[extropy-chat] Aspirin, life-extension, and the current spate of pain-reliever problems

[Damien Broderick]

Here's a response to Dan's interesting suggestion from Steve Harris, MD:

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COX-1 is the form of the enzyme found in all tissues. COX-2
is the form which is induced by, and contributes to, acute
inflammation, but otherwise is normally not active (except
in uninflammed kidney and brain, for reasons not obvious).

Naprosyn and aspirin ARE COX-2 inhibitors; that's how they
work. If they weren't, they wouldn't be much good for
inflammation. It's just that they're not selective, and they
inhibit COX-1 also, making them hard on the stomach. Since
COX-1 is what's in platelets, that makes these drugs inhibit
platelet function a bit, and therefore clotting. Aspirin
does this at far lower doses than Naprosyn (salt form =
naproxin), since its effect on COX-1 is irreversible; it
binds to and "kills" the enzyme, so the effect lasts for the
life of the platelet. Not so for Naprosyn. So if you're
taking Naprosyn/naproxin (Aleve and others) there may be
"holes" in your coverage of a few hours, where your clotting
goes back to normal. That might happen early in the AM when
you might be having your heart attack. Aspirin is a better
drug to make sure those holes don't happen.

Apparently Vioxx (which has so little COX-1 effect that it
has NO effect on platelets), by some odd mechanism INCREASES
clotting, over and above normal, in some other way. We don't
know how-- it's the question of the hour. It wasn't
suspected, to say the least, on theoretical grounds. And
yes, the (small) dose of aspirin which Vioxx doubtless
caused many people to forgo when they started on that drug,
probably did help to increase this effect, and thus stroke
and heart attack.

This effect has been looked for in Celebrex, and does not
seem to present.  We are presented with the interesting
hypothesis that maybe all NSAIDS are pro-clotting by their
nature, for reasons unknown, BUT the effect is masked in
dirty NSAIDS like aspirin and naproxin and ibuprofen, due to
their COX-1 antiplatelet effects. So Celebrex has been
carefully studied to see if it has the same problems as the
two COX-2 selective NSAIDS which have had to be removed from
the market. No stroke/MI effect has been detected so far.
Unfortunately, Celebrex is not QUITE as selective as Vioxx,
and it does have minor anti-clotting effects unlike Vioxx,
so this hypothesis is not quite dead yet. Perhaps Celebrex
is JUST dirty enough to not cause problems.

Summary: Is the entire pro-clotting effect of Vioxx due to
people stopping their aspirin or other non-selective COX
inhibitor drugs (aka dirty NSAIDS)?  No-- Vioxx users had
increased risk over placebo users, independent of aspirin
use. Vioxx does something to increase normal clotting. Did
aspirin use-reduction contribute to the problem seen with
Vioxx in the overall population?  No doubt, but it's hard to
say how much. We may never know.

Interestingly, I always put my over-40 male patients and
over-50 female patients taking Vioxx also on low-dose
aspirin, if they had no other reason not to take it, simply
because I knew that Vioxx was not helping with the known
risk-reduction from anti-platelet therapy. But like most
physicians I never in my wildest dreams thought Vioxx might
be a pro-clotting drug like (say) estrogen. I was as much
caught by surprise as any physician out there, by that.
Nature is complicated, and theories are simple. Sometimes
they fail.