Aspirin vs. Plavix
As a resident physician on an inpatient stroke service, I remember feeling clueless when it came to deciding on Aspirin or Plavix (generic: Clopidogrel). I remember saying things like, “I want to start the patient on aspirin,” and then attending would respond, “Don’t be an idiot.” And later, when talking about another patient, “I think I’ll start her on clopidogrel.” Then my attending would give me the 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? Stroke neurologists tend to be very picky (in my opinion), and they rely more heavily on evidence than most neurologists do. So even if the differences between two drugs are minor (as in the case of aspirin vs. clopidogrel) on a population-level where there are nearly 800,000 new strokes a year in the US, small differences can benefit a large number of patients. Take a listen.
One major take-home point for this show is to know whether you are trying to treat a patient with acute stroke, or a patient with remote stroke. Acute stroke is associated with a much higher risk of early recurrence and a higher risk of hemorrhagic transformation with antithrombotic therapy. It’s not surprising that the evidence for antiplatelet agents is different based on stroke timing.
ACUTE TREATMENT OF ISCHEMIC STROKE: Aspirin v. Clopidogrel
Aspirin. As you probably know, aspirin is an irreversible cyclo-oxygenase inhibitor. Platelets use cyclo-oxygenase to make endoperoxides and ultimately thromboxane A2, which simulates platelet activation and aggregation. By inactivating cyclo-oxygenase, aspirin effectively eliminates this mechanism of action for the entire lifespan of the platelets—about 7-10 days. As far as use in stroke goes, ≥300mg aspirin has level 1 evidence to support its use in the first 24 hours of acute stroke. So what’s the evidence? In the International Stroke Trial, (awesomely specific name) over 19,000 patients were randomized to receive unfractionated heparin, aspirin, both, or neither within 48 hours of stroke onset. Although the primary outcome of early death by 14 days was no different between the aspirin arm compared to the no aspirin arm, the risk of 14-day recurrent ischemic stroke occurred less frequently in the aspirin arm (2.8% vs. 3.9%, p<0.001), without a significant increase in hemorrhagic stroke (0.9% vs. 0.8%). The number needed to treat to prevent a recurrent stroke at 14 days was 100. A similar overall benefit for acute aspirin in 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.
Clopidogrel. As you know, the mechanism of clopidogrel is unique from aspirin–it antagonizes ADP receptors, which prevents platelet aggregation. What’s the evidence for clopidogrel as a monotherapy in acute stroke? NOTHING. With the exception of one observational study of 20 patients published in an extremely obscure journal. BUT, we have studied acute dual antiplatelet therapy before. In the pilot FASTER trial, patients with minor stroke or TIA within 24 hours of symptom onset were randomized to clopidogrel and aspirin or aspirin alone. There was mild but not statistically significant reduction in 90-day stroke risk with dual vs. monotherapy (7.1% vs. 10.8%, p=0.19). In 2013, the Chinese CHANCE trial reported that patients with acute minor stroke or TIA who received combination clopidogrel plus aspirin for 21 days, followed by clopidogrel alone, had a lower risk of subsequent stroke than those treated with aspirin alone (8.2% vs. 11.7%, p<0.001). So it seems that, together, aspirin and clopidogrel may be effective in tandem for minor stroke or TIA, at least during the first few weeks after the event when the risk of recurrence is greatest.
CHRONIC TREATMENT OF ISCHEMIC STROKE: Aspirin v. Clopidogrel
Beginning with the Antiplatelet Trialists’ 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 with an acute stroke (n=40,821), antiplatelet use was associated with an absolute risk reduction of 0.9% for myocardial infarction, recurrent stroke or vascular death when compared to placebo (8.2% vs. 9.1%, p=0.0009). This effect was observed over a mean of 0.7 months. Number needed to treat was about 100, similar to IST for acute aspirin use in stroke. However, in patients with a prior stroke or TIA (n=23,020) who received long-term antiplatelet therapy, that number needed to treat fell to about 30 over 2 and a half years.
Clopidogrel was compared to aspirin for the prevention of recurrent ischemic events in the 1996 CAPRIE trial (Clopidogrel versus Aspirin for the Prevention of Recurrent Ischemic Events). CAPRIE randomized patients with a recent stroke, myocardial infarction, or symptomatic peripheral arterial disease to clopidogrel 75 mg daily or aspirin with the primary outcome being a composite of recurrent ischemic stroke, myocardial infarction, or vascular death. Clopidogrel slightly, but significantly reduced the risk of the composite outcome compared to aspirin (5.32% vs. 5.83%, p=0.043), without significant reduction in the risk of recurrent non-fatal stroke in patients with prior stroke (4.92% vs. 5.39%). The number needed to treat to prevent stroke, MI or vascular death in this cohort was 200 when treating with clopidogrel over aspirin. Interestingly, in a subgroup analysis of the CAPRIE database, if you selected only the patients with prior ischemic stroke or MI, the number needed to treat to prevent the composite vascular endpoint was 29! Over the 3-year study period, there was a relative risk reduction of 15% for recurrent stroke, MI, or vascular death in patients randomized to clopidogrel over aspirin.
What’s the evidence for switching antiplatelet agents? What would you do if a patient has a new stroke while on aspirin? Or while on clopidogrel? Do you switch at that point? Consider something else like Aggrenox, or Cilostazol? Even anticoagulation? Certainly a patient can have a stroke or a heart attack while on aspirin or clopidogrel. But when you see it, you certainly want to think about other etiologies of stroke that aspirin or clopidogrel would be insufficient at treating. Does your patient have a nasty carotid artery plaque? Do they have atrial fibrillation? Cancer? Or something more unusual like vasculitis? If your workup is unrevealing, then maybe switching from aspirin to clopidogrel is reasonable, as long as the patient can afford it and you trust them to pay for it. You know clopidogrel is a little more effective than aspirin for secondary stroke prevention. But would you switch clopidogrel to aspirin in a patient with a break-through stroke? 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 about 5-30% of stroke patients treated with clopidogrel, and in more than 20% among patients with myocardial infarction who undergo coronary stenting. You can test for resistance using a platelet function assay, but I can’t say I’ve seen anyone ever do this in routine practice.
