GAITHERSBURG, Md. -- Although the problem of stent thrombosis has been acknowledged, it is not at all certain what the circumstances are that trigger formation of a thrombus.
GAITHERSBURG, Md., Jan. 12 -- Although the problem of stent thrombosis has been acknowledged, it is not at all certain what the circumstances are that trigger formation of a thrombus.
The makers of drug-eluting stents have agreed that compared with bare-metal stents there is a small, but significant increase in the rate of stent thrombosis for both the Cypher (sirolimus-eluting) and Taxus (paclitaxel-eluting) stents, beginning about 12 months after implantation. But they are at a loss to explain the increase.
And they are not alone in their befuddlement. The exact mechanism of stent thrombosis has not yet been fully explained.
The Un-Healed Stent
Drug-eluting stents prevent restenosis by inhibiting the proliferation of smooth muscle cells that cause neointimal thickening. They accomplish this by slowly releasing potent antiproliferative drugs, the eluting process.
One popular theory is that the drugs used to coat the stents --sirolimus and paclitaxel -- prevent the healing growth of endothelial cells on the stent surface.
Following this line of reasoning, months after implantation a drug-eluting stent is effectively denuded. The drug coating is depleted and there is no new tissue coating the stent struts. As a result, blood flows directly over a "bare" surface, a perfect set-up for thrombus formation.
Add Plavix to the Puzzle
This theory also would explain emerging data that strongly suggest that the risk of stent thrombosis increased when dual antiplatelet therapy, Plavix (clopidogrel) plus aspirin are stopped.
For example, researchers from Duke University said an observational study of 4,666 patients who had stenting procedures at their center found that Plavix use was a strong and independent predictor of death and myocardial infarction among patients who received drug-eluting stents.
But Plavix use was not predictive of outcome for patients who received bare-metal stents. Those patients usually receive Plavix for a month because it takes about 30 days for new tissue to grow over the bare-metal surface.
In the Duke study, Plavix use at six months was a significant predictor of lower adjusted rates of death (2.0% with versus 5.3% without; difference -3.3%; 95% CI-6.3% to -0.3%; P=0.03) at 24 months. Plavix use at six months was also a significant predictor of death or MI (3.1% versus 7.2%; difference -4.1%; 95% CI -7.6% to -0.6%; P=0.02) at 24 months.
Moreover, the apparent benefit of Plavix continued for those who were event free at 12 months. The 252 patients who remained on Plavix had a lower death rate at 24 months (0% versus 3.5%; difference-3.5%; 95% CI-5.9% to -1.1%; P=0.004) than the 276 patients who stopped taking Plavix.
Likewise, Plavix use at one year was predictive of lower death and MI rate at 24 months-0% versus 4.5%; difference -4.5%; 95% CI, -7.1% to -1.9% P
The AHA, meanwhile, has been working with a number of other disparate organizations-including groups like the American Dental Association and the American College of Physicians-as well as cardiology organizations to draft a statement on dual anti-platelet therapy and drug-eluting stents.
The details of that statement won't be released until Jan. 16, but those familiar with the language said that the statement will emphasize the need to adhere to 12 months of Plavix even for patients with uncomplicated, single-vessel disease.
An Alternate Theory
But although data suggest that Plavix use may be a key factor in determining risk of stent thrombosis, it is probably not alone.
Another contributing factor may be the effect of drug-eluting stents on collateral function.
Researchers at University Hospital Bern in Switzerland contend that drug-eluting stents impair collateral function. Six months after implantation of coronary stents, patients who received drug-eluting stents had 30% to 40% less collateral function than patients treated with bare-metal stents.
The collateral flow index averaged 0.154 +/- 0.097 in drug-eluting stent patients versus 0.224 +/-0.142 among patients treated with bare metal devices (P=0.0049), Christian Seiler, M.D., and colleagues reported in the Jan. 2, issue of the Journal of the American College of Cardiology.
As a result, 50 of 60 patients treated with drug-eluting stents had collaterals that were insufficient to prevent ischemia during occlusion, versus 33 of 60 patients getting bare-metal devices (P=0.001).
"Considering the salvaging effect of well-grown collaterals, a potential clinical impact of this finding is that in the presence of stent thrombosis myocardial infarction size and, thus, mortality may be larger in drug-eluting stents than in bare-metal stent-treated patients," Dr. Seiler and colleagues wrote.
They concluded that the study's findings suggested "a further clinical risk aside from that of more frequent clinical events due to endothelial dysfunction and deficit of endothelial progenitor cells."
Moreover, if stent thrombosis occurs, the lack of adequate collateral function could "render the thrombosis more dangerous (i.e. worsen the consequences of abrupt coronary occlusion by increasing mortality)."
To support this conclusion, Dr. Seiler cited published studies in which the six-month mortality after stent thrombosis in patients with bare-metal stents ranged form 11% to 21%, whereas mortality following drug-eluting stent thrombosis ranged from 29% to 45%.
Both theories are just that -- theories -- because more research, including better imaging technology that will allow researchers to view the stents in vivo,, is needed to confirm the true mechanism behind stent thrombosis.
Next: What does the future hold for drug-eluting stents?