Meeting Report: ESC Forum on Drug Eluting Stents European Heart House, Nice, 27-28 September 2007

Drug-eluting stents (DES) were introduced into clinical practice in 2002 in order to reduce restenosis that occurred in 15–25% of patients receiving bare-metal stents (BMS).1–3 Subsequent trials with different types of DES confirmed their efficacy in this regard.4 However, late stent thrombosis was reported as early as 2004, typically in patients discontinuing dual anti-platelet therapy.5 At the European and World Congress of Cardiology in Barcelona 2006, alarming data were presented on a worse long-term prognosis following DES implantation compared with BMS.6,7 As a result both randomized controlled trials and registry data were scrutinized to validate these concerns, bearing in mind the differential values of both types of studies.8,9 Furthermore, the worldwide discussion on the long-term safety and efficacy of DES triggered the European Society of Cardiology together with the European Association for Percutaneous Cardiovascular Interventions to organize a forum on DES. On 27 and 28 September 2007, key opinion leaders in (interventional) cardiology and representatives from industry and regulatory bodies gathered in the European Heart House with the intention to review: (i) the most recent data on the long-term efficacy (reduction of restenosis, re-intervention) and safety (late stent thrombosis, myocardial infarction, mortality) of DES and its effects on outcome (survival, event-free survival), (ii) specific indications for DES; (iii) health economical analyses currently performed with DES; (iv) the DES registration process in Europe; (v) current and possible future trial designs. The overall goal was to provide general recommendations to the medical community for the use, clinical development, and future assessment of DES. In several randomized controlled trials comparing sirolimus-eluting stents (SES) or paclitaxel-eluting stents (PES) and BMS, increased rates of death or myocardial infarction were observed at follow-up, beyond the first year,6–8,10 while no excess of such events occurred in the first year.11–14 Subsequently, several pooled analyses of individual patient-level data from these and other trials indicated similar safety up to 4 years.15–18 In particular, the long-term safety of DES was assessed in a network meta-analysis, including 38 randomized controlled trials in over 18 000 patients.18 While there was no difference in mortality up to 4 years in patients initially treated with either BMS, SES, or PES, the SES was associated with a 19% lower risk for myocardial infarction (MI) as compared with BMS and 17% as compared with PES. In the latest report of the Swedish SCAAR registry (n = 35 262) presented at the ESC congress in Vienna 2007, the incidence of death and MI were similar between DES and BMS up to 4 years.19 However, the survival curves showed a short-term survival benefit with DES up to ∼1 year followed by a late catch-up.9 Thus, the apparent early benefit is lost by an excess of subsequent events. A pattern of lower initial and increased late mortality rates following DES use was reported by RAVEL2,7 and the Basel Stent Kosten Effektivitäts Trial (BASKET-LATE; DES: n = 281) investigators.10 While there was no significant difference in death and MI at 3 years, this was the net result of a higher 6 month survival and a higher incidence of late (>6 months) death, or MI following DES. According to the authors, this latter might be the consequence of the discontinuation of clopidogrel at 6 months.10 It is noteworthy that the impaired outcome with DES that was reported earlier by the SCAAR investigators in patients treated up to 2004 was no longer present in the current analysis, which included patients treated in 2005.9,19 Additionally, the Western-Denmark registry (n = 12 395), Ontario registry data (n = 13 353), and data from the state of Massachusetts demonstrated a trend towards a lower mortality rate following DES in the first months, which was maintained up to 2–3 years.20–22 Similarly, in an analysis of 6129 consecutive patients from Rotterdam, the Netherlands, the use of SES, but not PES, was associated with a significantly higher 3 year survival as compared with BMS.23 The survival benefit with SES became apparent as early as 3 months. The ENDEAVOR programme, evaluating a new zotarolimus-eluting stent, showed significantly lower cardiac death and MI rates for the DES as compared with BMS up to 3 years.24 It should be appreciated that follow-up in different trials, meta-analyses, and registries varies from 1 or 2 years to 5 years. These differences should be taken into consideration when comparing these studies. Furthermore, it should be appreciated that there may be important differences in both efficacy and safety among different types of DES as well as among BMS (Figure 1). Not all DES are equal, nor are BMS! If the trend of an early benefit with some DES, with a later excess of death and MI as observed in some studies, would persist, long-term outcome beyond 5 years might gradually favour some types of BMS. This is, of course, highly speculative! Nevertheless, it is desirable that the investigators will continue to provide such very long-term follow-up data. Restenosis at clinically driven re-angiography (data from the SCAAR registry presented by Dr S. James; ACC 2008). There are major differences for in-stent restenosis in BMS ranging from 7% to ≥10.5% at 3 years (upper series of curves) as well as among DES, ranging from 3.3% to ≥4.6% at 3 years (lower 5 curves). Restenosis at clinically driven re-angiography (data from the SCAAR registry presented by Dr S. James; ACC 2008). There are major differences for in-stent restenosis in BMS ranging from 7% to ≥10.5% at 3 years (upper series of curves) as well as among DES, ranging from 3.3% to ≥4.6% at 3 years (lower 5 curves). Stent thrombosis has been linked to a wide variety of pathophysiological mechanisms and clinical and procedural risk factors.6,25–28 It has been associated with mortality rates varying between 15 and 45%.29,30 Data from registries and meta-analyses6–10,16–24 indicated that there is no difference in the risk of early (<30 days) and late (>30, <365 days) stent thrombosis between DES and BMS, but that an excess risk emerges after more than 1 year of follow-up (very late stent thrombosis). The incidence of angiographically documented stent thrombosis in the combined Bern–Rotterdam experience with PES and SES was 0.6% per year, without any sign of reduction up to 4 years after stent implantation, and with slightly higher rates for PES than SES.31 A comparable rate of 0.5% was observed in the SCAAR registry.9 This suggests that endothelial healing remains impaired up to 4 years, at least in some patients and/or with some DES. Of interest were the recently presented 2 and 3 year follow-up of the ENDEAVOR I, II, and III trials, which showed remarkably low rates of stent thrombosis (0.0–0.3%) and no cases of stent thrombosis after 30 days.24 Of note, these pivotal studies evaluating the relative safety and efficacy of the zotarolimus-eluting stent were restricted to relatively simple lesions and patients. It is possible that this zotarolimus-eluting stent has a better safety profile than SES or PES. However, no direct comparative data are available. The results of the large E-Five registry and the 8800 patients randomized PROTECT trial are eagerly awaited. It should be appreciated that documentation of stent thrombosis by angiography underestimates the real incidence of such event, since some of the patients with stent thrombosis develop MI, or die without angiographic documentation of stent thrombosis. To address this issue, new definitions were formulated by a consortium of interventional cardiologists from both sides of the Atlantic, representatives of the Food and Drug Administration (FDA), clinical research organizations, and representatives from major stent manufacturers (Figure 2).32 ARC definitions of stent thrombosis ARC definitions of stent thrombosis The clinical trials as well as registries consistently confirm lower (target lesion) revascularization rates at follow-up with DES compared with BMS.9,16,18,20,21,33 However, the reduction of subsequent revascularization in registries was less than in clinical trials. The absolute reduction in target vessel revascularization at 4 years in a network meta-analysis of 38 clinical trials was about 12 vs. 2–4% in the Swedish SCAAR registry at 3 years.9,18 While the target lesion revascularization (TLR) rate in SCAAR (Swedish Coronary and Angioplasty Registry) did not reach 6% at 3 years in the DES arm,9 the network meta-analysis18 showed TLR rates up to 9% at 3 years with DES, a discrepancy that was even more apparent in patients treated with BMS and is most probably explained by systematic angiographic follow-up in many trials, and the lack of such angiography in the ‘real world’ registries. Data quality in the registries may be limited by the absence of event adjudication by blinded outcome assessors and lack of data query and verification, while patient and device selections are often operator dependent. In registries, patients treated with at least one DES are allocated into the DES cohort regardless of the number of simultaneously or previously implanted BMS, although clinical events in the mixed cohort may be related to either stent type. In many registries, the BMS group is a mixture of many different types of bare metal devices, with different outcomes. Similarly different DES are mixed while outcome may vary. This was illustrated from the SCAAR registry reporting restenosis rates per individual BMS types ranging from 7 to 11% at 3 years (Figure 1). For different DES 3 year restenosis rates varied between 3.3 and 4.6%. Finally, the interpretation of long-term follow-up data is hampered by cross-overs: patients who receive first one type of stent and then another type of stent at a later point of time, for example, for in-stent restenosis. Following the ‘intention to treat’ principle, all events were attributed to the first stent that was employed, while some new events may pathophysiologically be related to a second or third type of stent in that patient. In the original trial protocols, secondary stent thrombosis—stent thrombosis in a patient who had previously undergone target-lesion revascularization—was not considered to be a stent thrombosis. Consensus should be reached on how these events should be classified and reported. In interventional cardiology as well as in other fields of medicine, post hoc subgroup analyses should be interpreted with caution. These may provide important directions for additional research, but the conclusions may only be accepted if these are very strong, consistent among all studies, and based on plausible pathophysiology and experimental data. In general, the effects