Aspirin + clopidogrel therapy: How does your care compare to the evidence?
Did you know that patients with drug-eluting stents should receive dual therapy for at least a year, and that dual therapy for stroke prevention may put patients at risk?
Clearly, the CARESS trial opens the door for further study into clinically important outcomes for carotid artery stenosis and dual antiplatelet therapy.
Stroke
The current American Heart Association/American Stroke Association guidelines recommend aspirin plus extended-release dipyridamole or clopidogrel alone for the secondary prevention of noncardioembolic stroke. The guidelines state that the “addition of aspirin to clopidogrel increases risk of hemorrhage and is not routinely recommended.” However, aspirin + clopidogrel combination therapy may be appropriate in stroke patients with recent ACS or vascular stents.17
When prevention efforts can harm patients
The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial studied the value of using aspirin + clopidogrel combination therapy for primary or secondary prevention of distant coronary events (longer than 12 months).3 CHARISMA researchers studied patients with either multiple cardiac risk factors (termed “asymptomatic”) or clinically evident cardiovascular disease (termed “symptomatic”) who did not have a current indication for dual antiplatelet therapy (ie, recent MI or coronary stent).
The patients were randomized to receive aspirin plus clopidogrel or aspirin plus placebo and were followed for a median length of 28 months. The primary outcome measure was a combination of MI, stroke, or cardiovascular death. Overall, there was no significant difference in the primary endpoint, which occurred in 6.8% of the combination group and in 7.3% of the aspirin-only group (RR=0.93).
Subgroup analysis revealed that asymptomatic patients actually had a 20% increase in primary events with the addition of clopidogrel to aspirin (6.6% vs 5.5%, RR=1.20), and an increase in death (3.9% vs 2.2%, RR=1.77). In the symptomatic group, however, there was a “marginally significant” reduction in primary events, with 6.9% of patients in the combination group and 7.9% of patients in the aspirin-only group experiencing primary events (RR=0.88). The rate of severe bleeding in the combination group was 1.7% compared with 1.3% in the placebo group (RR=1.25).
The authors of CHARISMA propose a hypothesis to explain the seemingly paradoxical effect of an increase of primary endpoints in the asymptomatic group. They suggest that established vascular disease could be a proxy for hyperactive platelets. Thereby, the action of combination therapy may be more effective in patients with established vascular disease and less effective in patients with normal platelets.
Primary prevention/secondary prevention of distant cardiovascular events
No evidence or recommendations currently exist to support using dual antiplatelet therapy for primary prevention or secondary prevention of cardiovascular events in patients not covered under current American Heart Association/American College of Cardiology guidelines for recent ACS or stent/PCI. Adding clopidogrel to aspirin may cause harm in patients without established cardiovascular disease.3
Ongoing studies explore stroke subtypes, CABG
Because of insufficient or conflicting data, it is unclear whether dual therapy is advisable for a number of disease states, including specific stroke subtypes, peripheral artery disease, and CABG.18 The following ongoing dual therapy studies may provide some answers:14
- The Secondary Prevention of Small Subcortical Strokes (SPS3) trial is investigating secondary prevention of subcortical stroke.
- The Fast Assessment of Stroke and Transient ischemic attack to prevent Early Recurrence (FASTER) trial is also investigating secondary prevention of stroke.
- The Aortic arch Related Cerebral Hazard (ARCH) trial is investigating aortic plaques and stroke.
- The Effects of Physical Training, ASA and Clopidogrel on the Walking Capacity of Patients with Stage II PAD trial is investigating walking capacity in patients with peripheral artery disease.
Correspondence
B. Brent Simmons, MD, 150 E. Wynnewood Rd., Apt. 18 J, Wynnewood, PA 19096; brentpsujmc@hotmail.com.
