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?
An analysis of the Prospective Registry Evaluating Myocardial Infarction: Events and Recovery (PREMIER) registry illustrates the catastrophic consequences of premature discontinuation of dual antiplatelet therapy.10 This study of 500 patients with acute MI treated with DES revealed a striking increase in mortality rate related to discontinuation of dual antiplatelet therapy within 3 months of their initial MI. Patients who prematurely stopped dual therapy had a mortality rate of 7.5% over the next 11 months compared to 0.7% in patients who continued dual antiplatelet therapy for a minimum of 3 months.
Of note: Researchers say that patients who self-discontinued the dual therapy were less likely to have been given instructions about their medication at discharge. In addition, these patients were less likely to have completed high school and more likely to avoid health care because of cost.
Finally, a recent study that evaluated the safety of off-label use of drug-eluting stents revealed further data in support of prolonged use of dual antiplatelet therapy in this group.11 (Off-label use included, among other things, using sirolimus- and paclitaxel eluting stents on lesions that were longer than specified in the stent manufacturer’s “information for use.”) Forty-seven percent of patients who received DES were for off-label indications.
Among the off-label patients, the 1-year rate of death, MI, or stent thrombosis was 7.7% for standard dual therapy duration (3 months for sirolimus-eluting stents and 6 months for paclitaxel-eluting stents) compared with 6.0% (RR=0.78) for prolonged duration (defined as beyond standard duration).
Cardiac stent placement
Current American Heart Association/American College of Cardiology recommendations state that full-dose aspirin (162–325 mg/day) should be used for 1 month after BMS implantation, at least 3 months after sirolimus DES implantation, and 6 months after paclitaxel DES implantation, then continued indefinitely at low dose (75 to 162 mg/day).1
Clopidogrel 75 mg/day should be added to aspirin for a minimum of 1 month, and ideally up to a year for BMS; and for a minimum of 12 months for all DES regardless of type.1 In addition to the duration and type of therapy, the American Heart Association states it is not appropriate to withhold dual therapy in stent patients for minor surgery or dental procedures within their recommended treatment period.12
Of note: The American Heart Association and American College of Cardiology guidelines, cited above, are an August 2007 revision to the groups’ 2002 guidelines.1 Although specifically written for UA /NSTEMI, the revision states that clopidogrel should be added to aspirin for at least 12 months in “all post-PCI patients receiving DES.” A revised AHA/ACC PCI guideline, however, has not yet been published to reflect these new data and recommendations.
Bleeding rates offset stroke prevention benefits
The Management of ATherothrombosis with Clopidogrel in High-risk patients (MATCH) trial is the only major trial that has evaluated combination clopidogrel and aspirin therapy for secondary prevention of stroke.13 The MATCH trial, first published in 2004, differed from the cardiovascular antiplatelet trials in that it used clopidogrel in its control group instead of aspirin.
Patients who’d had a recent ischemic stroke or transient ischemic attack (TIA) and at least 1 additional vascular risk factor were randomized to receive clopidogrel plus aspirin therapy or clopidogrel plus placebo for 18 months. Primary outcome measure was a composite of ischemic stroke, MI, vascular death, or rehospitalization for acute ischemia. Although researchers observed a consistent reduction of vascular events in the combination therapy group, the differences did not reach statistical significance. In addition, higher bleeding rates “offset any beneficial effect” of combination therapy.
Overall, treatment with aspirin and clopidogrel compared with aspirin alone might prevent 10 ischemic events per 1000 treated (not statistically significant) at a cost of 13 life-threatening hemorrhages per 1000 treated. The researchers concluded that there was no demonstrable benefit of adding aspirin to clopidogrel for secondary prevention of stroke.
A major limitation of this study was that the majority of patients enrolled had lacunar strokes, a stroke subtype that is not believed to be of pure atherothrombotic origin and that has the lowest recurrence rates.13 Future studies on secondary stroke prevention will address issues of stroke subtype and location.14
Other trials that did not specifically look at clopidogrel + aspirin therapy for noncardioembolic stroke but examined relevant issues also warrant mention:
- The Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events—W (ACTIVE W) trial compared an aspirin + clopidogrel combination to warfarin in patients with atrial fibrillation.15 ACTIVE W showed warfarin to be superior to combination antiplatelet therapy for prevention of vascular events including stroke, non-central nervous system emboli, MI, or vascular death (RR=1.44 for combination therapy).
- The Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) trial investigated combination antiplatelet therapy in patients with recently symptomatic carotid artery stenosis.16 Researchers in this small study used doppler ultrasound to see if combination therapy would lead to a reduction in asymptomatic microembolism from the carotid plaques. Patients received clopidogrel plus aspirin or aspirin alone for 7 days. The patients in the combination group had a 40% relative reduction in microembolism.
