January 27, 2023

When it comes to stroke, treatment is dependent on the stroke mechanism. But most patients wind up on aspirin anyway. Or Plavix (clopidogrel). And sometimes both. The question this week is, Why? Hope you’re hungry for some fruit. We’re comparing a bunch of apples to oranges in this episode of the BrainWaves podcast.

A few weeks ago lindsay rapp and john past came on the show and they made fun of how stroke doctors are all over the place when deciding on aspirin or plavix for the purposes of the show today i’ll be using the generic name for plavix clopidogrel and what they said is true a lot of times residents and trainees are so confused as to which antiplatelet agent to

Use not infrequently a resident may be presented the case to an attending and say i want to start the patient on aspirin and then the attending will be like may i think this patient should be on clopidogrel or the resident might say about another patient you know this patient should be on clip integral and the attending will give you that evil how could you be so

Ignorant stare why would you even suggest that they might say what’s the evidence well what is the evidence which drug is better for which patient and for how long there’s a lot to cover and only 15 minutes to cover it so let’s just get started this one’s for you lindsay stick with us support for this episode of brain waves and the following message was brought

To you by audible the internet’s largest collection of ad free audiobooks if you are enjoying the episode so far you might like to hear my stroke of insight by jill bolte taylor it’s the intense story of a neuroanatomist who experiences a right-sided intracranial hemorrhage and recovers to tell the tale you can get this audiobook and listen to it in its entirety

In just five hours by going to audible trial calm brainwaves that’s audible trial calm brainwaves one of the major take-home points for the show is to know whether you’re treating an acute patient with stroke or patient who’s had a remote stroke acute stroke is associated with a much higher risk of early recurrence and a higher risk of hemorrhagic transformation

With antithrombotic therapy so it’s not surprising that the evidence for antiplatelet agents is different kind of based on the timing of the stroke aspirin is the main agent we’re talking about when it comes to acute stroke then let’s start with its mechanism as you probably know aspirin is an irreversible cyclooxygenase inhibitor platelets use cyclooxygenase to

Make into peroxides and ultimately thromboxane a2 which stimulates platelet activation and aggregation by inactivating the cyclooxygenase aspirin effectively eliminates this mechanism of action for the entire lifespan of the platelets about seven to ten days as far as use and stroke goes 300 milligrams of aspirin or more has level 1 evidence to support it’s used

In the first 24 hours of acute stroke as long as patients haven’t received iv tpa then you’ll have to wait at least 24 hours to reduce the risk of bleeding so where does this evidence come from the first international stroke trial ist was among the largest and the most recent to prove safety and efficacy of acute aspirin therapy in the prevention of early stroke

Recurrence in ist over 19,000 patients were randomized to receive unfractionated heparin aspirin both or neither which is a 2×2 factorial design and they were randomized within 48 hours of stroke onset although the primary outcome of early death by 14 days was no different between the aspirin arm versus the no aspirin arm 14-day recurrent ischemic stroke occurred

Less frequently in the aspirin arm 2.8 percent versus 3.9 percent without a significant increase in hemorrhagic stroke little less than 1% for both arms the number needed to treat to prevent a recurrent stroke at 14 days was 100 a similar overall benefit for acute aspirin and ischemic stroke was observed in the chinese acute stroke trial cast which randomized over

20,000 patients to aspirin or placebo within 48 hours of stroke symptoms however the difference in cast was less impressive and the number needed to treat was about 200 moving on to clopidogrel as an acute therapy and ischemic stroke as you know the mechanism of clopidogrel is unique from aspirin clip integral acts by antagonizing the atp receptors which prevents

Platelet aggregation now the question is is there evidence for acute clopidogrel use in stroke the simple answer is no but if you read the aj guidelines they do reference an observational study of 20 patients who received early loading of clip integral and it seemed to be safe but this was only in 20 patients so at least for now we don’t use clip integral alone

In an early stroke but we have studied a q2 dual antiplatelet therapy before and the pilot faster trial patients with minor stroke or tiaa within 24 hours of symptom onset were randomized to clopidogrel and aspirin or two aspirin alone although the trial was stopped prematurely due to recruitment failure dual antiplatelet therapy was associated with a potentially

Important but not statistically significant reduction in 90 day stroke risk by about 3% in 2013 the chinese chance trial reported that patients with acute minor stroke or tiaa who received the dual antiplatelet therapy for 21 days followed by clopidogrel alone this group had a lower risk of subsequent stroke than those treated with aspirin alone an absolute risk

Reduction of again about 3% so it seems that together aspirin and clopidogrel may be effective in tandem for minor stroke or tiaa at least during the first few weeks after the event when the risk of recurrence is the greatest dual antiplatelet therapy also has a role and acute symptomatic intracranial atherosclerosis given the extremely high risk of stroke recurrence

