Current Recommendations for the Use of Antiplatelet Therapy in Secondary Prevention of Non-Cardioembolic Ischemic Stroke
Author: Sarah Tortora, PharmD, PGY1 Pharmacy Practice ResidentPreceptor: Jackie Harris, PharmD, BCPS, PGY1 Pharmacy Practice Residency Director, Christian Hospital Northeast – St Louis, MO
Program Number: 2018-11-04Approval Dates: December 1, 2018 - June 1, 2019Approved Contact Hours: One (1) CE(s) per LIVE session.
IntroductionCardiovascular disease (CVD) is a major source of morbidity and the leading cause of mortality in the United States. The American Heart Association (AHA) has found that 11.5% of the adult population (27.6 million) has a diagnosis of cardiovascular disease (including coronary heart disease (CHD), hypertension, heart failure, and stroke)1. Stroke can be particularly devastating, and is the fourth most common cause of death in the United States. There are approximately 795,000 new or recurrent cases of stroke each year in the United States, and as of 2015, there were 6.6 million American stroke survivors2. Having a history of stroke is, in itself, a risk factor for having another one; one meta-analysis showed that there was a recurrence risk of 3.1% at 30 days, 11.1% at one year, 26.4% at five years, and 39.2% at 10 years3. In fact, nearly 25% of strokes annually in the United States are not first-time events, and these recurrent events are more likely to result in death than first-time strokes4,5.
The financial cost of stroke is staggering as well: an estimated $40.1 billion was spent on direct and indirect costs associated with stroke in 20131. Over 40% of that cost was due to loss of productivity and mortality. The AHA expects that, by 2035, 45.1% of American adults will have CVD in some capacity, and costs may exceed $1.1 trillion annually. Clearly, CVD is an extremely common aspect of American life, and one that will continue to have huge human and financial costs going forward. Primary prevention is and will be extremely important, but as the incidence of CVD, and thus, ischemic stroke increases, efficacious and efficient secondary prevention will be key to controlling excess morbidity and mortality. As the number of patients living with a history of stroke increases, pharmacists should be prepared to play a role in taking care of this vulnerable patient population.
The most common manifestation of CVD is CHD, with stroke not far behind; together, these plus peripheral vascular disease constitute atherosclerotic cardiovascular disease (ASCVD)1. ASCVD is characterized by a narrowing of the blood vessels, limiting blood flow to tissues downstream and putting tissues at risk of ischemic damage. In ischemic stroke, this narrowing can either be due to atherosclerosis or thromboembolism, and the damage can be especially catastrophic and potentially fatal, depending on where in the brain this ischemia occurs. While there are a number of proven strategies to mitigate the risks of having a devastating event associated with ASCVD, arguably the mainstay is antiplatelet therapy. For many years, this simply meant aspirin. But as new drugs have come to the market in the last 20 years and new data has come out, there are many more options for treating patients with a history ASCVD, including stroke. Recommendations about which agents to use and for how long vary based on the clinical scenario, time since the event, and patient characteristics. This article will review those agents, summarize current guideline recommendations, and address gray areas and current data where guidelines have not with respect to the use of antiplatelet therapy in non-cardioembolic ischemic stroke.
Risk FactorsAs with many disease states, risk factors for non-cardioembolic ischemic stroke can be modifiable or non-modifiable in nature. Well-documented non-modifiable risk factors include increased age, race, sex, low birth weight (less than 5.5 pounds), and genetic factors6. As patients age, their risk of stroke doubles with each decade they are older than 55, on average2. African Americans, Asian-Pacific Islanders, Native Americans, and Latinos experience worse outcomes for a number of metrics than whites in the United States. Among these, incidence and mortality rates are higher, age at the time of first-ever stroke tends to be lower, and as incidence of ischemic stroke has been shown to be decreasing overall and for whites in the United States since the 1990s, a similar decrease has not been noted in African Americans or Latinos2. Women represent a disproportionately high share of annual strokes in the United States, and have a one in five lifetime risk, compared to men’s one in six. However, men are more likely than women to have a stroke at a younger age2. The exact effect genetics has on one’s stroke risk is not yet fully understood, but one meta-analysis found that a “positive family history” of stroke increases one’s risk by about 30%7. In addition, having a parent with a history of stroke younger than age 65 is associated with a three-fold increase in stroke risk in their children.