in with limited of patients and events are by the overall effects in the trials. a should be in this follow-up of the cohort of the registry showed a lower mortality in the DES a similar mortality rate from the of up to 6 months, but a significantly higher mortality rate from 6 to 2 years in patients treated with DES (n = as compared with BMS (n = rates following DES or BMS were similar in both the overall and in the A recent meta-analysis of trials including patients with MI showed no difference in the clinical of death and MI in these patients. However, most of the trials had a follow-up limited to 1 The recently presented 3 year results of the reported the safety and efficacy of SES (n = as compared with the randomized (n = and (n = of for patients with The that the higher clinical and angiographic risk profile of the the incidence of was significantly lower than in the and similar to the the significantly lower rates in as compared with associated with the rates compared with both These were in with the 3 year results of the Coronary Angioplasty vs. Coronary in n = similar rates of death, and MI up to 3 years in patients treated with DES as compared with either or with BMS and significantly lower revascularization in the group as compared with both of the was by an analysis of the randomized data from (n = and data from a registry of all in (n = 15 In these studies, the DES benefit was apparent in and patients with DES in the for revascularization in all lesion types and regardless of recent MI the benefit of DES was more limited but was apparent in and when both in the network meta-analysis, the number to to TLR was lower in patients as compared with patients.18 Of note, in a meta-analysis of pivotal randomized controlled trials, significant in the effects was for patients with or without The 4 year survival rates among patients without did not significantly between the while the survival rate for patients with was significantly lower in the SES group = from both and in (n = were more in the SES In the subgroup of patients with stent thrombosis more than 1 year after the was more among the patients with SES than among with BMS. to the low number of these should be interpreted with it not that the observed difference in survival among patients with in the in the network meta-analysis, no significant difference in mortality was observed in patients with trials comparing different stents in these patient are Drug when compared with BMS as an initial are associated with lower subsequent revascularization but an excess risk of late stent thrombosis, which not to on the of clinical death and myocardial infarction up to 4 years. the overall relative safety and efficacy of DES compared with BMS to be consistent different of at of absolute benefit and The long-term safety and efficacy of DES in patient such as and patients with MI remains to be There are important differences between the types of with and and subsequent differences in clinical all DES are equal, nor are of long-term follow-up data is hampered by and mixed DES and BMS patients who receive first one type of stent and another type of stent at a later point in time, for example, for in-stent restenosis. These new to the initial that to the of this and for to and in the to the of However, the current conclusions the safety and efficacy of DES should not the from the to continue of or to the about and of DES, and the higher of DES compared with BMS, health economical analyses been in different analyses were consistent In since the of has allocated a of for DES between the 12 in that was data from patients with at least 12 follow-up receiving only BMS or DES from 1 the of DES vs. BMS were ranging from very and lesions in A significant benefit (reduction of at in a limited group of patients with lesion and/or In its first of DES reported in the for and restricted the use of DES to and lesions based on assessment a The use of DES at that was while in practice the increased up to of patients in the In 2007, its second of DES in and that DES are not in any and be for patients with This was driven by a lower than for revascularization with BMS in patient lower than in the randomized controlled trials, with the very of DES that did not as Furthermore, the was driven by an in the differential between DES and BMS. This has been by and industry and has been the of It should be appreciated that the more the new the more and the of the that it is is to This may reduce the relative of the new its is The their in and their 3 year with the latest in and did in In the 18 month data presented from the follow-up were similar for both DES and BMS and relatively low to higher stent the use of DES was associated with an of In of clinical DES most in patients and while the showed no outcome in patients and lesions in of analyses that at 18 months, the for DES was if the use was limited to patients with of the patients into these the of SES in the Stent at Cardiology registry and that the SES was not at 1 or 2 years follow-up when compared with BMS. The per target vessel revascularization would be at 1 year, and at 2 years in the On the of these the after 1 year of follow-up is per SES for or to in the The of these analyses are that DES are not at the current for most patients for while the use of DES be in a of patients at risk for restenosis. It was that DES would for most patients if the relative to BMS, would not data on the use of DES