Antithrombin Plus Preloading with Clopidogrel May Reduce Stent Thrombosis

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Early preloading with an antithrombin plus high-dose antiplatelet therapy may help reduce the risk of stent thrombosis in patients with ST-segment acute myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI). The findings come from a subanalysis of the HORIZONS-AMI trial, published online April 11, 2011, ahead of print in Circulation.

The HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial included 3,602 patients with STEMI undergoing primary PCI who were randomized to heparin plus a glycoprotein IIb/IIIa inhibitor (GPI; n = 1,802) or bivalirudin monotherapy (n = 1,800). Taxus Express2 paclitaxel-eluting stents or otherwise identical BMS (both Boston Scientific, Natick, MA) were implanted in 3,202 patients.

For the current analysis, researchers led by George D. Dangas, MD, PhD, of Mount Sinai Medical Center (New York, NY), evaluated the frequency and predictors of stent thrombosis within the first 2 years after PCI.

Overall, there were 142 Academic Research Consortium-defined definite or probable cases of stent thrombosis in 137 patients (4.4%) during follow-up, including 0.9% acute (≤ 24 hours), 1.6% subacute (> 24 hours-30 days), 1.0% late (> 30 days-1 year), and 1.1% very late (1-2 years). Most of the 142 cases (83.8%) were definite.

Independent predictors of stent thrombosis differed according to the timing of events:

• Acute: Angiographic ulceration, baseline TIMI 0/1 flow, younger age, use of bivalirudin, no prerandomization heparin
• Subacute: Insulin-treated diabetes, history of congestive heart failure, baseline platelet count, baseline and final TIMI 0/1 flow, no 600-mg loading dose of clopidogrel
• Early (acute + subacute): Higher baseline platelet count, insulin-treated diabetes, angiographic ulceration, baseline TIMI 0/1 flow, no prerandomization heparin
• Late: Cigarette smoking, prior MI
• Very late: Insulin-treated diabetes, prior PCI, baseline platelet count, use of heparin plus GPI

Two-year cumulative rates of stent thrombosis were 4.4% with both DES and BMS (P = 0.98) and 4.3% vs. 4.6% in patients randomized to bivalirudin monotherapy or heparin plus a GPI, respectively (P = 0.73).

Lesions with stent thrombosis were more likely to be aneurysmal, to have a larger baseline thrombus burden, and to have a greater residual stenosis after the procedure. Stent thrombosis also was associated with a significantly higher prevalence of baseline and postprocedural TIMI flow 0/1 and a lower corrected TIMI frame count.

The rate of acute stent thrombosis was higher in the bivalirudin group than in the heparin plus GPI group (1.4% vs. 0.3%; P < 0.001), a difference that was evident almost entirely within the first 5 hours after stent implantation. However, stent thrombosis occurring after 24 hours was seen less often in the bivalirudin group than in the heparin plus GPI group (2.8% vs. 4.4%; P = 0.02).

Early Dosing Is Key

“Stent thrombosis rates after primary PCI in STEMI are higher than most people would like to believe, although the rates are not increased with DES vs. BMS, which is what most people mistakenly believe,” said Gregg W. Stone, MD, of Columbia University Medical Center (New York, NY), in an e-mail communication with TCTMD.

Dr. Stone, a coauthor of the paper, said numerous studies including HORIZONS-AMI show that more potent P2Y12 antagonists can reduce stent thrombosis when given early prior to primary PCI.

“These agents (high-dose clopidogrel, and prasugrel/ticagrelor in patients not at high risk for bleeding) should be given as soon as possible,” he said. “In patients treated with bivalirudin, a single 2,500- to 5,000-unit dose of heparin may mitigate acute stent thrombosis, and did so without increasing bleeding or ameliorating the mortality benefit of bivalirudin—so this may also be considered. This is also the easiest way to give the anticoagulation: Administer a single heparin bolus IV in the ER, and then start the bivalirudin (bolus plus drip) in the cath lab.”

In an editorial accompanying the study, Lorenz Räber, MD, and Stephan Windecker, MD, of Bern University Hospital (Bern, Switzerland), say the results of HORIZONS-AMI “not only contribute to the current standard of care, but also stimulate numerous important questions and hypotheses.”

One example, they contend, is whether a prolonged infusion of bivalirudin might be beneficial given the positive effects of prolonged heparin observed in the study.

However, Dr. Stone countered that there is no direct evidence to suggest this would be a good idea and said without data he would not recommend it.

“Bivalirudin decreases mortality in STEMI principally through . . . reducing major bleeding,” he said. “We don’t know if prolonging the infusion in an attempt to reduce the acute stent thrombosis rate wouldn’t increase bleeding and mortality. Rather, a more potent, rapid acting thienopyridine such as prasugrel or ticagrelor, and/or a single pre-randomization heparin bolus is likely to mitigate this adverse event.”

Moreover, since bivalirudin did not increase stent thrombosis by the end of 2-year follow-up, he added, “caregivers shouldn’t overreact to the stent thrombosis increase within 24 hours with bivalirudin.”

Attention Drawn to Limitations

In a telephone interview with TCTMD, Stephen G. Ellis, MD, of the Cleveland Clinic (Cleveland, OH), asserted that stronger efforts need to be made to reduce the risk of stent thrombosis. The current findings “offer us 2 relatively easy to implement treatments that we can use right now to improve upon the situation,” he said. “It’s an important paper that draws attention to some of the limitations of how we manage patients.”

Despite the fact that thrombosis rates tend to be higher in STEMI patients, Dr. Ellis said, the rates in the study for both DES and BMS are higher than they should be at 2 years.

“As someone who puts in a lot of stents, 4.4% is too high,” he said. Although HORIZONS-AMI is underpowered to detect differences in stent thrombosis between DES and BMS, Dr. Ellis commented that the stent thrombosis rates “raise questions about whether we need better stents or we need better techniques. Regardless, we certainly need to address this issue of 4.4% stent thrombosis at 2 years.”

Note: Drs. Stone, Dangas and several coauthors of the paper are faculty members of the Cardiovascular Research Foundation, which owns and operates TCTMD.

 

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Sources:
1. Dangas GD, Caixeta A, Mehran R, et al. Frequency and predictors of stent thrombosis after percutaneous coronary intervention in acute myocardial infarction. Circulation. 2011;123:1745-1756.

2. Räber L, Windecker S. Primary percutaneous coronary intervention and risk of stent thrombosis: A look beyond the HORIZON. Circulation. 2011;123:1709-1712.

 

 

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