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CLINICAL RESEARCH: INTERVENTIONAL CARDIOLOGY

Angiographic Surrogate End Points in Drug-Eluting Stent Trials

A Systematic Evaluation Based on Individual Patient Data From 11 Randomized, Controlled Trials

Stuart J. Pocock, PhD^_*, Alexandra J. Lansky, MD, FACC, Roxana Mehran, MD, FACC, Jeffrey J. Popma, MD, FACC, Martin P. Fahy, MSc, Yingbo Na, MSc, George Dangas, MD, PhD, FACC, Jeffrey W. Moses, MD, FACC, Tereza Pucelikova, MD, David E. Kandzari, MD, FACC, Stephen G. Ellis, MD, FACC^¶, Martin B. Leon, MD, FACC and Gregg W. Stone, MD, FACC^,_*

^_* London School of Hygiene and Tropical Medicine, London, United Kingdom
Columbia University Medical Center and the Cardiovascular Research Foundation, New York, New York
Brigham and Women’s Hospital, Boston, Massachusetts
Duke University Medical Center, Durham, North Carolina
^¶ Cleveland Clinic Foundation, Cleveland, Ohio.

Manuscript received April 11, 2007; revised manuscript received July 27, 2007, accepted July 30, 2007.

^_* Reprint requests and correspondence: Dr. Gregg W. Stone, Columbia University Medical Center, The Cardiovascular Research Foundation, 111 East 59th Street, 11th Floor, New York, New York 10022. (Email: gs2184{at}columbia.edu).

Objectives: We sought to validate 4 angiographic measures as potential surrogates for clinical restenosis (target lesion revascularization [TLR]) after stent implantation.

Background: Given the low revascularization rates with drug-eluting stents (DES), an angiographic surrogate of TLR is desirable to reduce the sample size required to demonstrate efficacy in future trials of antirestenosis devices.

Methods: We evaluated 4 potential angiographic measures (late loss [LL] and percent diameter stenosis [%DS], both in-stent and in-segment) as a surrogate for TLR at 1 year. From 11 multicenter, prospective randomized stent trials, 9 comparing DES with bare-metal stents (BMS) and 2 comparing different DES, individual data on 5,381 patients with a single treated lesion and follow-up angiography at 6 to 9 months were analyzed.

Results: By 4 well-defined criteria of surrogacy, LL and %DS strongly predicted the risk of TLR, with in-segment %DS being the most highly predictive (0.95). Differences in TLR risk were fully explained statistically by their differences in LL or %DS, although LL as a surrogate was dependent on vessel size whereas %DS was not. However, because of the curvilinearity of the logistic model, trials comparing 2 effective DES can have significant differences in mean LL and %DS but small expected differences in TLR risk, especially at the lower ranges of LL and %DS.

Conclusions: From in-stent and in-segment LL and %DS measures, logistic models can reliably estimate TLR rates for DES and BMS. These angiographic measures are thus suitable surrogate markers for clinical stent efficacy and can be used as primary end points in future DES trials to significantly reduce sample size.

Abbreviations and Acronyms   BMS = bare-metal stent(s)   DES = drug-eluting stent(s)   %DS = percent diameter stenosis   LL = late loss   MLD = minimal lumen diameter   PCI = percutaneous coronary intervention   RVD = reference vessel diameter   TLR = target lesion revascularization

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