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Role of Dual Antiplatelet Therapy in Secondary Stroke Prevention

By Currents Editor posted 03-30-2018 23:00


Jason_Kurian__PharmD.bmpSalia_Farrokh__PharmD__BCCCP.bmpBy Jason Kurian, PharmD and Salia Farrokh, PharmD, BCCCP

For secondary stroke prevention, the 2013 American Heart Association (AHA) and American Stroke Association (ASA) joint guidelines recommend aspirin within 24 to 48 hours after stroke onset for most patients and state that the use of clopidogrel is not well established. The 2012 American College of Chest Physicians (ACCP) guidelines recommend treatment with aspirin, clopidogrel or aspirin/dipyridamole extended-release (ER) over no antiplatelet therapy or the combination of clopidogrel plus aspirin. Of the recommended antiplatelet regimens, they suggest clopidogrel or aspirin/dipyridamole ER over aspirin alone. This review will discuss the evidence regarding the use of dual antiplatelet therapy (DAPT) for secondary stroke prevention given the varying guideline recommendations and controversy in appropriate use.

DAPT with aspirin and dipyridamole ER was initially assessed in several trials with conflicting results. Two of the more robust trials include ESPS-2 and ESPRIT. ESPS-2 assessed low-dose aspirin, dipyridamole ER, and both antiplatelet agents together in patients who experienced a transient ischemic attack (TIA) or ischemic stroke within the preceding three months. The authors concluded that the combination of low-dose aspirin and dipyridamole ER offered a significant additive protective effect against ischemic stroke. ESPRIT compared DAPT of aspirin and dipyridamole ER to aspirin alone in patients with a TIA or minor ischemic stroke of arterial origin within the prior six months. The DAPT arm was associated with lower rates on the composite outcome of vascular mortality, non-fatal stroke, non-fatal myocardial infarction (MI) and non-fatal major bleeding when compared to aspirin alone.

Clopidogrel was evaluated against DAPT of aspirin and dipyridamole ER in non-cardioembolic stroke patients in the PRoFESS trial. While the incidence of recurrent ischemic stroke was similar in both groups, the incidence of intracranial hemorrhagic stroke was more common in the aspirin and dipyridamole ER group.

Aspirin and clopidogrel were then evaluated against aspirin monotherapy in patients with lacunar infarcts in the preceding six months in the SPS3 trial. DAPT did not reduce the recurrence of stroke but had increased all-cause mortality and all major hemorrhages compared to aspirin alone.

The MATCH trial showed that the addition of clopidogrel to aspirin therapy did not reduce the incidence of ischemic events compared to clopidogrel alone in patients with ischemic stroke or TIA in the prior three months after 18 months of follow up. Furthermore, DAPT was associated with an increase in minor, major and life-threatening bleeding. Although not statistically significant, patients who were randomized within a week after an ischemic stroke or TIA had numerically less ischemic events in the DAPT group compared to the clopidogrel monotherapy group. The lower ischemic event rate in patients randomized within a week along with the initial lack of intracranial bleeding between groups suggest a potential advantage of DAPT in the acute phase after ischemic stroke or TIA.

All of the prior trials had not specifically assessed early treatment with antiplatelet therapy after a cerebral ischemic event. It has been shown that most recurrent ischemic events occur within 30 days, particularly within the first 24 hours. This along with the results of the MATCH trial prompted the FASTER and CHANCE trials to see if DAPT of aspirin and clopidogrel started within 24 hours after TIA or minor stroke reduced subsequent strokes after 90 days. The FASTER trial showed a trend favoring, though not statistically significant, secondary stroke prevention in patients receiving DAPT compared to aspirin alone. Subsequently, the CHANCE trial showed that DAPT is more effective than aspirin alone in preventing secondary ischemic stroke with similar bleeding rates. It is important to note that the DAPT in the CHANCE trial only lasted for the first 21 days in which patients were then transitioned to clopidogrel monotherapy. In addition, the study was performed in a Chinese population, which may not be generalizable to the United States population.

The recently published COMPRESS trial included patients treated with DAPT of clopidogrel and aspirin against aspirin alone within 48 hours of onset of ischemic stroke caused by large artery atherosclerosis. The 30-day new ischemic lesion recurrence and bleeding rates were similar between both groups. Of note, about 75 percent of patients were enrolled between 24 and 48 hours from stroke onset, and a loading dose of clopidogrel was not used. This limits the assessment of DAPT initiation within the first 24 hours, which is where the CHANCE trial showed benefit.

To better evaluate administration of dual antiplatelet therapy in this early stage, the POINT trial is currently underway to assess prevention of major ischemic vascular events up to 90 days in patients with TIA or minor stroke being treated within 12 hours.

