Outcomes of DES in Real World Practice: Realizing the Potential
Since the approval of the drug-eluting stents (DES) in April of 2003 by the U.S. Food and Drug Administration (FDA) and a year earlier in Europe, the rise of DES had been phenomenal, a feat rarely seen in contemporary medicine. With much lower in-stent restenosis compared to their bare metal counterparts, use of DES in interventional cardiology immediately become the default choice in the cardiac catheterization laboratory. The randomized trials that led to the approval of both initial DES [sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES)] were applicable to a highly select group of patients with select types of lesions ("on-label use"), SES were approved only for use in the de novo lesions of ″ 30 mm in length and vessel diameter of ≥2.5 mm and ″ 3.5 mm whereas PES for de novo lesions of ″ 28 mm with diameter ≥2.5 mm and ″ 3.75 mm. However, a dramatic reduction of both angiographic and clinical ISR (5–6% at 6 months compared to that of nearly 30% with bare metal stents (BMS), a benefit that seemed to persist even at 4 years following intervention encouraged the interventionalists to use these stents even for lesions not studied in the trials ("off-label use"). Extrapolation of the efficacy data from the pivotal trials have led these stents to be quickly adopted as the panacea in coronary intervention. Like any other success story, this practice has quickly come to the scrutiny of regulators, and reports of adverse outcomes such as stent thrombosis (both early and late) with the use of DES started to pour in. In response to these reports of the adverse events, the FDA convened a panel to review all the data available from DES trials. It was the consensus recommendation of this panel that there is no increased risk of stent thrombosis from the on-label use of DES. In spite of this recommendation, use of drug-eluting stents for off-label indications (in-stent restenosis, bypass graft lesion, long lesions, vessel size > 3.75 mm <2.5 mm, left main lesions, ostial lesions, bifurcation lesions or for chronic total occlusions) has been reported to be as high as 47–55%. Off-label use of DES is associated with higher adverse events (death, MI, or stent thrombosis) both at 30 days and at 1 year.
In this issue of the journal, Ramsdale et al. report 1-year outcome of 411 patients from their single center, prospective registry of DES use for "off-label" indications among patients presenting with both stable angina (60%) and non-ST elevation acute coronary syndromes (40%) between January 2003 and December 2006. Their lesions mainly included lesions > 20 mm long, vessel size <3.0 mm diameter, chronic total occlusion, bifurcation lesions, aorto-ostial lesions, left main lesions, post-rotational atherectomy, lesions in or beyond saphenous vein grafts, patients with multi-vessel disease, several lesions in a single vessel, patients with ISR, and those with diabetes mellitus. Nearly two thirds of their patients had single vessel PCI, and two thirds had multi-lesion PCI. All patients were followed for at least 12 months (range 12–59; mean 34.3 months). A total of 9 deaths with 1 death due to ruptured hemorrhagic MI following rescue PCI and eight deaths (1 cardiac and 7 non-cardiac) during the 1–5 years of follow-up were reported. Among the 402 survivors at 12 months, more than 80% patients were free of angina, 18% with very occasional or minimal angina and nearly 2% frequent angina. The target vessel failure (TVF) was about 6% with a TVR rate of 5% due to in-stent restenosis (ISR). After 1 year of follow-up, total major adverse cardiac events (MACE) were nearly 4% (Q-wave MI 0.2%, death 1.2%, TVR 3.1%, late stent thrombosis 0.2%). Beyond 1 year after implantation, 2 patients had very late stent thrombosis at 14 and 24 months respectively (0.5%).
The authors have done an excellent job in presenting their outcome data in a very succinct and elaborative way. Most of their patients had complex coronary lesions and a large number of their patients also presented with non-ST elevation acute coronary syndrome. In spite of these adversities, their one year outcome paralleled the results seen in the randomized trials with DES in terms of low rate of MACE and TVR over longer term follow up. However, their study had several limitations. This is a prospective registry from a single center with all the interventions done by a single operator, and included a relatively small number of patients with no control group to which to compare the results.
In the just presented Synergy between PCI with Taxus and cardiac surgery (SYNTAX) trial at the European Society of Cardiology Congress 2008 in Munich, Germany, 1800 patients with left main disease or 3 vessel disease were randomized to multivessel PCI or coronary bypass graft surgery (CABG). At one year, major adverse cardiovascular end points (composite of death, MI, stroke or TVR) were 12% with CABG versus 18% with DES, and the non-inferiority criteria with the CABG were not met. There were no statistical differences between two groups in terms of death/MI/stroke or all cause death. TVR was more frequent with PCI (14% with PCI versus 6% with CABG, p <0.0001) whereas stroke was more frequent with CABG (2.2% with CABG versus 0.6% with PCI, p = 0.003). This trial validates the feasibility and safety of PCI in patients with left main lesions or with 3 vessel disease even though the need for repeat interventions remains to be the main limitation of PCI.
In summary, the best outcome of PCI with the DES comes with the on-label use of these stents. However, when done in the appropriate settings and by the expert operators, similar outcomes can be achievable even with their off-label use.