There are a number of modifiable risk factors that have been shown to increase one’s risk of stroke. They include cigarette smoking, hypertension, diabetes, carotid stenosis, dyslipidemia, poor diet, obesity, physical inactivity, and other cardiovascular diseases, such as coronary artery disease, heart failure, and peripheral artery disease6. Many of these risk factors are addressed in various guidelines related to treating stroke and have high quality evidence for modifying them in order to reduce the risk of an ischemic event. For example, for those with a history of stroke (not in the first 72 hours after an acute event) should have antihypertensive therapy initiated when their blood pressure is >140/90 mmHg, with a goal of <130/80 mmHg according to the 2017 AHA/ACC guidelines8. Great care should be taken in treating patients with a history of stroke and these concomitant risk factors, as this population is already at a higher risk of having a recurrent stroke than those who haven’t had such an event.
Current Guidelines and LiteratureThere are several different guidelines that make recommendations for the use of antiplatelet therapy in the setting of secondary prevention of stroke. While their overall recommendations are quite similar, they do vary slightly. Relevant guidelines are summarized in Appendix 1. Landmark studies referenced will be summarized in Appendix 2.
As previously stated, prevention of recurrent strokes is of the utmost importance. Central to this treatment plan is the use of antiplatelet therapy. Anticoagulation in the form of vitamin K antagonists or the newer direct acting anticoagulants has been shown to be beneficial for the treatment of cardioembolic ischemic events, especially those as a result of atrial fibrillation. The majority of strokes, however, are due to progressive atherosclerosis and are better treated by antiplatelet agents9,10.
In 2018, the American Heart Association and American Stroke Association released a guideline for the early management of patients with acute ischemic stroke11. This new guideline make new and revised recommendations for the use of antiplatelet therapy in the early secondary prevention period, in which patients are particularly vulnerable to recurrence. Firstly, aspirin should be initiated within 24-48 hours of the onset of stroke symptoms. They do not make a specific dosing recommendation, and an optimal aspirin dose has yet to be determined, but numerous studies have shown that doses between 50-325 mg daily are appropriate, and higher doses within this range offer no benefit over lower doses12-16. This is similar to the corresponding recommendation made by the 2012 American College of Chest Physicians Guideline on Antithrombotic and Thrombolytic Therapy in Ischemic Stroke; they recommend 160-326 mg of aspirin daily, and then 75-100 mg daily starting one week after acute stroke treatment17.
The International Stroke Trial (IST) and Chinese Acute Stroke Trial (CAST) demonstrated the benefits of aspirin vs. placebo; 9 fewer deaths, 7 more good functional outcomes, and just 4 more occurrences of nonfatal major bleeding occurred per 1000 patients18. Another 2009 meta-analysis showed this benefit is even more pronounced when follow-up time was extended to two years19. Aspirin is considered the mainstay of secondary prevention of non-cardioembolic ischemic stroke as it is the most well studied, is relatively safe and effective, and is extremely cheap.
Until just two decades ago, this would have been the end of the discussion about antiplatelet therapy. However, a number of potential replacements or additions to aspirin have been introduced, with the workhorse being clopidogrel. Clopidogrel inhibits platelet activation by irreversibly blocking the P2Y12 site within the adenosine diphosphate receptor on the platelet surface, thus inhibiting platelet aggregation20. The 2012 ACCP guidelines make a strong recommendation for the use of clopidogrel 75 mg daily long-term, and actually less strongly recommends clopidogrel over aspirin (Grade 2B)17. This is largely the result of the CAPRIE trial (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events), which showed that in patients with a history of stroke, myocardial infarction, or peripheral vascular disease, clopidogrel significantly reduced the composite of ischemic stroke, MI, or cardiovascular death (5.32% vs. 5.83%, 95% CI 0.84-0.97; p = 0.043)21. Although insignificant, clopidogrel also resulted in 10 fewer nonfatal recurrent strokes per 1,000 patients when treated for two years, with little or no effect on mortality or major bleeding. Clopidogrel is also a good option for patients with an allergy to aspirin or another indication for antiplatelet therapy (e.g. history of MI, percutaneous coronary intervention, etc.).
The PRoFESS trial (Aspirin and Extended-Release Dipyridamole versus Clopidogrel for Recurrent Stroke) sought to compare clopidogrel to another agent approved for secondary prevention of ischemic stroke, extended-release dipyridamole plus aspirin22. In summary, there was no difference between the two drugs with regards to recurrent stroke, major bleeding, or overall mortality. However, headache was much more common with dipyridamole/aspirin than clopidogrel (30% vs. 10%); this along with the more inconvenient twice daily dosing than clopidogrel’s once daily are major reasons for why clopidogrel is used more often in practice.