Overall, the population that may benefit from DAPT is unclear. It appears that it may be beneficial when given early for a specified duration, as there is data that the risk of major bleeding may outweigh the benefits when continued long-term. Also, DAPT may not be beneficial after specific types of ischemic strokes such as lacunar infarcts or large artery atherosclerosis. Furthermore, clopidogrel’s antiplatelet effect may be diminished in patients with particular CYP2C19 gene polymorphisms. In the absence of clear evidence and guidelines reflecting the more recent evidence, a rational clinical approach for the use of DAPT would take into account the timing after the cerebral ischemic event, the type of ischemic stroke, and the patient’s bleeding and thrombosis risk.

Table 1: Summary of trials assessing dual antiplatelet therapy in secondary stroke prevention


Stroke type

Time after stroke onset to randomization


Follow up

Incidence of stroke events

Incidence of bleeding events

ESPS-2 (1996)


TIA, ischemic stroke

< 3 months

ASA 25 mg BID +

DP-ER 200 mg BID


ASA 25 mg BID


DP-ER 200 mg BID

2 years


ASA + DP-ER: 9.5%

ASA: 12.5%

DP-ER: 12.8%

p<0.05 for ASA + DP-ER vs other groups

Severe or fatal bleeding:

ASA + DP-ER: 1.6%

ASA: 1.2%

DP-ER: 0.4%

p<0.05 for DP-ER vs other groups

ESPRIT (2006)


TIA, minor stroke

< 6 months

ASA 30-325* mg daily +

DP-ER 200 mg BID


ASA 30-325* mg daily

3.5 years (mean)

Ischemic stroke:

ASA + DP-ER: 7.0%

ASA: 8.4%

HR (95% CI): 0.84 (0.64-1.10)

Major bleeding:

ASA + DP-ER: 2.6%

ASA: 3.9%     

HR (95% CI): 0.67 (0.44-1.03)

PRoFESS (2008)


Ischemic stroke

< 90 days

ASA 25 mg daily +

DP-ER 200 mg BID


Clopidogrel 75 mg daily

2.5 years (mean)

Recurrent stroke:

ASA + DP-ER: 9.0%

Clopidogrel: 8.8%

HR (95% CI): 1.01 (0.92-1.11)

Intracranial hemorrhage:

ASA + DP-ER: 1.4%

Clopidogrel: 1.0%


SPS3 (2012)


Lacunar stroke

2 weeks to 6 months

ASA 325 mg daily +

Clopidogrel 75 mg daily


ASA 325 mg daily

3.4 years (mean)

Recurrent ischemic stroke:

ASA + clopidogrel: 2.0% per year

ASA: 2.4% per year


Major hemorrhage:

ASA + clopidogrel: 2.1% per year

ASA: 1.1% per year


MATCH (2004)


TIA, ischemic stroke

< 3 months

ASA 75 mg daily +

Clopidogrel 75 mg daily


Clopidogrel 75 mg daily

1.5 years

Ischemic stroke:

ASA + clopidogrel: 8.1%

Clopidogrel: 8.8%


Life-threatening bleeding:

ASA + clopidogrel: 2.6%

Clopidogrel: 1.3%


FASTER (2007)


TIA, minor ischemic stroke (NIHSS < 3)

< 1 day

ASA 162 mg loading doseα, then 81 mg daily +

Clopidogrel 300 mg loading dose, then 75 mg daily


ASA 162 mg loading doseα, then 81 mg daily

90 days


ASA + clopidogrel: 7.1%

ASA: 10.8%


Intracranial hemorrhage:

ASA + clopidogrel: 1.0%

ASA: 0%


CHANCE (2013)


TIA, minor ischemic stroke (NIHSS < 3)

< 1 day

Clopidogrel 300 mg loading dose, then 75 mg daily +

ASA 75-300 mg loading dose, then 75 mg daily x 21 days


ASA 75 mg daily

90 days

Ischemic stroke:

ASA + clopidogrel: 7.9%

ASA: 11.4%


Severe bleeding:

ASA + clopidogrel: 0.2%

ASA: 0.2%




Ischemic stroke caused by large artery atherosclerosis

< 48 hours

Clopidogrel 75 mg daily +

ASA 300 mg loading dose, then 100 mg daily


ASA 300 mg loading dose, then 100 mg daily

30 days

New symptomatic or asymptomatic ischemic lesion on MRI:

ASA + clopidogrel: 36.5%

ASA: 35.9%


Life threatening or major bleeding:

ASA + clopidogrel: 4.0%

ASA: 1.1%


TIA: Transient ischemic attack; ASA: Aspirin; DP-ER: Dipyridamole extended-release; NIHSS: National Institutes of Health Stroke Scale; HR: Hazard ratio; CI: Confidence interval

*ASA mean dose was 75 mg; αIf ASA-naïve


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