NPC Archive Item: How long should clopidogrel be prescribed for after implantation of drug-eluting stents?

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31 March 2010

An interim analysis of data from two studies suggests no benefit for continuing to use clopidogrel in addition to aspirin for more than 12 months after implantation of drug-eluting stents. However, because of limitations, further studies are required to confirm or refute these findings.

Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.

The findings of this analysis are insufficient to recommend a change in practice. Current NICE guidance for drug-eluting stents does not recommend any specific duration of clopidogrel therapy in addition to aspirin. However, NICE refers to the recommendations from the American College of Cardiologists/American Heart Association PCI guidelines and the British Cardiovascular Intervention Society advising a duration of at least 12 months, after which time continuation of clopidogrel should be reviewed taking into account the risk for further events on an individual patient basis.

What is the background to this?
Antiplatelet therapy using a combination of clopidogrel and aspirin is recommended following implantation of stents to reduce the risk of stent thrombosis. Some studies have shown that drug-eluting stents, as opposed to bare-metal stents, are associated with an increased risk of late stent thrombosis, death or myocardial infarction (MI), and early discontinuation of dual antiplatelet therapy may be a factor in this. Although some guidelines recommend use of this combination for at least twelve months, the optimal duration of therapy is uncertain — the evidence for long-term clopidogrel plus aspirin use is not compelling (for a review see Terpening 2009).

Two randomised controlled trials(RCTs) of similar design, REAL-LATE and ZEST-LATE, were initiated to examine the benefits and risks of clopidogrel plus aspirin over and above those of aspirin alone in patients who had received drug eluting stents at least 12 months previously. Because of slow enrolment, it was decided to analyse the interim, merged results of these two studies. In both studies patients were randomised to receive clopidogrel (75mg daily) plus low-dose aspirin (100–200mg daily) or low-dose aspirin alone, and the primary outcome was MI or death from cardiac causes.

What does this study claim?
The results from 2,701 patients found that the use of clopidogrel in addition to aspirin for longer than 12 months in patients who had received drug-eluting stents was not significantly more effective than aspirin alone in reducing the rate of MI or death from cardiac causes (clopidogrel plus aspirin 1.8%, aspirin alone 1.2%; hazard ratio [HR] 1.65, 95%confidence interval [CI] 0.80 to 3.36, P=0.17). However, larger, RCTs with longer-term follow-up are required to required to confirm or refute this finding, as the study lacked the statistical power to provide a firm conclusion.

So what?
The low number of primary outcome events (MI, death from cardiac causes), which was less than 25% of that anticipated, means that the study was underpowered to demonstrate a statistically significant difference between treatments. The 95% confidence intervals suggest that the use of clopidogrel and aspirin could increase the relative risk of having one of these events by more than 300% or reduce the risk by 20%. Similarly, no definitive conclusions can be drawn about the effects of clopidogrel on the risk of individual cardiovascular events or other composite outcomes which included stroke and death from any cause. Any apparent increase in risk with clopidogrel was not statistically significant and could have been a chance finding. There are other limitations of the study also, for example, as it was not blinded this could have introduced bias on the part of both investigators and patients.

Although there were too few events to identify if there was any significant difference in the risk of major bleeding (3 clopidogrel plus aspirin, 1 aspirin alone) in this study, other studies such as CURE have shown that in other populations combined use of aspirin and clopidogrel is associated with a greater bleeding risk than aspirin alone.

Despite this study it remains unclear whether long-term clopidogrel has any benefit in reducing long-term stent thrombosis and the associated cardiac events, or indeed if it may actually increase them. For some patients, long-term use of clopidogrel is unlikely to be feasible or likely to be problematic (e.g. planned surgery requiring clopidogrel discontinuation, those at high bleeding risk, and those requiring warfarin). As for other patients, the accompanying editorial points out, “we find ourselves in a situation in which the requisite duration of essential concomitant therapy for a widely used device — among the best-studied medical devices in history — is unknown”.

Larger studies addressing the benefit of long vs. short dual antiplatelet regimens are ongoing, most notably the DAPT study, a RCT of more than 20,000 patients, comparing 12 vs. 30 months of dual antiplatelet therapy among patients who have been treated with a drug-eluting or a bare-metal stent.

Study details
Park S-J, et al. Duration of dual antiplatelet therapy after implantation of drug-eluting stents. New Engl J Med 2010. Published online March 15th (10.1056/NEJMoa1001266d)

Interim analysis of merged data from two RCTs (REAL-LATE and ZEST-LATE)

2,701 patients (mean age 62 years, 30% women) who had received drug-eluting stents and had been free of major adverse cardiac or cerebrovascular events and major bleeding for a period of at least 12 months.

Intervention and comparison
Clopidogrel 75mg plus low-dose aspirin (100–200mg) or low-dose aspirin alone (all daily) for a median duration of 19.2 months (33.2 months after index procedure).

Outcomes and results
The cumulative risk of the primary outcome (a composite of MI or death from cardiac causes) at 2 years was 1.8% with dual antiplatelet therapy, compared with 1.2% with aspirin alone (HR 1.65, 95%CI, 0.80 to 3.36, P=0.17). The total number of cardiovascular events or deaths from any cause was small (35 in the clopidogrel plus aspirin group and 20 in the aspirin group); HR 1.73, 95%CI 0.99 to 3.00, P=0.051). The individual risks of MI, stroke, stent thrombosis, need for repeat revascularization, and death from any cause, or of any of the composites of these events investigated in the study were also not statistically significantly different between groups. The risk of major bleeding was not significantly different between groups at 2 years (0.2% clopidogrel plus aspirin, 0.1% aspirin alone; HR 2.96, 95%CI 0.31 to 28.46; P=0.35).

The study was supported by grants from the Cardiovascular Research Foundation of South Korea and the Korea Health 21 Research and Development Project, Ministry of Health and Welfare.

More information on the use of antiplatelets can be found on the cardiovascular section of NPC. Specific information on antiplatelets is currently being prepared and will be located in the National Support Materials section.

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