EDITORIAL COMMENT
Peeling-Off LabelsMounting Evidence for Benefit of Drug-Eluting Stents With Off-Label Use*
Heinz Joachim Büttner, MD2 and
Franz-Josef Neumann, MD*
Herz-Zentrum, Bad Krozingen, Germany.
* Reprint requests and correspondence: Dr. Franz-Josef Neumann, Herz-Zentrum Bad Krozingen, Südring 15, 79189 Bad Krozingen, Germany. (Email: franz-josef.neumann{at}herzzentrum.de).
On the basis of the results of the pivotal randomized trials on sirolimus- (SES) or paclitaxel-eluting stents, the Food and Drug Administration (FDA) approved the use of drug-eluting stents (DES) for previously untreated coronary lesions of <30 mm in length and a reference vessel diameter of 2.50 to 3.75 mm (1). The risk of target vessel revascularization (TVR) in these relatively simple lesions, however, is fairly low, thus limiting the potential benefit from DES. It is intuitive that the absolute reduction in TVR by DES as compared with bare-metal stents (BMS) might be substantially larger in the more complex lesions outside the labeling for DES, which carry a high risk of restenosis. Hence, it is not surprising that an estimated 60% of the use of DES is off label (1). Nevertheless, the safety of this practice is still a matter of debate.
Meta-analyses of pivotal trials on DES, reported at the European Society of Cardiology meeting in Barcelona in 2006, suggested an excessive long-term risk of death and myocardial infarction (MI) with DES as compared with BMS (2). These analyses, however, were flawed by the use of study-level data. Reanalysis of the same data sets with patient-level data did not confirm the earlier reports (3): for the pivotal trials of both SES and paclitaxel-eluting stents, the incidence of death and MI during 4-year follow-up after placement of DES was not significantly different from that after BMS (3). These reassuring results were challenged by alarming observations during 3-year follow-up of the Swedish Coronary Angiography and Angioplasty Registry (SCAAR) (4). This registry comprised 19,771 consecutive patients undergoing percutaneous coronary intervention, 6,033 thereof treated with DES, and 13,738 treated with BMS (4). After the initial 6 months, when clopidogrel was usually discontinued, SCAAR found an absolute increase of 0.5% in the risk of deaths per year associated with DES and an absolute increase in the composite of death and MI of 0.5% to 1.0%/year (4). The discrepancy in the results of the pivotal trials was attributed to differences in patient selection. The pivotal trials included patients on the basis of selection criteria that subsequently constituted the FDA-approved on-label use of DES. In SCAAR, however, most of the use of DES was off-label. Hence, it was speculated that off-label use of DES was associated with an excessive late risk of death and MI. The FDA thus cautioned against the off-label use of DES (1).
As an alternative explanation, the discrepancy between SCAAR and the pivotal trials might be attributed to the nonrandomized nature of SCAAR. In SCAAR, the sicker patients with a poorer prognosis might have been assigned predominantly to DES. Although propensity-score methods were used to compensate for this, differences in baseline characteristics or selection criteria that might not have been recorded could remain (4). Indeed, some important variables, such as lesion length, reference vessel diameter and left ventricular ejection fraction, could not be included in the analysis. As the authors of SCAAR state in their manuscript, "randomized studies with an adequate number of patients and long-term follow-up" are needed to clarify the long-term safety and efficacy of the off-label use of DES (4).
Up to now, no single study fulfills these requirements. However, Kastrati et al. (5,6) performed a meta-analysis of 17 randomized trials with SES, among them 13 trials comprising 3,467 patients addressing off-label indications. In this analysis, off-label use of SES as compared with BMS was associated with a relative risk of 0.97 (95% confidence interval [CI] 0.70 to 1.33) for death and 0.88 (95% CI 0.51 to 1.52) for stent thrombosis (5,6). For on-label indications, however, SES were associated with a relative risk of 1.04 (95% CI 0.75 to 1.46) for death and 1.60 (95% CI 0.53 to 4.82) for stent thrombosis (5,6). The odds ratios comparing SES with BMS for major adverse cardiac events, largely driven by TVR, were similar, irrespective of on-label or off-label use, and highly favored the use of SES (5). Currently available data from randomized studies on off-label indications, hence, strongly suggest the use of SES in this setting.
