Six Months Sufficient for Dual Antiplatelet Therapy

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Patients treated with zotarolimus-eluting stents (ZES) suffer no excess late ischemic events if they take dual antiplatelet therapy for 6 months instead of 12 months or longer, according to a study in the October 2011 issue of JACC: Cardiovascular Interventions.

Researchers led by David E. Kandzari, MD, of the Piedmont Heart Institute (Atlanta, GA), looked at 2,032 patients undergoing PCI with ZES in 5 registration trials from Medtronic’s (Santa Rosa, CA) Endeavor program. Of these, 1,414 were identified as event-free and on dual antiplatelet therapy at 6 months. Outcomes were compared in patients based on antiplatelet therapy duration at 6, 12, and 24 months.

Outcomes Not Dependent on Therapy Duration

Following adjustment for clinical and angiographic risk factors, there was no difference in 3-year ischemic and bleeding events between patients on antiplatelet therapy for 6 or 12 months (table 1).

Table 1. Risk-Adjusted Clinical Outcomes According to Dual Antiplatelet Duration

^a On dual therapy at 6 months but not at 12 months.

The same results were maintained between patients on antiplatelet therapy for 6 or 24 months (table 2).

Table 2. Risk-Adjusted Clinical Outcomes According to Dual Antiplatelet Duration

^a On dual therapy at 6 months but not at 24 months.

On multivariable analysis, characteristics such as history of diabetes and total stent length were not predictive of 3-year events. Also, dual antiplatelet therapy for 6 vs. 12 months was not an independent predictor:

• Death: OR 1.26; 95% CI 0.63-2.54; P = 0.51
• MI: OR 0.26; 95% CI 0.05-1.27; P = 0.10
• Stroke: OR 1.30; 95% CI 0.41-4.11; P = 0.66

The same held true for dual antiplatelet therapy for 6 vs. 24 months:

• Death: OR 1.02; 95% CI 0.42-2.47; P = 0.97.
• MI: OR 0.31; 95% CI 0.08-1.25; P = 0.10
• Stroke: OR 3.16; 95% CI 0.69-14.46; P = 0.14
• Definite/probable stent thrombosis: OR 0.63; 95% CI 0.04-10.03; P = 0.74

Dual antiplatelet therapy compliance was 100% at 6 months, 47.9% at 12 months, 38.5% at 24 months, and 28.8% at 3 years.

“In this analysis limited to clinically stable patients undergoing elective percutaneous revascularization with ZES and censored for early (< 6 months) adverse events, late (3 years) safety outcomes were independent of [dual antiplatelet therapy] treatment durations ranging from 6 months to [greater than] 2 years,” the researchers conclude.

Implications for Guidelines?

Current US guidelines recommend that patients with DES implantation should receive clopidogrel therapy for at least 12 months if they are not at increased risk of bleeding, but these are not based on any definitive data. The study authors do note that observational studies have consistently shown an association between premature discontinuation of dual therapy and a higher risk of stent thrombosis, and that long-term therapy may be linked with reduced death and MI. Other reports, however, have demonstrated late stent thrombosis after DES implantation even on long-term dual therapy. As recently as the European Society of Cardiology Congress, August 28-31, 2011, data were presented showing no association between prolonged dual antiplatelet therapy and reduced ischemic events.

“What we need to acknowledge is that current guideline recommendations represent opinion more than evidence, and that an inability to take 12 months [of dual antiplatelet therapy] is also not an absolute contraindication to receiving treatment with DES,” Dr. Kandzari told TCTMD in an e-mail communication. “The majority of evidence suggests a consistent message that continuing [dual antiplatelet therapy] beyond the initial 6 months of PCI does not prevent the risk of stent thrombosis, which has been by far the major driver of extending [dual therapy] to 12 months if not a perception of lifetime commitment.”

Dr. Kandzari added that in clinical practice, physician reaction in this area has been “all across the board,” noting that some clinicians “stop thienopyridine therapy at 12 months in asymptomatic patients, and yet others would continue indefinitely for the same patient.”

Limitations Cited

It remains uncertain whether these outcomes can be generalized to broader risk populations receiving other stent types or with different durations of dual therapy. “There may be additional benefit in higher clinical risk patients in continuing dual antiplatelet therapy for longer durations for prevention of events independent of the stent territory. This is an area of research that should be revisited,” Dr. Kandzari acknowledged. “Importantly, this and other studies should not be mistaken for discontinuing antiplatelet therapy altogether for patients with CAD—this issue is specific to long term continuation of aspirin and thienopyridine treatment.”

In an editorial accompanying the study, Adnan Kastrati, MD, of the Deutsches Herzzentrum (Munich, Germany), and colleagues note that the study is in line with previous reports suggesting no need for dual therapy beyond 6 months. However, the current report does have important limitations, such as selection bias due to the patients who continued clopidogrel for 12 months or longer being much sicker than those on clopidogrel for 6 months. Also, high-risk patients were excluded, and outside of the United States, the Endeavor stent has largely been replaced with Medtronic’s next-generation Resolute DES.

“Although the study of Kandzari et al. provides some further reassurance that a 6-month duration of clopidogrel treatment might be safe in certain patients treated with a particular type of DES, the optimal duration of [dual antiplatelet therapy] to be used in patients who receive DES remains unknown,” the editorial states.

Results Apply to All DES?

“To be sure, our estimates with other DES were challenged by too small of a sample size to enable more accurate conclusions. However, other observational and randomized data do support similar conclusions with other DES types,” Dr. Kandzari maintained. “At the same time, comparative DES trials have highlighted differences in late and very late stent thrombosis. So, I also believe this is an issue that should be studied specific to stent type.”

Regardless, Dr. Kandzari stated, “I believe these results, combined with an increasing number of additional studies with similar findings, should challenge the writers of guidelines to revise their existing recommendations that many have interpreted as an absolute prerequisite for whether patients may receive the benefits associated with DES compared with other treatments.”

Sources:

1. Kandzari DE, Barker CS, Leon MB, et al. Dual antiplatelet therapy duration and clinical outcomes following treatment with zotarolimus-eluting stents. J Am Coll Cardiol Intv. 2011;4:1119-1128.
2. Kastrati A, Byrne RA, Schulz S. Will we ever know the optimal duration of dual antiplatelet therapy after drug-eluting stent implantation? J Am Coll Cardiol Intv. 2011;4:1129-1132.

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