How Should You Choose the Best Anti-platelet Agents for Secondary Stroke Prevention?

February 16, 2012

By Demetrios Tzimas, MD

Faculty Peer Reviewed

You are about to discharge a 75-year-old female with hyperlipidemia, hypertension, peripheral vascular disease, who was admitted to the hospital for an ischemic stroke. Being an astute physician, you would like to mitigate this patient’s risk of having a second stroke. But you ask yourself, “with all of the agents available today, what anti-platelet agents should I put this patient on to decrease her risk for a second stroke?”

The etiology of an ischemic stroke, as defined by Adam’s and Victor’s Principles of Neurology, is thrombosis from atheromatous plaques in the cerebral arteries [1]. Thus, it makes sense that after a stroke, as in cardiovascular disease, anti-platelet therapy can help mitigate the onset of a second stroke. Although aspirin has traditionally been the anti-platelet agent of choice [2], currently, there are a variety of anti-platelet agents at our disposal to help in the secondary prevention of ischemic stroke, including: aspirin (irreversible inhibitor of platelet aggregation), aspirin-dipyridamole (inhibitor of platelet aggregation and adhesion), clopidogrel (inhibits adenosine diphosphate-induced platelet aggregation), and cilostazol (inhibits cellular phosphodiesterase and thus platelet aggregation).

In 2006, the American Heart Association and the American Stroke Association published “Guidelines for Prevention of Stroke in Patients With Ischemic Stroke or Transient Ischemic Attack.” This article describes the Class 1 A recommendations for secondary stroke prevention in patients with non-cardioembolic ischemic stroke or transient ischemic attacks, stating that aspirin (at any dose), aspirin-dipyridamole, and clopidogrel as all being acceptable options for secondary prophylaxis [3]; yet, this does not solve our dilemma of which agent to start in our patient. Therefore, you decide to look at the literature yourself to help come up with an answer of what anti-platelet agents to place your patient on post-hospitalization.

The CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events) Trial, conducted by Gent et al in 1996, looked at clopidogrel 75 mg vs. aspirin 325 mg in 19,185 patients with recent ischemic stroke, myocardial infarction, or symptomatic peripheral vascular disease [4]. The primary outcomes were defined as the reduction of ischemic stroke, myocardial infarction, or vascular death. Investigators found an 8.7% significant relative-risk reduction in favor of clopidogrel in the primary outcomes (939 events in clopidogrel group versus 1021 events in aspirin group), although when looking specifically at recurrent stroke there was no difference between the aspirin and clopidogrel groups. Of note, gastrointestinal bleeding was significantly more common in the aspirin group.

Diner et al (2004) conducted the MATCH (Management of Atherothrombosis with Clopidogrel in High Risk Patients) Trial, which was a follow-up to CAPRIE. In this trial, authors investigated the efficacy of aspirin 75 mg plus clopidogrel 75mg vs. clopidogrel 75mg plus placebo in 7, 276 patients with risk factors for stroke (previous stroke, previous MI, angina, diabetes mellitus, or symptomatic peripheral artery disease) as well as previous manifestations of atheroembolic disease (previous transient ischemic attacks or ischemic stroke) [5]. The study’s primary endpoint was the first occurrence of ischemic stroke, myocardial infarction, vascular death, or rehospitalization for any ischemic event over 18 months. Although there was no difference between the two groups in reaching the primary endpoint (15.7% in aspirin plus clopidogrel vs. 16.7% in clopidogrel plus placebo), there was a significantly higher rate of life-threatening bleeding in the clopidogrel plus aspirin group than in the clopidogrel plus placebo (3% versus 1 %, respectively). The study demonstrated that the addition of aspirin to clopidogrel did not add any benefit in terms of prevention of stroke, and actually increased the rate of serious bleeding.

In a follow-up of the MATCH Trial, Bhatt et al (2006) followed 15, 603 patients at high risk for atherothrombotic events in the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) Trial, who were randomized to either low-dose aspirin plus clopidogrel 75 mg or low-dose aspirin plus placebo[6]. The primary endpoint of the trial was the first occurrence of myocardial infarction, stroke, or death from cardiovascular causes in the median 28 month follow-up. Similar to the MATCH Trial, there was no difference between the two groups in the rates of the primary outcomes (6.8% in the aspirin plus clopidogrel group, and 7.3% in the aspirin plus placebo group). Unlike the MATCH Trial, in terms of bleeding, there were no differences in severe bleeding, but there was a significantly increased relative risk for moderate bleeding in the aspirin plus clopidogrel group when compared to the aspirin plus placebo group. Thus, as in MATCH, authors found no benefit with clopidogrel plus aspirin in reducing the rate of stroke in patients with multiple cardiovascular risk factors.