It is the role of large registries to verify whether the results of randomized studies are applicable to daily practice. In this respect, the findings from the National Heart, Lung, and Blood Institute’s Dynamic Registry reported in this issue of the Journal represent an important milestone (7). This registry comprises the full spectrum of patients treated with DES in North America; 1,460 patients who received at least one DES in 2004 were compared with 1,763 patients enrolled in the recruitment period immediately preceding the approval of DES (2001 to 2002) who received at least one BMS (7). During 1-year follow-up, the cumulative incidence of death and MI was 7.6% with DES and 8.7% with BMS (adjusted hazard ratio [HR] 0.88, 95% CI 0.68 to 1.15, p = 0.34), and the incidence of any repeat revascularization was 8.3% after DES and 14.9% after BMS (adjusted HR 0.38, 95% CI 0.25 to 0.60, p < 0.001) (7). The authors thoroughly investigated their cohort with respect to lesion characteristics that indicate complexity and constitute off-label use. Consistent with the meta-analysis of the randomized trials on off-label indications for DES, the HRs for the 1-year rate of death and MI, adjusted for pertinent covariables, favored DES over BMS by trend in the presence of any criterion for lesion complexity, whereas in absence of any criterion for lesion complexity, the 1-year safety of DES and BMS was almost identical (7). Considering the 1-year incidence of TVR, DES were similarly efficacious irrespective of the presence or absence of criteria for lesion complexity (7).
Two recent registries indicated that the safety and efficacy of DES is reduced in off-label use as compared with on-label use. Both the EVENT (Evaluation of Drug Eluting Stents and Ischemic Events) (8) registry, comprising 3,323 patients, and the D.E.S.cover Registry (9), comprising 5,541 patients, reported a significantly increased risk of death and MI early (<30 days) after placement of DES for off-label indications as compared with placement for on-label indications but no significant further increase in the difference between on-label and off-label use during the subsequent months up to 1 year. In addition, in both studies the need for TVR during 1-year follow-up was significantly higher after off-label use than after on-label use (8,9). Although neither EVENT nor D.E.S.cover had a BMS comparator, the authors of EVENT cautioned about extrapolating the benefits of DES over BMS observed in the pivotal trials to higher-risk clinical settings (8). It is the merit of the Dynamic Registry (7) to shed more light on this matter. Although the efficacy and safety of DES might be inferior in off-label use compared with that in on-label use, the Dynamic Registry clearly demonstrates that DES are still superior to BMS used in the same setting (7). These findings concur with currently available evidence from randomized studies (5,6).
The termination of follow-up at 1-year has to be considered as an important limitation of the Dynamic Registry. In this respect, we are lucky to have other large registries with longer follow-ups: REAL (REgistro AngiopLastiche dell’Emilia Romagna) with 10,629 patients (n = 3,064 with DES, n = 7,565 with BMS) and 2-year follow-up (10); the Western Denmark Heart Registry (11) with 12,395 patients (n = 3,548 with DES, n = 8,247 with BMS) and 15-month follow-up; as well as ARTS (Arterial Revascularization Therapies Study) II comprising 607 patients with SES followed for 3-years and a historic control of 600 patients with BMS from ARTS I (12,13). In each of these registries, the majority of stents were implanted for indications not covered by current labeling. No significant difference in the composite of death and MI between DES and BMS was found during the entire follow-up in any of the 3 registries (10–13). In contrast, the need for repeat interventions was significantly reduced in each of the 3 registries with adjusted HRs in the range of 0.5 to 0.7 (10–13).
