As Leonard sits in the back of your ambulance, you ask him to describe his chest pain. He looks at you with small droplets of cold sweat on his forehead and says: " It feels... like .....someone.... is sitting on my chest." Your partner hands you four baby aspirin and you ask the patient to open up his mouth and chew these aspirin before swallowing. Your patient tells you he already took two baby aspirin before you arrived. Your protocols state the patient must receive 324mg. You stop for a second and wonder where the evidence for this dose came from.
How Does Aspirin Work?
As a non-selective cyclooxygenase (cox) inhibitor, acetylsalicylic acid (ASA) works by blocking the enzyme that leads to specific prostaglandins. For all intents and purposes, think of prostaglandins like little tattle tells in the body. They are signals that tell the body something bigger needs to happen.This could be clot formation, inflammation, or telling you to take your hand off the stove by amplifying a pain signal.
At smaller doses (0.45mg/kg), ASA will primarily effect deactivation of cox 1 hormones such as thromboxane a2 (hemostasis) and prostaglandin I2 (stomach mucosal defense). Larger doses are needed to inhibit cox 2 prostaglandin synthesis.
Think of cox 1 as physiological signals (platelet aggregation or stomach mucosal production)
Think of cox 2 as inducible signals (pain or inflammation)
As the endothelial wall of a vessel is damaged, the platelets which ride against its surface will release arachidonic acid from the phospholipid membrane (via phospholipase blah blah blah I sound smart) of the platelet. The arachidonic acid will then be converted to hormones through the cox enzyme. One of these hormones that ASA inhibits is thromboxane a2.
Whenever there is trouble in the world of hemostasis, the platelets release thromboxane a2 to constrict vasculature and increase platelet aggregation at the site of endothelial disruption (things that don't help in ACS!).
This is like the bodies way of throwing on a tiny tourniquet and quick clot
Once ASA deactivates the cox enzyme within a platelet, the mechanism is irreversible for the remaining life of that cell (10ish days depending on if the cell does crossfit). With that being said, could we reason that the more aspirin we administer, the more platelets that will be effected? If so, do the benefits outweigh the risks associated with impaired hemostasis?
Let's Look At Some Lit!
Most of the evidence we see from the American Heart Association (AHA) recommending ASA comes from the ISIS-2 study that was published in the Lancet of 1988. This was a randomized controlled trial that looked at aspirin alone, streptokinase alone, aspirin with streptokinase, and a control. The mortality at five weeks showed a statistical significant decrease in vascular death in both intervention groups (23% mortality reduction in ASA group P<0.0001). This is an old ass study with results that are hard to ignore.
The dose of ASA used in this study was 162mg, which initially struck me as interesting. While text books will say to administer 162-325mg of non-enteric coated baby aspirin, I typically see the latter given. In fact, I have even seen protocols that state if the patient has only taken one baby aspirin, you need to administer the remaining three. To my surprise, the 2015 guidelines recognize the lack of evidence and increased adverse effects of the higher dose.
Are they basing this recommendation off that old ass study?
If you look at the reference provided for this level of evidence (LOE), it brings you to a retrospective analysis in 2008 using data from the Global Utilization of Streptokinase to open Occluded arteries (GUSTO 1) and (GUSTO III) . This was a large data base of 58,080 patients presenting with ST-segment elevated myocardial infarction (STEMI) to assess immediate aspirin dose of 162mg compared to 325mg. Their hypothesis was that 162 mg would be correlated with similar effects as 325mg, but with reduced adverse bleeding effects.
Because GUSTO1 (N=35,529) patients were more likely to get 162 mg versus GUSTO2(N=12,893) who received 325, there was an adjustment needed for baseline imbalances. This retrospective analysis concluded with underwhelming results and this statement:
"This analysis of 50,000 patients with STEMI receiving fibrinolytic therapy from GUSTO I and III demonstrated that the initial dose of aspirin is significantly (and independently) associated with patient outcome. Specifically, a single initial dose of 325 mg was associated with a significant increase in the risk of moderate or severe in-hospital bleeding compared with 162 mg. Aspirin dose, however, was not significantly associated with a difference in the incidence of death, MI, or stroke. Although these data are nonrandomized, they suggest that for the first dose of aspirin, 162 mg may be as effective as and safer than 325 mg for the acute treatment of STEMI. This higher associated bleeding risk reinforces the impor- tance of finding the lowest effective aspirin dose as an important goal in each clinical setting."
The goal in all things medicine is not to give the most drug without adverse effect, but to give the least amount with therapeutic effect. -Me
While it may seem that giving two baby aspirin versus four is a moot point. I believe that adherence to evidence needs to be taken into account with bayesian priors and potential for risk. There is absolutely no data to recommend that administering 325mg of ASA decreases mortality more than 162mg does, but we do have data showing increased risk and adverse hemostasis effects at high doses. I encourage you to engage your medical directors in conversation on this topic and seek their opinion.
RANDOMISED TRIAL OF INTRAVENOUS STREPTOKINASE, ORAL ASPIRIN, BOTH, OR NEITHER AMONG 17 187 CASES OF SUSPECTED ACUTE MYOCARDIAL INFARCTION: ISIS-2. (1988). The Lancet, 332(8607), 349–360.doi:10.1016/s0140-6736(88)92833-4
Initial Aspirin Dose and Outcome Among ST-Elevation Myocardial Infarction Patients Treated With Fibrinolytic Therapy
Jeffrey S. Berger, MD, MS , Amanda Stebbins, MS , Christopher B. Granger, MD , Eric M. Ohman, MD , Paul W. Armstrong, MD , Frans Van de Werf, MD, PhD , Harvey D. White, DSc , R. John Simes, MD , Robert A. Harrington, MD , Robert M. Califf, MD , and Eric D. Peterson, MD, MPH
Selective Cumulative Inhibition of Platelet Thromboxane Production by Low-dose Aspirin in Healthy Subjects
Paola Patrignani, … , Paola Filabozzi, Carlo Patrono
Published June 1, 1982 Citation Information: J Clin Invest. 1982;69(6):1366-1372. https://doi.org/10.1172/JCI110576.