pressing risk to patients is the risk of ischaemic stroke, and trying to mitigate this risk through anticoagulation should be a priority wherever possible.

In summary, there is no evidence to support the use of aspirin for thromboprophylaxis in AF, and it may even risk net clinical harm to patients. Anticoagulation is the preferred treatment, with warfarin being safer and more effective that is often perceived, even in an elderly population. Newer oral anticoagulants seem to be at least as effective as warfarin, and in many cases safer, but come with a significantly higher cost attached.

For now, the take-home clinical message is to be aware of AF as an important clinical problem, and to give serious thought about what the best treatment is likely to be for your patients.

Further Reading:

For a more detailed overview of this topic, including information about the trials mentioned above, the following review is recommended:

Bassand, JP; Review of atrial fibrillation outcome trials of oral anticoagulant and
antiplatelet agents Europace (2012) 14(3): 312-324 http://europace.oxfordjournals.org/content/14/3/312.full

References:

(1) Hart et. al. “Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation.” Ann Intern Med 2007;146:857-67

(2) Stroke Prevention in Atrial Fibrillation Investigators. “Stroke Prevention in Atrial Fibrillation study. Final results.” Circulation 1991;84:527-39

(3) Sato et. al. “Low-dose aspirin for prevention of stroke in low-risk patients with atrial fibrillation: Japan Atrial Fibrillation Stroke Trial.” Stroke 2006;37:447-51

(4) Mant et. al. “Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial” Lancet 2007;370:493-503 DOI: 10.1016/S0140-6736(07)61233-1

(5) Connolley et. al. “Dabigatran versus warfarin in patients with atrial fibrillation.” N Engl J Med 2009;361:1139-51

(6) Patel et. al. “Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.” N Engl J Med 2011;365:883-91

(7) Granger et. al. “Apixaban versus warfarin in patients with atrial fibrillation.” N Engl J Med 2011;365:981-92

(8) Connolley et. al. “Apixaban in patients with atrial fibrillation.” N Engl J Med 2011;364:806-17

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Evidence Based Medicine & #twitjc

Two weeks ago saw one of the busiest but most incredible weeks of my life. On the Monday I presented at the Society for General Microbiology Spring Meeting in Dublin. In one of the most nerve wracking moments of my life I stood up, with no slides, and talked for half an hour about the journal club. The feedback was just incredible and I would like to thank everyone who sat and listened to me witter on and I would also like to thank @PaulHoskisson for inviting me to talk.

Then on the Thursday I spoke at the BMJ editorial meeting, again about the journal club. If I thought I was nervous in Dublin then I had no idea what was ahead. Stood in one of the rooms at BMA House with a microphone I have no idea how my voice didn’t waver as I spoke. Yet again I was completely overwhelmed by the support for the journal club and the enthusiasm for this project.

And this is a project, this is very much a work in progress. I have recently had time to sit down and start to think about how the journal club and this website could develop. Several weeks ago a clinician tweeted from a conference he went to and wrote a blog post that caught my attention and gave me an idea – what about asking clinicians to write evidence based medicine summaries of different clinical topics?

Tonight I am very pleased to publish the first such summary. Written by Dr Mark Garside, a registrar in elderly care and stroke medicine this is a summary of thrombopropylaxis and AF – a very important clinical topic. Mark has written a fanastic summary including the latest evidence and I would like to thank him for the time and effort he put into this.

The aim is to publish a new summary on alternate weeks to those that the journal club runs. Suggestions of topics are welcome and any doctors I know on twitter please beware that I may well be asking you to contribute soon….

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