DEBATE ARTICLE

Drug-eluting stents for all patients

A.T.L. Ong, W.J. van der Giessen

Drug-eluting stents (DES) conclusively reduce clinical restenosis and the occurrence of major adverse cardiac events, both in randomised trials' with simple lesions and in heterogeneous populations where all-comers are enrolled,2 when compared with bare stents. Since the publication of our previous article in 2003,3 encouraging the use ofdrug-eluting stents in all patient subsets, to our knowledge only two other centres out of 18 in the Netherlands have taken up the challenge. In the Netherlands, most patients still receive bare stents: currently, DES account for only 40% of stent implantations, which is much lower than in the United Kingdom (60%) or Switzerland (90%). In the United States, which lagged behind Europe by one year, 85 to 90% of all patients now receive DES. Treatment benefit It remains inconceivable why other centres in the Netherlands have not adopted this technology to treat all their patients. Certainly, while restenosis does not alter the irreversible endpoint of mortality, preventing restenosis reduces morbidity and discomfort for the patient. From the RESEARCH registry, at two years the absolute risk reduction of clinically driven targetvessel revascularisation is 8% with DES, that is to say that for it requires only 12 patients to be treated to prevent one reintervention. The treatment benefit of DES applies to all patient subsets studied, both high and low risk. Table 1 presents our published results of DES use in various high-risk subgroups studied. Where performed, the comparison with bare stents is given, and reductions in events of between 48 to 79% are consistently seen in the groups studied.

A.T.L Ong W.J. van der Glessen Thoraxcentre, Erasmus Medical Centre, Rotterdam, the Netherlands

Correspondence to: W.J. van der Giessen Thoraxcentre, Ba-587, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands E-mail: [email protected]

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Netherlands Heart Journal, Volume 14, Number 5, May 2006

Expansion of Indications As devices for interventional cardiology improve, the scope of lesions that are treatable by percutaneous methods widens. Patients who were previously submitted for coronary artery bypass grafting can now be treated percutaneously using drug-eluting stents. Long-term results from the ARTS study demonstrate that mortality rates are similar in patients treated for multivessel disease irrespective ofwhether they were treated by bare metal stenting or bypass.4 To further scientifically determine the role of DES, studies are currently in progress comparing DES with CABG for three-vessel and left main disease (SYNTAX) and for diabetics with multivessel disease (FREEDOM).' Added benefits A previously undescribed added benefit ofdrug-eluting stent implantation in all patients is the reduction in asymptomatic restenosis. This benefit has added significance in the diabetic population. Patients who are completely revascularised consistently perform better than patients who are not completely revascularised, and by inference, patients receiving DES would be more completely revascularised than those who received bare stents, even after restenosis is treated, as there would be substantially less asymptomatic restenosis with DES.

Low-risk subgroups It is recognised that low-risk subgroups (short lesions, large vessels, in nondiabetic patients) benefit less than high-risk subgroups from DES.6 It is therefore tempting to consider DES for high-risk subgroups only. This is, however, incorrect as the absolute benefit of DES is still present in low-risk patients, and it would be unfair to penalise these patients by implanting a bare stent. Given the limited resources available from the authorities, it is recognised that one is often forced to prioritise as an inadequate response. Concems Concerns have been raised regarding the short- and long-term safety of drug-eluting stents, when used in large patient subsets, in an unrestricted way. The 171

Drug-eluting stents for all patients

Table 1. Published results of target-vessel revascularisation and major adverse cardiac events at 12-months follow-up in patient subgroups treated with drug-eluting stents at the Thoraxcentre of Erasmus Medical Centre. Target-vessel revascularisatlon DES (%) BMS (%)

Total population (n=958) Left main stem (n=181) Acute Ml (n=369) Chronic total occlusions (n=160) Bifurcations (n=207) Saphenous vein grafts (n=52) Small-vessel stenting (n=197) Multivessel stenting (n=527)

3.7 6.0 1.1

10.9 23.0 8.2

-

-

8.6 5.0 2.2 8.0

Major adverse cardiac events DES (%)

BMS (%)

9.7 24.0 9.4 3.6 10.3 16.0 7.7 10.0

14.8 45.0 17.0 17.9 -

-

Where comparisons with bare metal stents were performed, the results are also stated; all differences are statistically significant in favour of drug-eluting stents. DES=drug-eluting stents, BMS=bare metal stents, Ml=myocardial infarction.

longest follow-up ofpatients treated with DES is five years in the First-In-Man study in Brazil and four years in RAVEL. In 'real-world' patients, we now have twoyears of follow-up with sirolimus stents, which demonstrates sustained benefits over bare stents.7 Longterm follow-up is ongoing for both sirolimus and pacitaxel stents, and to date, no excessive untoward effects have been noted. Recently, there have been preliminary reports on endothelial dysfunction in vessels implanted with DES, but these have not been associated with adverse clinical outcomes to date.89 Concerns regarding stent thrombosis have been raised, and in our study of2500 patients the incidences were similar between DES and bare stents; however the study was underpowered to detect a difference, given its infrequent occurrence.'0 The incidence of late stent thrombosis (i.e. >30 days after stent implantation) was analysed too, and also found to be infrequent at 0.35% at a mean follow-up of 1.5 years. It will therefore take mega-trials including tens ofthousands of patients to detect a difference in late stent thrombosis compared with BMS. However, considering the serious consequences of late stent thrombosis it may remain of concern until true long-term results of drug-eluting stents in large population subsets can be determined." Cost-effectiveness While the effectiveness is certain, the other pertinent issue that has to be addressed is the issue of costeffectiveness. Formal cost-effectiveness studies in randomised trials differ from that seen in real-world studies. That is because in real-world studies, with less mandatory angiographic follow-up compared to randomised trials, the difference in effects is narrower. Although the RAVEL and SIRIUS studies both showed that sirolimus-eluting stents were cost-neutral at one year, we have recently presented data to show that DES were not cost-effective at the prices paid

