CREDO-Kyoto Published: Extended DAPT Appears to Raise Bleeding Without Curbing Ischemic Events

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In patients receiving drug-eluting stents (DES), prolonging dual antiplatelet therapy (DAPT) beyond 13 months does not reduce serious cardiovascular events at 3 years but may increase bleeding, according to landmark analyses from a Japanese registry published online May 22, 2012, ahead of print in Circulation: Cardiovascular Interventions.

Portions of the data were originally presented at the European Society of Cardiology Congress 2011 in Paris, France.

Takeshi Kimura, MD, of Kyoto University Hospital (Kyoto, Japan), and colleagues assessed the influence of extended aspirin and thienopyridine therapy in 6,802 patients from the CREDO-Kyoto PCI/CABG Registry Cohort-2 who received at least 1 DES between January 2005 and December 2007. The majority of patients had stable coronary artery disease (73%) and received sirolimus-eluting stents (93%). Most were taking ticlopidine (88%) with the remainder receiving clopidogrel (12%). The researchers conducted landmark analyses of thienopyridine use at 4 and 13 months, assessing the effect of DAPT at those respective time points on ischemic and bleeding outcomes at 3 years.

Antiplatelet therapy use at either 4 or 13 months was not associated with decreased rates of death/MI/stroke at 3 years after DES implantation. However, the rates of GUSTO moderate/severe bleeding were higher in patients taking DAPT at both time points (tables 1 and 2).

Table 1. Event Rates Through 3 Years: Thienopyridine Use at 4 Months

Table 2. Event Rates Through 3 Years: Thienopyridine Use at 13 Months

After multivariate adjustment, thienopyridine use at the 4-month landmark did not affect the 3-year risk of the primary ischemic endpoint (HR 1.13; 95% CI 0.89-1.43; P = 0.32) or of the individual endpoints. The similarity between patients on vs. off thienopyridines was still observed at 13 months for the composite endpoint (HR 1.14; 95% CI 0.90-1.45; P = 0.29) and its components.

Counterintuitively, the 3-year cumulative incidence of ischemic stroke was higher in patients on thienopyridines at 13 months than in those who had stopped therapy (2.1% vs. 1.3%; P = 0.04), whereas that of hemorrhagic stroke did not differ between the 2 groups (0.6% vs. 0.5%; P = 0.17). In addition, cumulative incidence of Academic Research Consortium-defined definite stent thrombosis tended to be lower with thienopyridine use in both the 4-month (0.4% vs. 0.8%; P = 0.052) and 13-month analyses (0.2% vs. 0.6%; P = 0.051).

When looking at bleeding, adjustment for potential confounders did not change the effect of thienopyridine continuation at 4 months (HR 1.51; 95% CI 1.00-2.23; P = 0.049) or at 13 months (HR 1.44; 95% CI 0.99-2.09; P = 0.057). The association was of borderline significance in both cases.

Weighing Risks vs. Benefits

According to the authors, the findings are essentially in line with data from at least 2 randomized controlled trials suggesting no benefit for extended DAPT beyond either 6 months or 1 year.

“Although we found a small albeit statistically significant difference in the incidence of [stent thrombosis] favoring prolonged [dual antiplatelet therapy], it was not translated into any meaningful reduction in cardiac death nor MI,” they write. “Effect of long-term use of more aggressive antithrombotic therapy in patients undergoing PCI should be evaluated based not on reduction of [stent thrombosis] but on reduction of overall cardiovascular events.”

The fact that the 4-month landmark analysis was “entirely consistent with” the 13-month results suggests that a duration of DAPT “shorter than the current recommendation might be appropriate when the risk of bleeding overweighs the potential benefit,” Dr. Kimura and colleagues suggest. Clinicians should therefore assess the net effect of prolonged therapy by balancing efficacy (potential reduction in thrombotic events) and safety (hemorrhagic risk), they conclude.

Looking to DAPT Trial for Answers

In a telephone interview with TCTMD, Neal S. Kleiman, MD, of the Methodist DeBakey Heart and Vascular Center (Houston, TX), said the study findings are of limited relevance given that they come from a registry in which both the type of stent and particular thienopyridine used in the majority of patients are outdated.

In addition, he noted that unmeasured confounders, as well as inaccurate reporting of continuous thienopyridine use and bleeding events are common issues in registry studies that make it difficult to extrapolate findings with any level of certainty. Clinicians need data they can feel secure about, he said, such as those expected to come from the 4-year DAPT study, which will prospectively assess the ability of 12 vs. 30 months DAPT to prevent stent thrombosis and other major adverse events. The randomized, double-blind trial is ongoing at 256 international centers.

Though it is too early to make predictions, “I think people are looking forward very eagerly to DAPT,” Dr. Kleiman said. “The design is great, but whether it is truly executable remains to be seen. We are all basically looking for something randomized and definitive that will tell us when the bleeding risk outweighs the benefit [of prolonged antiplatelet therapy]. But the other side of that coin is late stent thrombosis and MI.”

Study Details

The 4-month and 13-month landmark points were selected because the product label of sirolimus-eluting stents specify DAPT for at least 3 months and current guidelines recommend DAPT for at least 12 months after DES implantation.

Source:

Tada T, Natsuaki M, Morimoto T, et al. Duration of dual antiplatelet therapy and long-term clinical outcome after coronary drug-eluting stent implantation: Landmark analyses from the CREDO-Kyoto PCI/CABG Registry Cohort-2. Circ Cardiovasc Interv. 2012;Epub ahead of print.

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