Since the approval of the drug-eluting stents (DES) in April of 2003 by the U.S. Food and Drug Administration (FDA) and a year earlier in Europe, the rise of DES had been phenomenal, a feat rarely seen in contemporary medicine. With much lower in-stent restenosis compared to their bare metal counterparts, use of DES in interventional cardiology immediately become the default choice in the cardiac catheterization laboratory. The randomized trials that led to the approval of both initial DES [sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES)] were applicable to a highly select group of patients with select types of lesions ("on-label use"), SES were approved only for use in the de novo lesions of ″ 30 mm in length and vessel diameter of ≥2.5 mm and ″ 3.5 mm whereas PES for de novo lesions of ″ 28 mm with diameter ≥2.5 mm and ″ 3.75 mm. However, a dramatic reduction of both angiographic and clinical ISR (5–6% at 6 months compared to that of nearly 30% with bare metal stents (BMS), a benefit that seemed to persist even at 4 years following intervention encouraged the interventionalists to use these stents even for lesions not studied in the trials ("off-label use"). Extrapolation of the efficacy data from the pivotal trials have led these stents to be quickly adopted as the panacea in coronary intervention. Like any other success story, this practice has quickly come to the scrutiny of regulators, and reports of adverse outcomes such as stent thrombosis (both early and late) with the use of DES started to pour in. In response to these reports of the adverse events, the FDA convened a panel to review all the data available from DES trials. It was the consensus recommendation of this panel that there is no increased risk of stent thrombosis from the on-label use of DES. In spite of this recommendation, use of drug-eluting stents for off-label indications (in-stent restenosis, bypass graft lesion, long lesions, vessel size > 3.75 mm <2.5 mm, left main lesions, ostial lesions, bifurcation lesions or for chronic total occlusions) has been reported to be as high as 47–55%. Off-label use of DES is associated with higher adverse events (death, MI, or stent thrombosis) both at 30 days and at 1 year.
In this issue of the journal, Ramsdale et al. report 1-year outcome of 411 patients from their single center, prospective registry of DES use for "off-label" indications among patients presenting with both stable angina (60%) and non-ST elevation acute coronary syndromes (40%) between January 2003 and December 2006. Their lesions mainly included lesions > 20 mm long, vessel size <3.0 mm diameter, chronic total occlusion, bifurcation lesions, aorto-ostial lesions, left main lesions, post-rotational atherectomy, lesions in or beyond saphenous vein grafts, patients with multi-vessel disease, several lesions in a single vessel, patients with ISR, and those with diabetes mellitus. Nearly two thirds of their patients had single vessel PCI, and two thirds had multi-lesion PCI. All patients were followed for at least 12 months (range 12–59; mean 34.3 months). A total of 9 deaths with 1 death due to ruptured hemorrhagic MI following rescue PCI and eight deaths (1 cardiac and 7 non-cardiac) during the 1–5 years of follow-up were reported. Among the 402 survivors at 12 months, more than 80% patients were free of angina, 18% with very occasional or minimal angina and nearly 2% frequent angina. The target vessel failure (TVF) was about 6% with a TVR rate of 5% due to in-stent restenosis (ISR). After 1 year of follow-up, total major adverse cardiac events (MACE) were nearly 4% (Q-wave MI 0.2%, death 1.2%, TVR 3.1%, late stent thrombosis 0.2%). Beyond 1 year after implantation, 2 patients had very late stent thrombosis at 14 and 24 months respectively (0.5%).
The authors have done an excellent job in presenting their outcome data in a very succinct and elaborative way. Most of their patients had complex coronary lesions and a large number of their patients also presented with non-ST elevation acute coronary syndrome. In spite of these adversities, their one year outcome paralleled the results seen in the randomized trials with DES in terms of low rate of MACE and TVR over longer term follow up. However, their study had several limitations. This is a prospective registry from a single center with all the interventions done by a single operator, and included a relatively small number of patients with no control group to which to compare the results.
In the just presented Synergy between PCI with Taxus and cardiac surgery (SYNTAX) trial at the European Society of Cardiology Congress 2008 in Munich, Germany, 1800 patients with left main disease or 3 vessel disease were randomized to multivessel PCI or coronary bypass graft surgery (CABG). At one year, major adverse cardiovascular end points (composite of death, MI, stroke or TVR) were 12% with CABG versus 18% with DES, and the non-inferiority criteria with the CABG were not met. There were no statistical differences between two groups in terms of death/MI/stroke or all cause death. TVR was more frequent with PCI (14% with PCI versus 6% with CABG, p <0.0001) whereas stroke was more frequent with CABG (2.2% with CABG versus 0.6% with PCI, p = 0.003). This trial validates the feasibility and safety of PCI in patients with left main lesions or with 3 vessel disease even though the need for repeat interventions remains to be the main limitation of PCI.
In summary, the best outcome of PCI with the DES comes with the on-label use of these stents. However, when done in the appropriate settings and by the expert operators, similar outcomes can be achievable even with their off-label use.
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