Role of Dual Antiplatelet Therapy in Secondary
By Jason Kurian, PharmD, and Salia Farrokh, PharmD, BCCCP
For secondary stroke
prevention, the 2013
and American Stroke
Association (ASA) joint
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.
HR: Hazard ratio; CI: Confidence interval
*ASA mean dose was 75 mg; αIf ASA-naïve
1. Jauch EC et al. Stroke. 2013;44:870–947.
2. Guyatt GH et al. Chest. 2012;142(6):1698-1704.
3. Diener HC et al. J Neurol Sci. 1996 Nov;143(1-2):1-13.
4. Halkes PH et al. Lancet. 2006 May 20;367(9523):1665-73.
5. Sacco RL et al. N Engl J Med 2008;359:1238-51.
6. Benavente OR et al. N Engl J Med 2012;367:817-25.
7. Diener HC et al. Lancet 2004; 364: 331–37.
8. Kennedy J et al. Lancet Neurol 2007; 6: 961–69.
9. Wang Y et al. N Engl J Med 2013; 369:11-19.
10. Hong KS et al. Stroke. 2016;47(9):2323-3.