why is IV tPA ≤4.5hrs? and other quirks of current medical guidelines

It’s hard to believe I’m nearing the end of my preclinical journey in medical school. In theory at this stage, I am supposed to have learned all of the preparatory content for the first step of the board exams that are required to become a licensed physician (“Step 1”).

In reality, I feel like I have merely scratched the surface, despite many hundreds of hours of lectures. I feel that especially when I am sitting in a lecture and hear a small factoid mentioned in passing and then decide to go down the rabbit hole to investigate the factoid a little more.

Such as a few weeks ago in neurology lecture. We learn that in the case of an ischemic stroke, “time is brain” and one must strive to give IV tPA within 4.5 hours. Miss the 4.5 hour cutoff, and it’s too late—there’s no (purported) benefit.

I was curious why the cutoff of 4.5 hours existed—why 4.5, and not 5 hours? Or 3 hours? It turns out that the 4.5hrs is sort of arbitrary, but is thought to be a proxy for reversibility of ischemia: if you catch a stroke within 4.5hrs of onset, it’s more likely that the ischemia is reversible, whereas >4.5hrs it’s more likely the tissue has infarcted and is not salvageable.  IV tPA will always have a risk of intracranial hemorrhage (which is bad, because you can die from a brain bleed). So, once the brain tissue is dead from the infarct and lysing the clot wouldn’t really benefit you at all, it’s better NOT to give IV tPA—the risks outweigh the (nil) benefit.

The history behind the 4.5hrs? In 1995, some people at the NIH showed IV tPA was effective for ischemic stroke within 3hrs (this was after the introduction of thrombolytic agents in the US and a rapid burst of research into how effective they are at treating things that cause thromboses, like DVT, PE, MI, stroke). Then in 1998 some Europeans found IV tPA was NOT effective within 6hrs. The Europeans came back at it in 2008 showing IV tPA was effective from 3-4.5hrs, leading to the current guidelines…However, this is still controversial (see, e.g., “Treating ischaemic stroke with intravenous tPA beyond 4.5 hours under the guidance of a MRI DWI/T2WI mismatch was safe and effective” and the 2018 NEJM WAKE-UP trial results). A more accurate way of deciding whether or not to give someone IV tPA would probably be doing an MRI and looking for signs of ischemic tissue that is not yet infarcted (but MRI takes a while, is expensive/not available everywhere, etc.).

More generally, it’s interesting to think about how current guidelines are formed and how the research design of studies that aim to prove or disprove their effectiveness can really shape what the guideline ends up being. In the case of the 4.5 hours of IV tPA, reaching the current ‘equilibrium’ seems analogous to damped harmonic motion…first they were too high (6hrs), then swung too low (3hrs), finally settling on the sweet spot (4.5hrs). But who knows if that is *truly* the best cutoff, and that is probably also some product of the population level characteristics of the study sample. Anyway, the cutoff is really a proxy for a process (infarction) that is known to have a more accurate form of measurement (MRI).

Each lecture of preclinical time has been packed with factoids—factoids that alone could be an entire person’s career. The expanse of medical knowledge is so vast, and yet even then we are so limited by what we have chosen to study.

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