stroke

Dual Antiplatelet Therapy with Aspirin and Clopidogrel for Secondary Stroke Prevention

Eric A. Dietrich, PharmD, BCPS, and Kyle Davis, PharmD, BCPS

Volume 55 - Issue 7 - July 2015

Ischemic stroke affects millions of Americans and is associated with significant morbidity and mortality. Each year nearly 800,000 people will experience a new or recurrent stroke in America, and it is reported that a stroke occurs on average every 40 seconds.1 

While preventing an initial stroke is ideal, secondary prevention is equally important as these patients are at significant risk of recurrent stroke. Antiplatelet therapy has become the standard of care for secondary prevention of ischemic stroke. However, given the superior results of combination antiplatelet therapy in myocardial infarction, there is a growing theory that increased platelet inhibition in individuals who have had a stroke could yield to further risk reduction. What does the clinical evidence suggest?

A Case Study

JB is a 58-year-old white male with a history of uncontrolled hypertension. Two months ago, after waking up from a night’s sleep, JB experienced a significant headache and slurred speech. Upon hospital admission, he was diagnosed with an ischemic right middle cerebral artery stroke. Hospital records show that JB was not a candidate for tissue plasminogen activator therapy, and he was later discharged with prescriptions for daily doses of aspirin 325 mg, clopidogrel 75 mg, rousouvastatin 40 mg, lisinopril 20 mg, and chlorthalidone 25 mg.

Two months later, JB has come to your clinic for follow-up care. His blood pressure is 129/71 mm Hg and his heart rate is 82 beats per minute. His lipid profile demonstrates a low-density lipoprotein cholesterol level of 90 mg/dL and total cholesterol of 190 mg/dL. He has only minimal residual speech difficulty that is continuing to improve with speech therapy.

Clinical Question

Ischemic strokes are frequently the cause of plaque development and rupture, similar to that of a myocardial infarction. As the use of dual antiplatelet therapy in acute coronary syndromes has proven superior over single antiplatelet therapy, the concept of using this treatment modality in the secondary prevention of ischemic stroke has become of significant interest. The question that healthcare providers must ask when considering dual antiplatelet therapy in this instance is: Does added antiplatelet therapy provide significant benefit to outweigh the potential bleeding risk? 

Evidence

Current guidelines from the American Heart Association (AHA) recommend the use of antiplatelet therapy for secondary stroke prevention. Specifically, these guidelines recommend the use of aspirin, clopidogrel, or aspirin in combination with extended release dipyridamole as the antiplatelets of choice.2 

When comparing each of these agents individually, the data is inconsistent. The use of dipyridamole and aspirin in combination has demonstrated superior stroke reduction when compared to dipyridamole or aspirin alone.3 In contrast, the use of clopidogrel showed no difference in the rate of recurrent stroke when compared to aspirin or the combination of aspirin and dipyridamole.4,5 As a result of these inconsistencies the AHA gives all 3 of these agents a Class IA recommendation for use, indicating that each agent is considered a reasonable first-line treatment option.2 

Research

There are 3 noteworthy large, randomized, controlled clinical trials that have evaluated the use of dual antiplatelet therapy with aspirin and clopidogrel. The Management of Atherothrombosis with Clopidogrel in High-risk (MATCH) trial compared the use of aspirin 75 mg daily and clopidogrel 75 mg daily with aspirin 75 mg daily alone for secondary stroke prevention. The study concluded that the addition of aspirin to clopidogrel did not reduce the rate of the primary composite outcome, which included ischemic stroke, myocardial infarction, vascular death, or rehospitalization for acute ischemia. Furthermore, the use of dual antiplatelet therapy with aspirin and clopidogrel was associated with a significant increased rate of life-threatening and major bleeding compared to clopidogrel monotherapy. 

The Secondary Prevention of Small Subcortical Strokes (SPS3) trial was carried out in a similar fashion as the MATCH study, however, it only enrolled patients with lacunar strokes (those arising from small vessel disease). Patients were randomized to clopidogrel 75 mg daily or placebo in conjunction with aspirin 325 mg daily. After a follow-up period of over 3 years, dual antiplatelet therapy failed to provide further ischemic stroke reduction. Additionally, the rate of major hemorrhage was nearly doubled in patients receiving aspirin and clopidogrel. 

The Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) study recently evaluated the use of aspirin and clopidogrel for secondary stroke prevention. This study enrolled patients with recent minor stroke or transient ischemic attack. While the MATCH and SPS3 studies enrolled patients with any history of stroke or transient ischemic attack, patients in CHANCE were enrolled within 24 hours of the index event. Patients were randomized to aspirin 75 mg daily or to clopidogrel 75 mg daily and aspirin 75 mg daily for the first 21 days followed by clopidogrel monotherapy. Unlike the MATCH and SPS3 trials, patients receiving clopdiogrel and aspirin demonstrated lower rates of recurrent stroke when compared to aspirin alone. Patients receiving dual antiplatelet therapy also had no increased risk of hemorrhagic events overall. 

The ongoing Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial is further investigating the role of dual antiplatelet therapy following ischemic strokes, but the study is not expected to be completed until late 2018.6

Clinical Application

When used in patients with a remote history of stroke, the risks of dual antiplatelet therapy do not outweigh the risk of hemorrhagic complications (MATCH and SPS3). While the results of the CHANCE trial appear promising, we must consider a few key points. Patients enrolled in this study experienced only minor strokes, therefore these results cannot be generalized to all patients with stroke or transient ischemic attack. Furthermore, the antiplatelet regimen was initiated early and for a short fixed period of time; it was not continued indefinitely. Finally, the CHANCE study occurred in only Chinese patients. 

Given these limitations, dual antiplatelet therapy should be reserved for only a select few. Therefore, the best option for most patients remains antiplatelet therapy with aspirin, clopidogrel, or aspirin plus dipyridamole in addition to blood pressure and cholesterol management. 

Outcome of the Case 

JB is meeting his blood pressure and cholesterol targets, so his current medications treating these conditions should be continued. He is receiving dual antiplatelet therapy with aspirin and clopidogrel. As discussed, JB likely will not received additional benefit with dual antiplatelet therapy but will incur a higher risk for bleeding. 

If the results of the CHANCE study are considered strong enough to consider dual antiplatelet therapy for JB, dual antiplatelet therapy would be discontinued after the first 21 days in the study; since JB is 2 months from his stroke, dual therapy should not be continued. He was asked to discontinue his aspirin therapy and continue with clopidogrel monotherapy. If aspirin therapy was preferred instead of clopidogrel, this would be acceptable (although the dose should be reduced to 81 mg daily as opposed to 325 mg daily). He was encouraged to continue taking his medications, monitor for changes in blood pressure or bleeding, and continue work with his speech therapist.

Eric A. Dietrich, PharmD, BCPS, graduated from UF College of Pharmacy in 2011 and completed a 2-year fellowship in family medicine where he was in charge of a coumadin clinic. He now works for the UF Colleges of Pharmacy and Medicine. 

Kyle Davis, PharmD, BCPS, graduated from the University of Florida College of Pharmacy in 2011 and completed a PGY-1 at Jackson Memorial Hospital and a PGY-2 in internal medicine at Indiana University Health and Butler College of Pharmacy. He currently works at Jackson Memorial Hospital in Miami, FL. 

References:

  1. Go AS, Mozaffarian D, Roger VL, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation. 2013;127(1):e6-e245. 
  2. Furie KL, Kasner SE, Adams RJ, et al. American Heart Association Stroke Council, Council on Cardiovascular Nursing, Council on Clinical Cardiology, and Interdisciplinary Council on Quality of Care and Outcomes Research. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42(1):227-276.
  3. Diener HC, Cunha L, Forbes C, et al. European Stroke Prevention Study 2: dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996;143(1-2):1-13.
  4. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet. 1996;348(9038):
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  6. Sacco RL, Diener HC, Yusuf S, et al; PRoFESS Study Group. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med. 2008;
  7. 359(12):1238-1251.
  8. ClinicalTrials.gov. Platelet-oriented inhibition in new TIA and minor ischemic stroke (POINT) trial. http://clinicaltrials.gov/ct2/show/NCT00991029. Accessed October 28, 2014.