We believe that the Dynamic Registry makes an important contribution to the discussion of the use of DES in lesion subsets that are not yet covered by the FDA-approved labeling (7). Many of these lesion subsets carry a very high risk for restenosis. The mounting evidence on this matter confirms the superior efficacy of DES with respect to the prevention of repeat revascularization and does not suggest inferior safety compared with BMS. Nevertheless, the acute and long-term risk in off-label indications will be higher than with on-label use. Thus, alternative treatment strategies, specifically bypass surgery, deserve serious consideration. Once the decision for percutaneous coronary intervention has been made, DES probably will be the best choice in most instances.
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Footnotes
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* Editorials published in the Journal of American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
2 Dr. Büttner has received lecture honoraria from Cordis and Boston Scientific.
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References
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1. Farb A, Boam AB. Stent thrombosis redux—the FDA perspective N Engl J Med 2007;356:984-987.[Free Full Text]2. Camenzind E, Steg PG, Wijns W. Stent thrombosis late after implantation of first-generation drug-eluting stents: a cause for concern Circulation 2007;115:1440-1455.[Free Full Text] 3. Stone GW, Moses JW, Ellis SG, et al. Safety and efficacy of sirolimus- and paclitaxel-eluting coronary stents N Engl J Med 2007;356:998-1008.[Abstract/Free Full Text] 4. Lagerqvist B, James SK, Stenestrand U, Lindback J, Nilsson T, Wallentin L. Long-term outcomes with drug-eluting stents versus bare-metal stents in Sweden N Engl J Med 2007;356:1009-1019.[Abstract/Free Full Text] 5. Kastrati A, Mehilli J, Pache J, et al. Analysis of 14 trials comparing sirolimus-eluting stents with bare-metal stents N Engl J Med 2007;356:1030-1039.[Abstract/Free Full Text] 6. Kastrati A, Schoemig A. Drug-eluting stents is their future as bright as their past? J Am Coll Cardiol 2007;50:146-148.[Free Full Text] 7. Abbott JD, Voss MR, Nakamura M, et al. Unrestricted use of drug-eluting stents compared with bare-metal stents in routine clinical practice: findings from the National Heart, Lung, and Blood Institute Dynamic Registry J Am Coll Cardiol 2007;50:2029-2036.[Abstract/Free Full Text] 8. Win HK, Caldera AE, Maresh K, et al. Clinical outcomes and stent thrombosis following off-label use of drug-eluting stents JAMA 2007;297:2001-2009.[Abstract/Free Full Text] 9. Beohar N, Davidson CJ, Kip KE, et al. Outcomes and complications associated with off-label and untested use of drug-eluting stents JAMA 2007;297:1992-2000.[Abstract/Free Full Text] 10. Marzocchi A, Saia F, Piovaccari G, et al. Long-term safety and efficacy of drug-eluting stents: two-year results of the REAL (REgistro AngiopLastiche dell’Emilia Romagna) multicenter registry Circulation 2007;115:3181-3188.[Abstract/Free Full Text] 11. Jensen LO, Maeng M, Kaltoft A, et al. Stent thrombosis, myocardial infarction, and death after drug-eluting and bare-metal stent coronary interventions J Am Coll Cardiol 2007;50:463-470.[Abstract/Free Full Text] 12. Serruys PW, Ong ATL, Morice MC, et al. Arterial Revascularisation Therapies Study part II—sirolimus-eluting stents for the treatment of patients with multivessel de novo coronary artery lesions EuroInterv 2005;1:147-156. 13. Serruys PW, Ong AT, van Herwerden LA, et al. Five-year outcomes after coronary stenting versus bypass surgery for the treatment of multivessel disease: the final analysis of the Arterial Revascularization Therapies Study (ARTS) randomized trial J Am Coll Cardiol 2005;46:575-581.[Abstract/Free Full Text]
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