Extending the duration of dual antiplatelet therapy after percutaneous coronary intervention (PCI) may increase the risk of bleeding without reducing ischemic events, according to a meta-analysis published online October 22, 2012, ahead of print in the European Heart Journal.

Researchers led by Adnan Kastrati, MD, of the Deutsches Herzzentrum (Munich, Germany), pooled results from 4 randomized trials investigating the clinical impact of lengthening dual therapy in patients with significant coronary artery disease undergoing PCI. In total, 8,231 patients were assigned to extended (50.2%; median 16.8 months) or control (49.8%; median 6.2 months) therapy duration.

At a median follow-up of 16.8 months, extended dual therapy did not reduce the likelihood of all-cause death (primary endpoint), MI, stent thrombosis, or stroke, but it did increase the risk of TIMI major bleeding (table 1).

Table 1. Clinical Outcomes

Additional analysis confirmed the lack of advantage of extending dual therapy, suggesting a higher risk of bleeding associated with 24-month vs. 3-month duration (P = 0.046) and 24-month vs. 6-month duration (P = 0.047).

Tailored Therapy the Best Strategy

“The aggregate results of direct comparisons suggest that the extension of [dual antiplatelet therapy] is related to no measurable benefit beyond 6 months and possible harm beyond 12 months,” Dr. Kastrati and colleagues write. “However, we strongly believe that increasing knowledge of clinical, mechanical, and pathophysiological factors associated with [stent thrombosis] after PCI may lead to a paradigm shift, with tailoring of treatment duration according to the need of the individual patient.”

Citing limitations of the meta-analysis, the authors point out that, by design, the individual trials restricted enrollment to patients who remained event-free for a period after the index PCI. “Thus, the present results might not be generalizable to such higher-risk patients,” they write.

Also, because the median follow-up period was only 16.8 months, “more extended follow-up would have been highly desirable,” the investigators note. “[W]e cannot exclude that significant differences may emerge at long term, even though the available 24-month follow-up did not reveal directional changes in events.”

Different Trial Objectives Muddle Meta-analysis

In an accompanying editorial, Pascal Meier, MD, of University College London Hospitals (London, United Kingdom), and Alexandra J. Lansky, MD, of Yale School of Medicine (New Haven, CT), question whether the results support or challenge current guidelines. “The study certainly raises relevant questions regarding current [dual antiplatelet therapy] recommendations, by highlighting a lack of clear evidence rather than by providing a definitive answer,” they write. “Furthermore, this study has important limitations which need to be considered when interpreting the data.”

The biggest limitation they cite is the inclusion of trials that were all trying to answer different questions. “It therefore remains unclear which question this meta-analysis is addressing exactly,” Drs. Meier and Lansky note.

In a telephone interview with TCTMD, Sorin J. Brener, MD, of Weill Cornell Medical College (New York, NY), agreed with the editorial. “From a methodological point of view, you cannot say that you are comparing an average of 17 months to an average of 6 months [dual therapy duration]. That’s a very misleading statement that they make,” he said, adding that another issue is that most of the studies looked at first-generation DES.

At this point, Dr. Brener said the optimal duration for dual therapy would be between 3 and 6 months. “Beyond that, if there is benefit, it’s not to prevent stent thrombosis. I think dual antiplatelet therapy has other benefits, potentially to prevent new artherosclerotic events, like we saw in CHARISMA,” he commented.

As stent designs and antiplatelet drugs continue to change, “[i]t is unlikely that we will ever find a definite answer on optimal [dual antiplatelet therapy] duration,” Drs. Meier and Lansky predict. “In this context, optimal duration [dual therapy] will continue to be a moving target. In the future, the golden rule will hopefully be ‘the shorter the dual antiplatelet therapy, the longer the event-free survival.’”

Study Details

Clinical characteristics were typical and well balanced between treatment arms in all studies. Mean patient age ranged from 62 to 68 years, the percentage of males from 64% to 77%, and the percentage of patients with diabetes from 24% to 38%.

2. Meier P, Lansky AJ. Optimal duration of clopidogrel therapy: The shorter the longer? Eur Heart J. 2012;Epub ahead of print.

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