Registries Confirm Worse Outcome When Drug-Eluting Stents Are Used Off-Label

CHICAGO, May 9 -- The use of drug-eluting stents was off-label, or for untested purposes, for at least half the Americans who received them in 2004 and 2005, and those patients fared worse than those who met approved indications, found two registry trials.

But the similar conclusions were interpreted quite differently by the authors of the studies, both published in the May 9 issue of the Journal of the American Medical Association.

Nirat Boehar, M.D., of Northwestern here, and colleagues, said that although the short-term outcomes appear to be worse with off-label use, the overall event rates were low low, which he called reassuring.

By contrast Htut K. Win, M.D., M.B.C.P., of Baylor in Houston, and colleagues, said the EVENT (Evaluation of Drug Eluting Stents and Ischemic Events) off-label status was the strongest independent predictor of both in-hospital and adverse cardiac events in the multivariate model.

In an editorial, Robert A. Harrington, M.D., and E. Magnus Ohman, M.D., of the Duke Clinical Research Institute in Durham, N.C., said that a couple of factors might explain the opposing interpretations, including sponsor bias. The study by Dr. Win and colleagues was "funded by manufacturers of antiplatelet agents, whereas the study by Beohar et al was funded by a device manufacturer," they noted.

And the EVENT registry reported rates of early complications that were nine to 10 times higher than the event rates reported by Dr. Boehar and colleagues, which the editorialists said might be due to ascertainment bias.

Dr. Win and colleagues, the editorialists said, went looking for events by carefully tracking a number of variables including peri-procedural CK-MB levels as well as detailed pharmacological data. Dr. Boehar and colleagues did not.

The bottom line, said Drs. Harrington and Ohman, was that these registry data should be a lesson in humility to counteract the "irrational exuberance" that has gripped much of the interventional cardiology community since the introduction of drug-eluting stents.

Dr. Boehar and colleagues evaluated in-hospital, 30-day, and one-year outcomes for 5,541 patients who received drug-eluting stents at 140 U.S. hospitals from January to June 2005.

Standard or on-label use for sirolimus-eluting (Cypher) stents was defined as disease because of discrete de novo lesions of 30 mm or less in native coronary arteries with a reference vessel diameter of 2.5 mm or greater to 3.5 mm or less. For the paclitaxel-eluting (Taxus) stent, the standard use definition was de novo lesions of 28 mm or less, with a reference diameter of 2.5 mm to 3.75 mm or less.

Off-label use of the sirolimus-eluting stent was defined as "stenting of a restenotic lesion, lesion in a bypass graft, lesion length greater than 30 mm, or reference-vessel diameter less than 2.5 mm or greater than 3.5 mm."

For the paclitaxel-eluting stent the off-label definition was the same except lesion length that greater than 28 mm and vessel diameter less than 2.5 mm or greater than 3.75 mm.

For both paclitaxel- and sirolimus-eluting stents the untested definition included treatment of left main, ostial, bifurcation, or occluded lesions.

Among the findings:

• Forty-seven percent of the 5,541 patients received stents for off-label or untested indications.
• In-hospital death, myocardial infarction, or stent thrombosis did not differ among on-label, off-label, or untested indication patients.
• At 30 days the risk of death, MI, or stent thrombosis was significantly higher for off-label status with a hazard ration of 2.08 (95% confidence interval 1.24-3.48, P=0.005) but was not significantly higher for patients who received stents for untested indications (P=0.23).
• At one year the rate of target vessel revascularization was 49% higher in both the off-label and untested-use patients (P=0.005 for off label versus standard use and P=0.01 for untested versus standard use).
• The one-year absolute event rates were low in all three groups -- 4.4% in the standard use group, 7.6% in the off-label group, and 6.7% in the untested-use group.

Dr. Win and colleagues analyzed outcomes from 3,323 patients who received at least one drug-eluting stent from July 2004 through September 2005. Patients were treated at 42 participating centers.

The authors identified off-label patients as having the presence of at least "one of nine off-label characteristics based on the current FDA-approved indications for sirolimus- and paclitaxel-eluting stents.

Among the findings:

• Of the 3,323 patients, 54.7% received stents for off-label indications.
• During the initial hospitalization 198 (10.9%) patients who received stents for off-label indication reached the composite endpoint of death, MI, or target-vessel revascularization versus 76 (5%) of patients who received stents for label indications. Adjusted odds ration 2.32 (95% CI 1.75-3.07 P