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DITORIAL COMMENT

he Process of Bringing Newrug-Eluting Stents to Marketill They See the Light of Day?*

avid R. Holmes, JR, MD, FACC,†anesh Patel, MD‡

ochester, Minnesota; and Durham, North Carolina

he ZoMaxx stent (Abbott Laboratories, Abbott Park,llinois) is a product that will likely never see the light of dayespite the performance of pilot human registry experiencesnd a randomized trial that enrolled 401 patients presentedn this issue of JACC: Cardiovascular Interventions (1). Theessons from an experience such as this have importantmplications that extend beyond the scope of this individualrial. These lessons are derived from issues relating toconomic and business considerations and trial design.

conomic and Business Issues

s is true with any proposed commercial product, the goalf business is to provide shareholder value, service to thentended consumer, and a return on investment. In the

edical field, in this particular situation with drug-elutingtents (DES), the considerations are complex—in part

See page 524

ecause of regulatory issues. These regulatory issues havemportant implications for business decisions. Bringing aomplex product such as a DES—in this case a trilayeromposite with two outer layers of 316L stainless steel andn inner layer of tantalum (which would have been veryaluable because it improves radio opacity); zotarolimus, arug specifically developed for use in DES without anyther application; and a polymer drug carrier of phospho-ylcholine—involves many hurdles. With the heightenedwareness of safety, specifically late and very late stenthrombosis, and the need for longer term surveillanceollow-up even after device approval, the costs of bringing aew stent to market have significantly increased. Some new

Editorials published in JACC: Cardiovascular Interventions reflect the views of theuthors and do not necessarily represent the views of JACC: Cardiovascular Interven-ions or the American College of Cardiology.

bFrom the †Mayo Clinic, Rochester, Minnesota; and ‡Duke University, Durham,orth Carolina.

tents may never be marketed in the U.S. because of thesenancial and regulatory hurdles, even though these newtents may have specific advantages such as improvedide-branch access or better deliverability in tortuous arterialegments. The ZoMaxx stent had potential advantages, as itas designed to “address the need for thin stent width and

ow profile, while maintaining radial strength and adequateisibility on fluoroscopy” (1).

At the same time, increasing numbers of stent technol-gies have amplified the relative competition in the field.ompetitive products deemed to have an advantage may

eapfrog other existing or developing technology. Given theong regulatory process, the field may change significantlyrom the point of product conception to device application,uch that a “new” technology may be obsolete before it isver approved or fully adopted.

In the particular case of the ZoMaxx stent, after acquiringnother company with a competitive DES, the manufac-urer (Abbott Laboratories) apparently decided to shelvehis specific DES. That may be a real loss to the fieldecause of the potential advantages that this unique stentay have had in terms of deliverability and enhanced radio

pacity (related to the tantalum).

rial Design Issues

andomized trials demonstrating clinical benefit are theoundation required for device approval and use. TheoMaxx trial was based upon the surrogate end point of late

umen loss. Surrogate end points are used with increasingrequency because they typically require smaller trial patientopulation sizes and thus can be carried out more quicklyith less cost. By definition, surrogates such as late loss

epresent only a part of the physiology and clinical effect ofdevice, and thus they have the potential disadvantage of

ot reflecting what the patient and clinicians are reallyoncerned about, namely, clinical outcome such as death,yocardial infarction, or repeat revascularizations.Selection of late lumen loss in this trial as the primary end

oint was probably made in part based upon the results ofhe intravascular ultrasound trial (2), which enrolled 40atients in Brazil and which documented in-stent andn-segment late lumen loss of 0.20 � 0.35 mm and 0.17 �.35 mm, respectively, at 4 months. The expectation of thetudy investigators would have been that, compared with theell-described late loss with Taxus stents (3,4), this endoint would be positive for the ZoMaxx stent. However, notnly was the late lumen loss not favorable for the ZoMaxxtent, it was even worse and statistically inferior. Of interest,espite failing to meet preset noninferiority criteria, thenvestigators spend considerable time and space discussingn the manuscript why this is not relevant because aretrospective analysis revealed that the inherent distur-