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when they were initially introduced. Since then, DES prices have fallen, as have those of bare stents. However, as bare stent prices continue to fall, drug-eluting prices must also fall further in order to remain costeffective. This was confirmed in the BASKET trial. A huge but unrecognised advantage of implanting drug-eluting stents in all patients is the price reduction obtained with volume purchases and with sole-supplier agreements. Furthermore, as was predicted in our previous article, with the entrance of competitors, the cost of stents will and did come down. With the recent approval of the Medtronic zotarolimus system, we have a third major drug-eluting stent competitor. Other devices have also demonstrated efficacy and are awaiting approval, and it is expected that in the foreseeable future prices will continue to fall. More importantly, other smaller manufacturers will eventually successfully develop devices and obtain approval for them. For the time being, however, the current prices demanded per stent of approximately EI000 to E1450 are still unacceptably high. Both the government and insurance bodies possess the political power to exert downward pressure on the prices. However, given the inertia seen with both government and insurance bodies in approving drug-eluting stents in the Netherlands, it is currently left to the medical fraternity to push for lower prices. This puts doctors in a difficult and uncomfortable situation, as their primary role in society is to provide medical care, not to get involved in protracted price negotiations. But in the best interests of patients, it is imperative that they become involved to reduce prices, and to go ahead and implant DES, knowing that their patients are the ultimate beneficiaries. Conclusion

Drug-eluting stents irrefutably reduce restenosis, morbidity, and patient discomfort in all clinical settings. Netherlands Heart Journal, Volume 14, Number 5, May 2006

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Drug-eluting stents for all patients

Potential adverse late effects with drug-eluting stents probably occur no more frequently than with bare metal stents. The price of the device has fallen, and will continue to fall, but remains unacceptably high. More importantly, the role of the doctor is to provide the best medical care for the patient, and as such demands that drug-eluting stents are used for all. Failure to do so is unjustifiable and is tantamount to medical negligence. -

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Babapulle MN, Joseph L, Belisle P, Brophy JM, Eisenberg MJ. A hierarchical Bayesian meta-analysis of randomised clinical trials of drug-eluting stents. Lancet 2004;364:583-91. Lemos PA, Serruys PW, van Domburg RT, Saia F, Arampatzis CA, Hoye A, et al. Unrestricted utilization of sirolimus-eluting stents compared with conventional bare stent implantation in the "real world": the Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) registry. Circulation 2004; 109:190-5. Serruys PW, Ong AT. Wake up call for Dutch Cardiologists. Neth HeartJ2003;11:405-1 1. Serruys PW, Ong AT, van Herwerden LA, Sousa JE, Jatene AD, Bonnier JJ, et al. Five year Outcomes After Coronary Stenting versus Bypass Surgery for the Treatement of Multivessel Disease: The Final Analysis ofthe Arterial Revascularization Therapies Study (ARTS) Randomized Trial. JAm CollCardiol2005;46:575-81.

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Ong AT, Serruys PW, Mohr FW, Morice MC, Kappetein AP, Holmes DR, et al. The SYNergy between Percutaneous Coronary Intervention with TAXusrm and Cardiac Surgery (SYNTAX) Study: Design, Rationale and Run-In Phase. Am HeartJ2006. [In press] Molitemo DJ. Healing Achilles-sirolimus versus paclitaxel. NEngl JMed 2005;353:724-7. OngATL, van Domburg RT,Aoki J, Sonnenschein K, Lemos PA, Serruys PW. Sirolimus-Eluting Stents Remain Superior to Bare Metal Stents at 2 Years in the Real World - Long Term Results From the RESEARCH Registry. JAm Coll Cardiol 2006;47: 1356-60. Togni M, Wmdecker S, Cocchia R, Wenaweser P, Cook S, Billinger M, et al. Sirolimus-eluting stents associated with paradoxic coronary vasoconstriction. JAm Coll Cardiol 2005;46:231-6. Hofma SH, van der Giessen WJ, van Dalen BM, Lemos PA, McFadden EP, Sianos G, et al. Indication oflong-term endothelial dysfunction after sirolimus-eluting stent implantation. Eur Heart J2006; 27:166-71. Ong AT, Hoye A, Aoki J, Van Mieghem CA, Rodriguez Granillo GA, Sonnenschien K, et al. Thirty-Day Incidence and Six-Month Clinical Outcome ofThrombotic Stent Occlusion Following Bare Metal, Sirolimus or Paclitaxel Stent Implantation. J Am Coll Cardiol2005;45:947-53. Ong AT, Mc Fadden EP, Regar E, de Jaegere PP, van Domburg RT, Serruys PW. Late Angiographic Stent Thrombosis (LAST) Events with Drug-Eluting Stents. JAm Coll Cardiol 2005;45: 2088-92.

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