“Coagulation & Medications” – Aspirin

9 May

This is aspirin, credit to Bayer for discovering it!

I already was a big fan of #FOAMed and the different EM blogs out there, but working on this post made me even a bigger fan! It is impossible for me to discuss all the anticoagulation and antiplatelets, their purposes and the evidence for their use. It would probably take me years and me my relationship. That’s why a great part of this post is “borrowed” from others and a lot with be cardiology minded. In the end we also need to discuss thrombolytics in acute ischemic stroke. But today is about Aspirin, followed by posts about the other antiplatelets and one about anticoagulation!

ASPIRIN… aka acetylsalicylic acid (ASA). It is the best known antiplatelet out there! It is a COX-inhibitor, which inhibits the activation of platelets. I will discuss the evidence behind the use of aspirin in Acute Coronary Syndrome (ACS). Other reasons to use it, like ischemic stroke or Kawasaki disease won’t be discussed here.

Up till the beginning of the 90’s the spectrum of ACS was different than it is nowadays. It consisted of UA, Non-Q wave MI (NQMI) and Q wave MI (QwMI). Then came the meta-analysis FTT (Fibrinolytic Therapy Trialist), which found that the patients with ST-elevation benefit from fibrinolytics. After this the spectrum became UA and (N)STEMI.

So why all this (old) information, you think? Well, this means that older articles (from the 90’s and before) classified the patients with ACS differently than we do nowadays, which may lead to differences in results. For example, somebody with a STEMI back than could initially be in the UA group.

The article that looked at aspirin in acute MI was ISIS-2 in 1988. ISIS­2: Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17187 cases of suspected acute myocardial infarction. Lancet. 1988 Aug 13;2(8607):349-60. This article is discussed on the website: theNNT: http://www.thennt.com/nnt/aspirin-for-major-heart-attack/

This is what they did and found:

They looked at 17.000 subjects, who were believed to be suffering from an acute MI by treating physicians and were randomized to aspirin, streptokinase, both, or neither. There was a higher death rate in the first month among those assigned to placebo 1016/8600 (11.8%) versus aspirin 811/8587 (9.4%) with no significant increase in need for transfusion or intracerebral hemorrhage. There was a 0.6% increase in minor bleeding. Aspirin provides among the best mortality benefits (in the 1st month) of any intervention for MI, with minimal downside effects. The anti-platelet mechanism seems sensible and the data are strong. Aspirin should be given to all cases of confirmed or suspected STEMI unless a significant contraindication exists. But, we don’t know for certain that the patients entered into this trial were having heart attacks, as the entry criterion was an EKG showing ST elevation and MI was not confirmed with any other testing (i.e. cardiac biomarkers).

In summary: NNT: 42 NNH: 167 (minor bleeding events)

10 years later came ISIS-2: 10 year survival among patients with suspected acute myocardial infarction in randomised comparison of intravenous streptokinase, oral aspirin, both, or neither. The ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. (BMJ. 1998 May 2;316(7141):1337-43.) In this article they looked at the outcome after 10 years and what they found was that there was an known significant benefit of aspirin in the 1st 35 days (CI 95% = 0,78 (0,71 – 0,85) ) and that from days 36 till 10 years there was no real difference. So early survival advantages produced by aspirin started in patient (thought of) having AMI seems to be maintained after 10 years!

Off course we also have a guideline and since I am European, it is the ESC Guideline http://www.escardio.org/guidelines-surveys/esc-guidelines/GuidelinesDocuments/Guidelines_AMI_STEMI.pdf

They refer to the following article that showed benefit of aspirin in secondary prevention of vascular disease , but not to an article that looked at aspirin given directly during a MI. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. (Lancet. 2009 May 30;373(9678):1849-60. doi: 10.1016/S0140-6736(09)60503-1.) They did a meta-analysis of vascular events (MI, stroke, vascular death) and major bleeds, and compared long-term aspirin vs placebo. In the primary prevention trials the biggest benefit was found in a significant reduction of non-fatal MI’s (0,18 vs 0,23%/y), while in secondary prevention there was a significant reduction in serious vascular event (7,6 vs. 8,2%/y), with a non-significant increase in haemorrhagic stroke.

Now Aspirin in NSTEMI:

The ESC Guideline for ACS without ST-elevation http://eurheartj.oxfordjournals.org/content/32/23/2999.full.pdf referred to articles from more than 30 years ago and as you know the spectrum of ACS was different back than!

The 1st one is from Theroux, and if you want to know how to pronounce it…go to SMART EM  and listen to the podcast about Heparin for Coronary Syndromes!  In comes after 20 minutes. Very funny! Aspirin, heparin, or both to treat acute unstable angina. (N Engl J Med. 1988 Oct 27;319(17):1105-11.) This is a great trial, since they also had a placebo arm, which would be impossible today. There were 4 groups: Aspirin / Heparin / Aspirin+Heparin / Placebo. We will only discuss the aspirin part, while the heparin will be discussed in the “coagulation” post.  All patients enrolled had unstable angina with chest pain in the preceding 24h. What they found for aspirin was that the incidence of MI was decreased to 3.3%, compared to 11.9% for placebo (p=0.012). Death was so rare in this study that it was impossible to see a benefit from the aspirin and the incidence of refractory angina didn’t significantly reduce with aspirin alone, but did with aspirin+heparin (with 53%). There were no statistically significant differences between the 3 treatment groups.  Aspirin didn’t show an increase in (bleeding) complications when compared to placebo.

The 2nd article was also from Theroux and was published 5 years later Aspirin versus heparin to prevent myocardial infarction during the acute phase of unstable angina. (Circulation. 1993 Nov;88(5 Pt 1):2045-8.) This time there was no placebo arm and aspirin was compared to heparin in a double-blind randomized trial. During the study period (1st 5 days) they found 0,8% MI’s in the heparin group and 3.7% in the aspirin group (p=.035). Serious bleeding complications were lower (p=.008). Given these results they recommend heparin for acute phase of unstable angina (and aspirin for long-term treatment).

The last article is from Cairns from 1985 Aspirin, sulfinpyrazone, or both in unstable angina. Results of a Canadian multicenter trial. (N Engl J Med. 1985 Nov 28;313(22):1369-75.) They compared aspirin to sulfinpyrazone……??????? To What? Well, I had to look it up, but it can be used for gout, but it also sometimes is used to reduce platelet aggregation by inhibiting degranulation of platelets which reduces the release of ADP and thromboxane. That’s all I can tell you about it! They did a randomized, double-blind, placebo-controlled trial in coronary care units.  There was no benefit for sulfinpyrazone, but looking at the surviving curves in the article aspirin showed a great reduction in cardiac death in the 2 year follow-up (≈ 11% vs 3%). There was a relative risk reduction of about 70% (p=.004) with aspirin. Very few side-effects were mentioned.

So in conclusion: Aspirin is save and there is enough data supporting its use in ACS. Sadly the data are old and in these days the spectrum of ACS and its treatment were different. Ideally we have to do a study now. It would be a randomized, double-blind, placebo-controlled study on aspirin given in the ED in patients with ACS. Off course this would never be approved and I believe that the data that are already out there are enough. There were only very few (major) side effects and there seems to be enough benefit. Especially when you take into account that it is cheap! (on internet you can get a pack containing >100 tablets for less than $10) .

  • Finally, this was no journal club, so I would advise you all to take (one of) these articles and dive deep into it. Even deeper than I did! Let me know if you have any comments!

Egon

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