ances of normality, homogeneity, and similar shape were

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Holmes and Patel

Editorial Comment

534

ot met by either cohort” (1). Such post hoc retrospectivenalyses are not convincing for regulatory agencies oronvested parties.The reasons for the discrepancy between the pilot IVUS trial

esults may relate to differences in patient population andifferences in lesions treated. However, they also may relateo late lumen loss being measured at 4 months in the pilottudy but not until 9 months in this current study. That raiseshe possibility of late catch-up, which has now been docu-ented with another DES (Xience, Abbott Laboratories) (5).Yet another issue is the power calculation in these studies.f interest in this study are 8 patients who reportedly had

n impact on outcome. These 8 patients had treatment ofstial lesions and by random chance were all in the ZoMaxxtent group. In the final analyses, the presence of an ostialesion in only 8 patients was the most significant multivar-ate predictor of target vessel revascularization (p � 0.002).o have the development of a promising DES be decided inart on the random occurrence of 8 patients is disturbing.ad these patients been evenly distributed, the target lesion

evascularization rates might have been very different. In aighly competitive market, such small differences have great

mportance. The researchers conclude “that the efficacy of aiven DES continues to be difficult to predict empirically, andhat long-term comparative clinical testing of each new for-ulation is required prior to its widespread application.” This

s certainly true with the proviso that trial design and poweralculations must be optimized.

The final issue of a comparator is also important. Should allnew” DES be required to be compared with currently avail-ble DES? If so, which drug-eluting stent should be theontrol? Now with potentially 4 available DES, how arenvestigators, clinicians, and patients to decide and evaluate

hese different comparisons? Possibilities include the newest K

pproved DES, the DES with the longest track record (that iso say, the oldest one), or the newest bare-metal stent. Otherelated issues will be duration of follow-up and role ofost-market surveillance to name but a few.The ZoMaxx stent will presumably never see the light of

ay. In a time when the menu of DES in the pipelineemains relatively limited, the loss of a product that mightave substantial advantages is very real.

eprint requests and correspondence: Dr. David R. Holmes, Jr.,ayo Clinic, Cardiovascular Diseases and Internal Medicine, 200

irst Street, SW, Rochester, Minnesota 55905. E-mail:olmes.david@mayo.edu.

EFERENCES

. Chevalier B, DiMario C, Neumann F-J, et al., for the ZoMaxx IInvestigators. A randomized, controlled, multi-center trial to evaluatethe safety and efficacy of zotarolimus- versus paclitaxel-eluting stents inde novo occlusive lesions in coronary arteries: the ZoMaxx I trial. J AmColl Cardiol Intv 2008;1:524–32.

. Abizaid A, Lansky AL, Fitzgerald PJ, et al. Percutaneous coronaryrevascularization using a trilayer phosphorylcholine-coated zotarolimus-eluting stent. Am J Cardiol 2007;99:1403–8.

. Ellis SG, Popma JJ, Lasal JM, et al. Relationship between angiographiclate loss and target lesion revascularization after coronary stent implan-tation: analysis from the Taxus-IV trial. J Am Coll Cardiol 2005;45:1193–2000.

. Escolar E, Mintz GS, Popma J, et al. Meta-analysis of angiographicversus intravascular ultrasound parameters of drug-eluting stent efficacy(from Taxus IV, V, and VI). Am J Cardiol 2007;100:621–6.

. Serruys P. SPIRIT II study: a clinical evaluation of the Xience Veverolimus eluting coronary stent system in the treatment of patientswith de novo native coronary artery lesions. Presented at: AnnualScientific Session of the SCAI-ACC i2 Summit/American College ofCardiology, March/April 2008; Chicago, IL.

ey Words: DES � randomized clinical trial.