As we reach the end of the episode, what will you be choosing: Aspirin, or clopidogrel? 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 in the long-term, as you can probably tell by all the positive trials I preferentially cited. And I like clopidogrel for a number of reasons. The CAPRIE trial, which showed a relative risk reduction of 15% for recurrent stroke, MI, or vascular death in patients with prior stroke or MI when compared to aspirin. The CHANCE trial, which showed that short-term dual antiplatelet therapy followed by clopidogrel monotherapy reduced the rate of recurrent stroke, and did not increase the risk of major hemorrhage. But aspirin also has its merits. Its unbelievably cheap, and it’s over-the-counter. We know that it works, it’s worked for decades. And as far as evidence is concerned, it is the only safe and effective acute antithrombotic agent we’ve got right now. And while maybe it’s not as effective at preventing recurrent ischemic events than clopidogrel, and we didn’t talk about this today—aspirin does have a wide range of other health benefits which clopidogrel does not. According to one meta-analysis of 51 randomized trials, aspirin was shown to reduce the incidence of any cancer by 25%, it reduced cancer-associated death, and it 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 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 is plenty of data that recognizes the higher risk of major bleeding, which is approximately two-fold greater in aspirin users than non-aspirin users. Clopidogrel appears to carry an even slightly higher bleeding risk, but still not hugely concerning on a patient-to-patient basis. Now, knowing this information, which drug will you choose for your patient? And how will you carry out that conversation?
As usual, the BrainWaves podcasts and online content are intended for medical education and entertainment purposes only. While episodes like today’s are reviewing the evidence for stroke management, routine clinical decision making is up to the discretion of the treating physician and his or her knowledge of existing clinical guidelines. Podcasts are not clinical guidelines. The featured image for this blog entry is from https://www.flickr.com/photos/21022123@N04/24117471833/ under a CC license.
- Jauch EC, Saver JL, Adams HP, Jr., Bruno A, Connors JJ, Demaerschalk BM, Khatri P, McMullan PW, Jr., Qureshi AI, Rosenfield K, Scott PA, Summers DR, Wang DZ, Wintermark M, Yonas H, American Heart Association Stroke C, Council on Cardiovascular N, Council on Peripheral Vascular D and Council on Clinical C. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke; a journal of cerebral circulation. 2013;44:870-947.
- The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group. Lancet. 1997;349:1569-81.
- CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. CAST (Chinese Acute Stroke Trial) Collaborative Group. Lancet. 1997;349:1641-9.
- Kennedy J, Hill MD, Ryckborst KJ, Eliasziw M, Demchuk AM, Buchan AM and Investigators F. Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomised controlled pilot trial. The Lancet Neurology. 2007;6:961-9.
- Wang Y, Wang Y, Zhao X, Liu L, Wang D, Wang C, Wang C, Li H, Meng X, Cui L, Jia J, Dong Q, Xu A, Zeng J, Li Y, Wang Z, Xia H, Johnston SC and Investigators C. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. The New England journal of medicine. 2013;369:11-9.
- Hong KS, Lee SH, Kim EG, Cho KH, Chang DI, Rha JH, Bae HJ, Lee KB, Kim DE, Park JM, Kim HY, Cha JK, Yu KH, Lee YS, Lee SJ, Choi JC, Cho YJ, Kwon SU, Kim GM, Sohn SI, Park KY, Kang DW, Sohn CH, Lee J, Yoon BW and Investigators C. Recurrent Ischemic Lesions After Acute Atherothrombotic Stroke: Clopidogrel Plus Aspirin Versus Aspirin Alone. Stroke; a journal of cerebral circulation. 2016;47:2323-30.
- Liu L, Wong KS, Leng X, Pu Y, Wang Y, Jing J, Zou X, Pan Y, Wang A, Meng X, Wang C, Zhao X, Soo Y, Johnston SC, Wang Y and Investigators C. Dual antiplatelet therapy in stroke and ICAS: Subgroup analysis of CHANCE. Neurology. 2015;85:1154-62.
- Collaborative overview of randomised trials of antiplatelet therapy–I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists’ Collaboration. Bmj. 1994;308:81-106.
- Antithrombotic Trialists C. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Bmj. 2002;324:71-86.
- Committee CS. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet. 1996;348:1329-39.
- Ringleb PA, Bhatt DL, Hirsch AT, Topol EJ, Hacke W and Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events I. Benefit of clopidogrel over aspirin is amplified in patients with a history of ischemic events. Stroke; a journal of cerebral circulation. 2004;35:528-32.
- Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M, Leys D, Matias-Guiu J, Rupprecht HJ and investigators M. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364:331-7.
- Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Cohen EA, Creager MA, Easton JD, Flather MD, Haffner SM, Hamm CW, Hankey GJ, Johnston SC, Mak KH, Mas JL, Montalescot G, Pearson TA, Steg PG, Steinhubl SR, Weber MA, Brennan DM, Fabry-Ribaudo L, Booth J, Topol EJ and Investigators C. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. The New England journal of medicine. 2006;354:1706-17.
- Rothwell PM, Price JF, Fowkes FG, Zanchetti A, Roncaglioni MC, Tognoni G, Lee R, Belch JF, Wilson M, Mehta Z and Meade TW. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet. 2012;379:1602-12.