for the indications of or as compared with either BMS use or are currently available. analyses are to the of BMS vs. DES and However, interpretation is when specific patient from clinical trials that might not the real clinical At the current DES be when in patients. DES would be in the of patients at a the of comparable BMS, or It is that the will be by the of both the new and The more the new the more and the of the is to This may reduce the relative of the new its is the analyses not to patients such as and with BMS was to a survival benefit over It is this survival benefit will be by the use of DES. Not at the The current to the use of DES in and that the additional of the DES are or less Drug-eluting stents are that of a medical device with a as an DES were classified as III medical and a with the of the to by the the will the clinical data related to and of the The assessment report of the is the for the of DES by the In 2007, at least different DES while at the of the only the first DES and were by the for Of note, the has recently a for the and DES. The Society of Cardiology the data DES with as reported in randomized controlled trials. 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The the for performed randomized controlled trials. While there is a for both such as death, MI, and revascularization as well as for such as late restenosis, and there is no on how to use both of these for trials at different in the and Furthermore, there are many with to the of when evaluating new DES there are studies that should use or medical most as the of for the if DES are compared with BMS, data presented from the SCAAR registry the point that on the of BMS (Figure 1). 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In this it should be appreciated that new often are on or A new process may not be for of an although this of DES be for that and or To reach a on these bodies indicated that will and with in an to the from both a and a There is a for in interpretation and for safety and and to and/or in the overall Of note, the of and medical while new up to 15 years, the of medical is ranging between 3 to 5 years. DES types are and will in the years with the intention to the current of DES. A wide variety of to the stent and are of is no longer the but the of more or stents At the time, of BMS with new and Thus, future trials should not only new and DES, but new DES with new BMS. for randomized controlled trials are These trials at an for clinical and are often in a 2 2 to different stents and to simultaneously the of anti-platelet For example, the trial might 000 with a first to with either a DES or a BMS and for receiving 12 or of dual anti-platelet has a similar with a 5 year follow-up for death, MI, and revascularization and years follow-up for will be for the In the currently PROTECT patients will be randomized to receive either a zotarolimus-eluting stent or an of this trial will be stent thrombosis at 3 years. On a the in which and regulatory are is a on DES thrombosis and dual anti-platelet The of this is to develop a more registration to of a and a device when there is an between the and the safety of the randomized trials and are currently evaluating the and of new anti-platelet and will on the between a possible reduction of cardiac events by more long-term anti-platelet at the of higher anti-platelet with the clopidogrel and the risk of stent thrombosis. However, low to clopidogrel is and the risk for stent thrombosis. is a to an in a of studies demonstrated that the to anti-platelet with either clopidogrel and is highly when the to clopidogrel is with A low of has been reported in of the patients. clopidogrel is a but with more of and and more consistent without the low with the 38 trial (n = 13 compared with clopidogrel when or and for 15 in patients with the risk of MI and the rate of stent thrombosis both with DES and with BMS. associated with an increased rate of major and in the in patients with a low and in with documented The net clinical benefit MI, and major in most in the trials will the new direct and or of clopidogrel and might these several of these should be at different in with or new Finally, the has been that longer dual anti-platelet will not only reduce the risk for stent thrombosis but will The is to the of a for assessment of DES. The of of the and such as ESC and is in the of such for This should be in and in order to new on the If the might be in with the controlled trials should to which should be followed by registries to both the and late In of the goal of results after current and future DES, of and should to registries of all or with quality and follow-up to registries. should be to the of since DES and BMS continue to randomized trials and registries, the real clinical are to be in their for reporting and quality to be and should be as clinically driven or driven angiographic follow-up, and to should be based on efficacy as of might be based on assessment of restenosis or and stent endothelial including clinical These data should be followed by the assessment of death, MI, and stent thrombosis over longer follow-up up to 5 trials are to the and and of long-term anti-platelet including the new more the for trials to be a 2 2 that a to device and anti-platelet Data from clinical trials and registries should be in the and investigators should to all data for analyses and/or pooled

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