Although we have seen that the use of aspirin and clopidogrel together show no increased benefit, with the introduction of newer agents we are able to have more combination drugs. One such agent, dipyridamole, was studied in combination with aspirin in the ESPS2 (European Stroke Prevention Study) Trial in 1996 [7]. Authors studied the efficacy of low-dose aspirin, dipyridamole, and the agents in combination for the secondary prevention of ischemic stroke in 6, 602 patients with prior stroke or transient ischemic attacks. The primary endpoint was defined as stroke or death over two years. Investigators demonstrated that stroke risk was significantly reduced by 18.1% with aspirin 25 mg twice daily, 16.3% with dipyridamole 200 mg twice daily, and 37% with asprin/dipyridamole 25mg/200mg twice daily as compared with placebo; there was no significant difference on the stroke or transient ischemic attack rate between asprin alone or dipyridamole alone, but the combination pill was significantly better than both in regards to stroke reduction. In terms of bleeding, this study showed that all groups containing aspirin had significantly more bleeding than the non-aspirin groups (aspirin alone 8.4%, aspririn/dipyridamole 8.7%, dipyridamole alone 4.7%, placebo 4.5%).

The PRoFESS (Prevention Regimen for Effectively Avoiding Second Strokes) Trial in 2008 looked at 20, 332 patients who had an ischemic stroke in the previous 90 days and assigned them to either aspirin/dipyridamole 25mg/200mg twice daily with telmisartan 80 mg daily or placebo, and clopidogrel 75mg daily with telmisartan 80 mg or placebo, with the predefined primary endpoint being recurrent stroke of any kind [8]. In regards to the anti-platelet arms of the trial, authors found no significant differences in the number of recurrent strokes between the aspirin/dipyridamole group and clopidogrel group, but there were more major hemorrhagic events in the aspirin/dipyridamole group than the clopidogrel group (4.1 % vs 3.6%, hazard ratio 1.15).

A newer agent, cilostazol, was studied in the CSPS 2 (Cilostazol for the Prevention of Secondary Stroke) Trial, a non-inferiority study in The Lancet [9]. Authors compared cilostazol 100 mg versus aspirin 81 mg in preventing stroke in 2,757 patients who had a cerebral infarction in the previous 26 weeks. The primary endpoint was defined as the first occurrence of cerebral infarction, cerebral hemorrhage, or subarachnoid hemorrhage over a mean of 29 months. Investigators found that compared with aspirin, cilistazol was not inferior in reducing the risk of recurrent stroke, but they did report that patients in the cilostazol group had significantly fewer hemorrhagic events (hazard ratio of 0.458 in comparison with aspirin).

These trials reviewed demonstrate that there are several options for us to use as secondary stroke prophylaxis. In summary:

Trial Anti-Platelet Agents Result Caveat
CAPRIE Clopidogrel vs Aspirin No difference in rates of stroke Increased bleeding with Aspirin
MATCH Aspirin + Clopidogrel vs Aspirin No difference in rates of stroke Increased bleeding with Aspirin + Clopidogrel
CHARISMA Aspirin + Clopidogrel vs Clopidogrel No difference in rates of stroke Increased bleeding with Aspirin + Clopidogrel
ESPS2 Aspirin + Dipyridamole vs Aspirin, Aspirin + Dipyridimole vs Dipyridamole Combination better than either agent alone in secondary stroke prevention More bleeding see in all Aspirin containing groups
PRoFESS Aspirin + Dipyridamole vs Clopidogrel No difference in rates of stroke More bleeding with Aspirin + Dipyridamole
CSPS 2 Aspirin vs Cilostazol No difference in rates of stroke More bleeding in Aspirin group

