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Unselected patients who receive sirolimus-eluting stents (SES) typically comply with recommended dual antiplatelet therapy and have low 1-year rates of stent thrombosis and major bleeding, according to a registry study published in the March 29, 2011, issue of the Journal of the American College of Cardiology. The study also found that the 2 complications rarely occur in the same patient.

To ascertain the relative clinical impact of stent thrombosis and major bleeding, researchers led by Philip Urban, MD, of La Tour Hospital (Geneva, Switzerland), analyzed data from 15,147 unselected patients implanted with SES who were enrolled in the e-SELECT (Multi-Center Post-Market Surveillance) registry comprising 320 medical centers in 56 countries.

Dual antiplatelet therapy was interrupted or discontinued in approximately 2% during the first 30 days post PCI. Thereafter, the rate of discontinuation increased. However, excluding brief interruptions, 86.3% of patients received 6 months of dual antiplatelet therapy followed by another 6 months to 1 year of single or dual therapy, in accordance with European Society of Cardiology guidelines.

Stent Thrombosis, Bleeding Rates Similarly Low

By 1 year, the cumulative incidence of Academic Research Consortium-defined definite or probable stent thrombosis reached 1% and was matched by the same rate of major bleeding.

Importantly, the incidence of stent thrombosis was considerably lower between 6 months and 1 year than during the first 6 months despite a decline in use of dual antiplatelet therapy. On the other hand, there was a steady rise in the incidence of major bleeding as well as MI, TLR, and MACE (composite of death, MI, or TLR) over the year (table 1).

Table 1. Cumulative Outcomes at 30 Days, 6 Months, and 1 Year

Abbreviations: MACE, major adverse cardiac events; ARC, Academic Research Consortium.

Stent thrombosis was associated with a 35% risk of mortality, while major bleeding imparted a 10% risk. In addition, there was a 30% chance of dying within 1 week of stent thrombosis but only a 1.5% risk of death from major bleeding within that period. This finding suggests a more direct causal relationship between stent thrombosis and death than between major bleeding and death, the authors say.

Furthermore, the risk associated with discontinuing or interrupting 1 or both antiplatelet agents within the first 30 days was high—more than one-third of patients who experienced stent thrombosis during that period were not compliant with the dual antiplatelet regimen. Thereafter, the risk linked to discontinuation dropped off dramatically, falling to about 1%.

Stent thrombosis was closely tied to increased risk for cardiac death (34%) as well as MI (67%) and TVR (67%) but not to bleeding (1.5%). In fact, only 2 of 13,749 patients experienced both stent thrombosis and major bleeding during 1-year follow-up.

When various patient subgroups were analyzed for the incidence of the 2 complications, those who had insulin-dependent diabetes, AMI within 24 hours, prior CABG, or a Charlson index of ≥ 3 were more susceptible to stent thrombosis, while those who had creatinine concentrations ≥ 177 μmol/L, a hemoglobin level ≤ 117 μmol/L, or who were receiving vitamin K antagonists were more likely to experience major bleeding.

Complication-Specific Predictors

Multivariate analysis based on multiple demographic, clinical, angiographic, and procedural characteristics determined independent correlates of stent thrombosis and major bleeding. For the former, these included:

• Insulin-dependent diabetes (HR 2.1; 95% CI 1.4-3.2)
• Age (HR1.2; 95% CI 1.0-1.4)
• Charlson comorbidity index (HR 1.2; 95% CI 1.1-1.4)
• Bypass graft target lesion (HR 4.3; 95% CI 2.4-7.7)
• Any discontinuation of dual antiplatelet therapy within 30 days (HR 3.2; 95% CI 1.8-5.5)
• ACS at presentation (HR 1.8; 95% CI 1.3-2.6)
• Multivessel disease (HR 1.6; 95% CI 1.1-2.2)
• Target lesion calcification (HR 1.6; 95% CI 1.2-2.3)
• History of MI (HR 1.4; 95% CI 1.0-2.0)

The correlates for major bleeding were:

• Age (HR 1.4; 95% CI 1.1-1.6)

• Charlson comorbidity index (HR 1.1; 95% CI 1.0-1.2)
• Glycoprotein IIb/IIIa inhibitor (HR 2.3; 95% CI 1.5-3.4)
• Chronic antivitamin K therapy in the first 30 days (HR 3.7; 95% CI 1.6-8.4)

The only factors common to both complications were age and Charlson comorbidity index.

Potential Reasons for Low Complication Rates

The authors observe that in previous studies rates of stent thrombosis have ranged from 1.8% to 9.2%. The very low incidence observed in this registry may be explained in part by its limitation to patients who had undergone technically successful procedures and were highly compliant with dual antiplatelet therapy, they suggest. Moreover, patients considered to be at high bleeding risk may have been preferentially given BMS and thus not included in the study. Finally, SES, which were used exclusively, have shown consistently lower rates of stent thrombosis than PES, the authors add.

Differing temporal patterns of stent thrombosis and major bleeding “challenges the wisdom of continuing [dual antiplatelet therapy] beyond 6 months after implantation of SES in all patients—considering the risk of [major bleeding] associated with the prolonged administration of [dual antiplatelet therapy], which might outweigh the protection it confers against [stent thrombosis],” Dr. Urban and colleagues write. “The issue should be resolved by ongoing randomized trials,” they add, which include the ongoing ISAR-SAFE and DAPT trials.

Clotters vs. Bleeders

The investigators also point to another important observation: Despite sharing some risk factors, patients who experienced adverse events tended to be either ‘bleeders’ or ‘clotters’ but not both. This might limit the clinical value of bleeding scores in adjusting long-term antithrombotic therapy after stent implantation because such scores typically define a population at increased risk of both bleeding and stent thrombosis, the authors explain.

They note, however, that use of new, more potent antiplatelet agents such as prasugrel may alter the relative incidence of stent thrombosis and major bleeding.

As for different complication patterns in patient subgroups, the authors note that the risk of stent thrombosis was increased in insulin-dependent diabetics whereas the risk of major bleeding was not. Thus, more potent antiplatelet agents such as prasugrel may be especially beneficial in this patient subset, they say.

The investigators acknowledge that the relative risks of stent thrombosis and major bleeding may change with longer follow-up, especially because the prevalence of dual antiplatelet therapy would likely decline sharply after 1 year.

Dr. Urban and colleagues conclude, “These observations suggest that the safety of SES could be enhanced by the precise identification of the hemostatic profile and response to antithrombotic therapy of an individual patient as well as by new DES designs, which would allow shorter and less intense antithrombotic regimens.”

Nonetheless, it is reassuring that “in this real-world population, the sirolimus-eluting stent performed remarkably well,” noted Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), in an e-mail communication with TCTMD.

Study Details

Stent length ranged between 8 and 33 mm, and nominal stent diameter ranged between 2.25 and 3.50 mm. Multiple SES were implanted in 38.5% of patients.

At hospital discharge, 98.6% of patients prescribed a thienopyridine received clopidogrel, while 1.4% received ticlopidine.

Major bleeding was assessed according to the STEEPLE (Safety and Efficacy of Enoxaparin in PCI) definition.

Source:

Urban P, Abizaid A, Banning A, et al. Stent thrombosis and bleeding complications after implantation of sirolimus-eluting coronary stents in an unselected worldwide population: A report from the e-SELECT (Multi-Center Post-Market Surveillance) registry. J Am Coll Cardiol. 2011;57:1445-1454.

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