Dos and Don'ts of Antiplatelet Use for Secondary Stroke Prevention

Despite aggressive public health initiatives aimed at curtailing common risk factors like hypertension, diabetes, and hyperlipidemia, stroke remains the fifth-leading cause of death in the United States.¹

Roughly 80% of all strokes are ischemic in etiology, and thus antiplatelets are the backbone pharmacologic agents for the prevention of recurrent strokes.² Several antiplatelet agents are available, including aspirin, clopidogrel, and the combination of aspirin and extended-release dipyridamole (Aggrenox).

The following are the dos and don’ts of antiplatelet use in patients who have experienced an ischemic stroke.

DO use aspirin as first-line therapy.

Data from meta-regression analysis demonstrate that aspirin therapy produces a 15% relative reduction in the rate of any subsequent stroke in patients with a previous stroke.³

This benefit was seen across doses ranging from 50 mg/day to 1500 mg/ day, although the risk of toxicity was elevated with higher doses. For patients taking ≤325 mg/day, the risk of serious gastrointestinal hemorrhage was about 0.4% per year.

Aspirin also costs significantly less than the other available antiplatelet agents. Given the drug’s favorable efficacy, safety, and cost profile, the American Heart Association (AHA) recommends aspirin monotherapy (50-325 mg/day) as initial therapy after a stroke or transient ischemic attack (TIA) for prevention of future stroke (Class I recommendation, level of evidence A).²

DO consider adding clopidogrel to an aspirin regimen early after TIA or minor stroke.

Two recently published trials explored the value of early dual-antiplatelet therapy with aspirin and clopidogrel in the early period after minor stroke and TIA.

While the FASTER trial was terminated early, the larger CHANCE trial demonstrated that this dual therapy significantly reduced the risk of secondary stroke (8.6%) compared with aspirin monotherapy (11.7%).⁴ Rates of moderate and severe bleeding were similar between groups.

It is worth noting that the therapy was started early (within 24 hours of presentation) and dual therapy was only continued for 21 days. The CHANCE study was also exclusively conducted in China, making extrapolation to other countries difficult.

In light of these findings, the AHA suggests that the combination of clopidogrel and aspirin might be considered within 24 hours of a minor ischemic stroke or TIA and continued for up to 21 days (Class IIb recommendation, level of evidence B).²

DON’T combine aspirin and clopidogrel long after stroke presentation.

Three randomized, controlled trials have evaluated the use of combined clopidogrel and aspirin therapy outside of the immediate stroke period.

In the MATCH trial, this dual therapy led to no significant reductions in secondary stroke rates, but it did increase the rate of life-threatening bleeding by 1.3%.⁵ Similarly, the CHARISMA trial, which included patients with a history of stroke or TIA within the previous 5 years, showed that adding clopidogrel to background aspirin therapy did not reduce rates of subsequent stroke, but it did increase rates of bleeding.⁶

Finally, the SPS3 trial of more than 3000 patients with MRI-confirmed lacunar stroke within the previous 180 days found that while rates of ischemic stroke were slightly reduced with dual-antiplatelet therapy, the rates of hemorrhagic stroke and mortality were increased.⁷

With these findings in mind, the AHA recommends against using clopidogrel and aspirin together when initiated within days to years after a minor stroke or TIA (Class III recommendation, Level of evidence A).²

DO consider combination aspirin and extended-release dipyridamole.

Two randomized trials explored the benefit of the combination product of aspirin and extended-release dipyridamole with aspirin alone.

In the ESPS-2 trial, this combination therapy significantly reduced the risk of stroke and death, but it was limited by problems in data quality reporting.⁸ The ESPRIT trial also demonstrated a benefit for combination therapy, but its open-label design may have introduced bias, as suggested by the numerically lower rate of reported bleeding events in the combination therapy arm.⁹

Both of these trials noted significantly more adverse drug events with the combination (primarily headache and gastrointestinal symptoms), and the product is significantly more expensive than aspirin monotherapy.

Because of these limitations, this combination cannot be considered superior to aspirin monotherapy. Rather, the AHA guidelines recommend that the combination of aspirin 25 mg and dipyridamole 200 mg twice daily can be considered as an alternative initial therapy after a stroke or TIA for prevention of future stroke (Class I recommendation, level of evidence B).²

DON’T increase the dose of aspirin in patients who experience recurrent stroke.

In patients who experience a recurrent stroke or TIA while taking aspirin therapy, the initial impulse to increase the dose of aspirin must be resisted.

There is no evidence to suggest that increasing the dose of aspirin provides any further benefit. Unfortunately, there are no clinical trials to indicate that switching antiplatelet agents reduces the risk of subsequent events in patients who experience a stroke while taking aspirin.

For these “aspirin failures,” switching to the combination of aspirin and extended-release dipyridamole is a reasonable choice. Alternatively, clopidogrel monotherapy could be considered, as this regimen was proven effective in reducing the risk of recurrent stroke in the PRoFESS trial.¹⁰

The selection of the appropriate antiplatelet agent for secondary stroke prevention should be based on relative effectiveness, safety, and cost, in addition to patient characteristics and preference. Aspirin monotherapy is a reasonable first-line choice for most patients, but a short-term combination of aspirin with clopidogrel can be considered if initiated early after diagnosis. Aspirin with dipyridamole is also an acceptable first-line choice if the patient can afford it.

For those with intolerance to aspirin or aspirin-dipyridamole, clopidogrel is a good alternative.

References

1. Mozaffarian D, et al. Executive Summary: Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation. 2016 26;133:447-454.

2. Kernan WN, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45:2160—2162.

3. Johnson ES, et al. A meta-regression analysis of the dose-response effect of aspirin on stroke. Arch Intern Med. 1999;159:1248—1253.

4. Wang Y, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369:11—19.

5. Diener HC, et al. Aspirin and clopidogrel compared with clopidogrel alone after ischemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomized, double-blind, placebo-controlled trial. Lancet. 2004;364:331—337.

6. Bhatt DL, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354:1706—1717.

7. Benavente OR et al. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med. 2012;367:817—825.

8. Diener H, et al. European Stroke Prevention Study 2: dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci.1996;143:1—13.

9. The ESPRIT Study Group. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomized controlled trial. Lancet. 2006;367:1665—1673.

10. Sacco RL, et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med 2008;359:1238-1251.