In patients who suffer from this there are several trials to talk about the first one compress combination of clopidogrel and aspirin for the prevention of recurrence an acute a thorough thrombotic stroke study compress found no benefit of dual therapy over aspirin and the prevention of recurrent strokes or new ischemic lesions at 30 days and patients who had presumed

Large artery a thorough but there’s a twist here although the number of new strokes or recurrent ischemic lesions was about 36% in both groups 94% of those lesions were asymptomatic just identified on imaging and the thresholds for what met criteria for stenosis aren’t what we traditionally use compress investigators considered a cut-off of 30% carotid stenosis to

Be sufficient whereas we typically use 50 to 70% and intracranial stenosis was determined by the treating physician without any central adjudication as in compress chance investigators found that patients with stroke due to intracranial a throw did not have a lower risk of recurrent infarct when treated with combination therapy so you’re probably asking yourself

Why do we see patients being treated with dual antiplatelet therapy for symptomatic intracranial a throw it’s basically because of the sampras trial before sampras we knew that the rate of recurrent stroke due to integrate a throw could be about 19% by one and a half years according to the lawson trial or even as high as 30% by three and a half years among any

Patient tree with aspirin so if even you’re taking aspirin and you have this higher risk of recurrent stroke why couldn’t we just stent to the intracranial vessel well that’s what we did in sampras in san pristinely 500 patients were randomized to maximal medical therapy meaning aspirin plus clopidogrel plus statin plus blood pressure control and so on or maximal

Medical therapy and stenting for better or worse and perhaps surprisingly stinting was actually associated with a significantly higher rate of recurrent stroke among all patients by 30 days 14.7% of stented patients had a recurrent stroke or died whereas only 5.8 percent of those assigned to medical management had a stroke or died by two and a half years the risk

Of recurrence remained lower in the medical arm at about 15 percent so if you compare apples to oranges the recurrent stroke rates between different trials like the wasat trial versus the sampras trial intracranial a throw is associated with a 15% two and a half year risk of recurrent stroke if you treat with aspirin and clopidogrel or if you just use aspirin that

Risk is 19% at one and a half years or 30% at three years either way the risk is greater in aspirin alone i know we can’t legitimately make these comparisons the trials are just too different and probably has to do with the potency of the newer high-dose statins and the effect of blood pressure control and adequate follow-up but even so nobody’s going to conduct a

Clinical trial comparing aspirin to dual therapy for intracranial a throw anymore we simply lack the clinical equipoise moving on to the chronic management of patients with stroke a lot of other agents come into play but we’re gonna stick with aspirin and clopidogrel for now beginning with the antiplatelet trial is collaboration from 1994 287 randomized trials of

Antiplatelet agents for the primary and secondary prevention of vascular events were evaluated aspirin was the most common antiplatelet agent among patients from that cohort who had an acute stroke 40,000 patients antiplatelet use was associated with an absolute risk reduction of about 1% for mi recurrent stroke or vascular death when compared to placebo this effect

Was observed over an average of about half a year the number needed to treat was about a hundred similar to ist for acute aspirin use and stroke however among patients who had a prior stroke or ti a 23,000 patients who received long-term antiplatelet therapy that number needed to treat fell to about 30 over two and a half years so more improvement with aspirin over

Time clopidogrel was compared to aspen for the prevention of recurrent ischemic events in the 1996 capri trial clopidogrel vs. aspirin for the prevention of recurrent ischemic events capri randomized patients with a recent stroke mi or symptomatic peripheral arterial disease to clopidogrel 75 milligrams daily or aspirin was the primary outcome being composite of

Recurrent ischemic stroke myocardial infarction or vascular death clopidogrel slightly but significantly reduced the risk of the composite outcome compared to aspirin by about half a percent the number needed to treat to prevent stroke mi or vascular death in this cohort was 200 when you’re treating with clopidogrel over aspirin interestingly in a subgroup analysis

Of the capri database if you selected only the patients who had a prior ischemic stroke or mi the number needed to treat to prevent the composite vascular endpoint was now 29 over the 3-year study period there was a relative risk reduction of 15% for recurrent stroke mi or vascular death and patients who were randomized to clopidogrel over aspirin so if you break

It down and we’re gonna compare apples to oranges here again aspirin versus nothing in patients with stroke the number needed to treat is about 30 but clopidogrel versus aspirin in patients with stroke or mi the number needed to treat is also 30 and this is for patients who were on clopidogrel over aspirin victory for clitoral next i’d like to ask you what would

You do if a patient has a new stroke while on aspirin or while on clopidogrel do you consider those like an aspirin or clopidogrel treatment failure would you switch the patient between anti platelets at that point maybe consider something else like agron ox or selasa dissol that we haven’t even talked about what about anti coagulating them certainly a patient