At this point, a number of clinical questions still exist. Firstly, the use of dual antiplatelet therapy is common in other acute cardiovascular events; what role does it play in the secondary prevention of ischemic stroke? For a long time, it appeared that this was not a useful strategy in any stroke patients. The Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischemic Attacks or Ischemic Stroke (MATCH) trial in 2004 showed no benefit in using clopidogrel plus aspirin over aspirin alone for reducing mortality, recurrent stroke, or MI, and did carry with it a significant increase in major bleeding23. The MATCH trial has been criticized by some, however, because a majority of its patients had lacunar infarcts, rather than atherothrombotic ischemia, which tend to benefit less from antiplatelet therapy.
In 2013, the Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack (CHANCE) trial compared the early use of aspirin/clopidogrel vs. aspirin24. The combination was continued for the first 21 days, and then the aspirin component was discontinued. At 90 days, there was a significantly reduced rate of recurrent strokes in the combination group (8.2% vs. 11.7%, number needed to treat = 29) and no difference in major bleeding. CHANCE differs significantly from MATCH because patients were enrolled within 24 hours of acute stroke intervention, whereas MATCH allowed enrollment for the first six months after an acute event. In addition, CHANCE only enrolled Chinese patients, limiting its generalizability to other patient populations; Chinese patients tend to have a higher incidence of stroke and are known to have more polymorphisms that affect clopidogrel metabolism. However, the Platelet-Oriented Inhibition in New Transient Ischemic Attack and Minor Ischemic Stroke (POINT) trial published in 2018 utilized similar methods and had similar outcomes, and enrolled patients in North America, Europe, Australia, and New Zealand25. Further study is needed to zone in on the most effective combination, duration, and patient population in which to utilize dual antiplatelet therapy. As a result of these trials, the 2018 AHA/ASA guideline recommended dual antiplatelet therapy with aspirin and clopidogrel for the first 21 days after acute treatment (Grade IIa)11.
Unfortunately, recurrent stroke is all too common in the United States. This begs the question, how do we treat a patient who experiences a recurrent ischemic stroke despite adequate preventative antiplatelet therapy? Among those on preventative aspirin who fall into this population, a 2017 meta-analysis showed data supporting addition of or switching to a different antiplatelet agent was associated with reduced rates of recurrent stroke26. Data is less robust when the initial therapy in question is an agent other than aspirin. At this time, there isn’t enough information to make a high quality recommendation for any strategy, and will likely be the subject of more study in the future. As always, patient-specific factors need to be considered in order to make the most safe and efficacious decision possible.
Tools for CliniciansToday, it seems as if there’s a mobile application for everything, and that holds true for decision-making tools for antiplatelet therapy. For primary prevention of stroke, the Aspirin Guide, created by researchers at Brigham and Women’s Hospital and Harvard Medical School helps clinicians decide which patients would experience ASCVD benefits, including the prevention of ischemic stroke, from low-dose aspirin. Another widely used primary prevention app is the ASCVD Risk Estimator Calculator, created by the American College of Cardiology. The algorithm used in this app collects several patient characteristics and gives a current 10-year ASCVD risk, lifetime risk (for those under 60), and gives advice for statin, antihypertensive, and aspirin therapy. The ACC also supports the Dual Antiplatelet Therapy (DAPT) Risk Calculator, which gives an approximate risk of major bleeding in patients on DAPT, and what that risk would be if they discontinued therapy. The app was created for patients with an FDA indication for DAPT (e.g. MI, PCI with stents, etc.), but as data for DAPT in secondary prevention of stroke becomes more robust and the number of patients utilizing this strategy increases, it may be a useful tool for clinicians taking care of this patient population as well. All of these apps are free and available in the app store.
ConclusionStroke is a huge source of morbidity and mortality in the United States, and as the population ages, current trends suggest incidence and related costs will rise significantly. Therefore, it’s important to ensure that these patients are being appropriately treated in order to prevent a recurrent event, and antiplatelet therapy is an important feature of that. The concept of the use of dual antiplatelet therapy in stroke patients is a great example of how new data is outpacing guideline recommendations, and the importance for clinicians to remain up to date on this data in order to adequately treat patients. This will likely be the topic of much study in the future, and may result in groundbreaking changes in how to prevent current stroke from current standard of practice.
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