As the current guidelines for anti-platelet agents are not clear, it is our responsibility as physician-scientists to be knowledgeable on the current data, and to review each patient individually instead of relying on vague guidelines.  Upon this review of the literature, it seems that all of these anti-platelet agents have similar efficacy in reducing the incidences of recurrent strokes in high risk patients; a recurring theme of these trials is more bleeding in the aspirin groups and combination groups.  Since we always weigh the risks and benefits of our treatments to patients, in an older population we must seriously consider the risk of GI bleeding when placing our patients on secondary prophylaxis.  Since the combination groups mostly showed increased risk of bleeding with no real benefit, a single agent is probably the best method of secondary prevention.  Although aspirin was traditionally the anti-platelet agent of choice, this agent has been the culprit of bleeding in many trials.  Thus, since they all have similar efficacies in preventing recurrent strokes, whether we choose aspirin, clopidogrel, aspirin/dipyridamole, or cilostazol will depend on: the patient’s ability to tolerate the regimen, cost (aspirin pennies/pill, clopidogrel 5 dollars/pill, aspirin/dipyridamole 3 dollars/pill, cilostazol 1 dollar/pill), as well as compelling factors for certain anti-platelet agents (ie. having stents and requiring plavix).

Dr. Demetrios Tzimas is a contributing editor, Clinical Correlations and a 3rd year resident at NYU Langone Medical Center

Peer reviewed by Saran Jonas, Professor of Neurology, Director of Bellevue Department of Neurology

Image courtesy of Wikimedia Commons

References:

1. Ropper, Allan. Adams and Victor’s Principles of Neurology. 9. New York: McGraw Hill, 2009. 773. Print.

2. Antiplatlet Trialist’s Collaboration. 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. British Medical Journal. 1994 Jan; 308:81-106. Web. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2539220/?tool=pubmed

3. Sacco RL, Adams R, Albers G, et al. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke. Stroke. 2006; 37:577–561. Web. http://stroke.ahajournals.org/cgi/reprint/37/2/577

4. Gent M, Beaumont D, Blanchard J, et al. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). The Lancet. 1996; 348: 1329-1339. Web. http://www.sciencedirect.com.ezproxy.med.nyu.edu/science?_ob=MImg&_imagekey=B6T1B-3Y9GPP9-G1&_cdi=4886&_user=142623&_pii=S0140673696094573&_origin=search&_coverDate=11%2F16%2F1996&_sk=996510961&view=c&wchp=dGLbVtzzSkWb&md5=cdb48c26ac1fc872fe55a83dd0dac855&ie=/sdarticle.pdf

5. Diener HC, Bogousslavsky J, Brass LM, et al. 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. The Lancet. 2004 July; 364: 331-337. Web. http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6T1B4CXM224149&_cdi=4886&_user=142623&_pii=S0140673604167214&_origin=search&_coverDate=07%2F24%2F2004&_sk=996350568&view=c&wchp=dGLbVzzzSkWb&md5=23f76db79250bc04aeb0d15454516fb2&ie=/sdarticle .pdf

6. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. The New England Journal of Medicine. 2006 Apr; 354: 1706-1717. Web. http://www.nejm.org/doi/full/10.1056/NEJMoa060989

7. Diener HC, Cunha L, Forbes C, et al. Journal of the Neurological Sciences. 1996 Nov; 143: 1-13. Web. http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6T063YTCC2MS1&_cdi=4854&_user=142623&_pii=S0022510X96003085&_origin=search&_coverDate=11%2F30%2F1996&_sk=998569998&view=c&wchp=dGLbVlz-zSkWb&md5=3214efed51ae906c0281a6006414dae8&ie=/sdarticle.pdf

8. Sacco RL, Diener HC, Yusuf L, et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. The New England Journal of Medicine. 2008; 359: 1238-1251. Web. http://www.nejm.org/doi/pdf/10.1056/NEJMoa0805002

9. Shinohara Y, Katayama Y, Uchiyama S, et al. Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial. The Lancet Neurology. 2010; 9: 959-968. Web. http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6X3F-511B43J-2-G&_cdi=7297&_user=142623&_pii=S1474442210701988&_origin=search&_coverDate=10%2F31%2F2010&_sk=999909989&view=c&wchp=dGLbVtzzSkWA&md5=0d7483198b97151accc6cea2893e3b0d&ie=/sdarticle.pdf

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