Can have a stroke or heart attack while on aspirin or clitoral but when you see it you certainly want to think about other etiologies a stroke that aspirin or clopidogrel would be insufficient at treating does your patient have a nasty carotid artery plaque do they have a fib or cancer or maybe they’ve got something more unusual like vasculitis or rcbs if your work

Up is unrevealing then maybe switching from aspirin to clitoral is reasonable as long as the patient can afford it and you trust them to pay for it and take it every day you know clippety role is a little more effective than aspirin for secondary stroke prevention but would you switch clippety rule to aspirin and a patient with a breakthrough stroke and personally

I don’t know if i would there is a known phenomenon of clopidogrel resistance in patients who are rapid metabolizers this is seen in maybe 5 to 30% of stroke patients who received loop integral and in more than 20 percent of patients with myocardial infarction who undergo coronary stenting and you can test for this resistance using a platelet function assay but i

Can’t say that i’ve ever anyone do this in routine practice the next question you should be asking yourself is is there a role for chronic dual antiplatelet therapy in patients with prior stroke if acute dual therapy for two weeks to three months could be helpful could it be helpful over the longer term the answer for your average patient is no in the match trial

Over 7,000 patients with a recent ischemic stroke or tiaa were randomized to receive clopidogrel mono therapy or the combination therapy there was no difference the composite endpoint of stroke mi vascular death or rehospitalization for a vascular event but there was a significant increase in the life-threatening bleeding events three percent versus one percent

Similarly in the kharisma trial over fifteen thousand patients at high risk of primary or recurrent vascular events including stroke these patients were randomized to aspirin and clopidogrel or aspirin alone again no significant reduction in the composite endpoint between the treatment arms so for now at least dual antiplatelet therapy for your run-of-the-mill

Stroke is not part of the aj guidelines so i leave you with aspirin or clopidogrel to summarize in the acute setting there’s no evidence supporting the use of clopidogrel as a mono therapy but some experts have recommended acute dual therapy in a number of situations like symptomatic intracranial a throw where three months of therapy was proven effective in the

Sampras trial when compared to stenting or as we saw in the chinese trial chance which demonstrated effectiveness of combination therapy for 21 days in patients who have a minor stroke or tiaa but as this was a chinese cohort with different vascular risk factors we don’t know if this effect would also be observed in western populations so the point trial which

Is kind of like the western version of chance just close enrollment in december 2017 and we plan to hear about these results soon but since we haven’t heard from the investigators to discontinue the treatment arms and to unblind the patients we’re kind of assuming that maybe it is a positive trial moving on to the chronic management of patients with prior stroke

Using aspirin or clopidogrel that’s where things get a little hairy you’ll probably get a different answer depending on which vascular neurologist you ask and depending on the nuances of the clinical case personally i’m a fan of clopidogrel as you could probably tell by all the positive trials i cited the capri trial which showed a relative risk reduction of 15%

For recurrent stroke mi or vascular death the chance trial which showed that short term dual antiplatelet therapy followed by clopidogrel mono therapy reduced the rate of recurrent stroke and did not increase the risk of major hemorrhage but aspirin does also have its own merits it’s unbelievably cheap and it’s over-the-counter so patients are probably more likely

To take it we know that it works and it’s worked for decades and as far as evidence is concerned it’s the only safe and effective acute anti thrombotic agent we’ve got right now and while maybe it’s not as effective at preventing recurrent ischemic events when compared to clopidogrel and we didn’t talk about this today aspirin does have a wide range of other health

Benefits according to one meta-analysis of 51 randomized trials aspirin was shown to reduce the incidence of any cancer by 25% it reduced cancer so to death and it also reduced the incidence of death due to non vascular causes it’s got a mild but significant anti-inflammatory property to it by reducing prostaglandin synthesis and inflammation is increasingly being

Associated with the development of cancer and other chronic diseases so targeting this physiologic disturbance makes a good deal of sense but using aspirin is not exactly benign there’s plenty of data that recognizes a higher risk of major bleeding which is approximately two-fold greater and aspirin users than aspirin on users clopidogrel appears to carry an even

Slightly higher bleeding risk but still not hugely concerning on a patient to patient basis or so i think now knowing this information which drug will you choose for your patient and how will you plan to carry out that conversation i’d love to know what your thoughts are in the matter so just go to brain waves dot me and comment on this week’s blog entry that’s

All we got this week and all i can stand to discuss on the aspirin clopidogrel debate as always the brain waves podcast is not to be used for routine clinical decision-making the episode this week was produced by me jim sigler music courtesy of william ross turn-offs nomad’s steve coombs ruie little glassman and peter rudenko on the piano follow us on twitter at

Brain waves audio or facebook at facebook.com slash brain waves audio thanks for listening i’m jim sela from philadelphia and i’ll talk to you again soon you

Transcribed from video
#93 Aspirin vs. Plavix: The showdown By BrainWaves Staff