Response to Letters Regarding Article, “Effect of Rosuvastatin Therapy on Coronary Artery Stenoses Assessed by Quantitative Coronary Angiography: A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound–Derived Coronary Atheroma Burden”
We thank Dr Kaneda and Drs Sutton, Blumenthal, and Kapur for their interest and commentaries on our analysis.1 In response to Dr Kaneda’s request for sensitivity analyses, we applied the same conservative assumptions employed in the intravascular ultrasound (IVUS) analysis2 to all noncompleters and to those with ischemic events and found that statistically significant regression occurred in both percentage diameter stenosis (%DS) and minimum lumen diameter.
With regard to the assessment of disease progression, as in previous quantitative coronary angiography (QCA) studies that we referenced,3 the prespecified outcome variable was the change in baseline stenoses >25%. This is very reasonable because some studies have shown that only progression of stenoses present at baseline was predictive of coronary events.4 In A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound–Derived Coronary Atheroma Burden (ASTEROID), 379 of the 507 randomized patients (75%) had both a baseline and a follow-up QCA study. Sixteen of these patients (4.2%) developed a new lesion of >25% stenosis that represented an increase of at least 20% from baseline. Of those 379 patients, the 292 (77%) with baseline stenoses >25% made up the QCA study population, and 12 (4.1%) of these 292 patients developed a new lesion.
We agree that it would be of interest for a meta-analysis to combine the actual patient values from multiple trials, because individual statin studies are not large enough to correlate on-therapy low-density lipoprotein cholesterol (LDL-C) levels with changes in imaging surrogate markers. We examined the values in this study and found the same trend that we reported for on-therapy LDL-C to be present for the percentage change in LDL-C (ie, the quartile with the greatest percentage lowering of LDL-C had more benefit in %DS and minimum lumen diameter than those with the lowest quartile of LDL-C lowering).
On the topic of differences between IVUS and QCA imaging, investigators were instructed to select 1 target artery for IVUS that was free of significant luminal narrowing (prespecified with no lesion ≥50%). The subsegment with greatest disease by IVUS was defined as the region with the most atheroma in the wall; it was independent of the angiogram. Thus, IVUS and QCA focused on different segments of the coronary arteries. The QCA segments were not aligned with IVUS data, preventing direct comparison in this study.
With regard to the comments by Drs Sutton, Blumenthal, and Kapur, the prior IVUS analysis from ASTEROID focused on progression and regression of atheroma in coronary arteries that were free of significant stenoses. The current QCA analysis focused on coronary segments with baseline stenoses and showed small but significant regression of %DS and minimum lumen diameter. This contrasts with the monotherapy studies in our figures that showed progression that was significantly less than that of the natural history of atherosclerosis demonstrated in their placebo arms.
Relative to the calculation of %DS, the reference lumen diameter appeared stable during the study: 2.62 (0.60) mm [mean (SD)] at baseline and 2.62 (0.59) mm at end of study. The changes in %DS and minimum lumen diameter thus correlated closely with each other (r=0.97, P<0.0001).
With regard to the cross-sectional area, as noted above, the QCA and IVUS studies focused on different regions of the coronary arteries. Thus, no direct comparisons were made between segment diameters imaged by QCA and lumen volumes determined by IVUS.
No data on QCA were presented in the apolipoprotein A-I Milano article. We agree that the relationship between changes in atheroma volume and luminal dimensions merits additional analysis to better understand remodeling. To examine this, we are performing additional analyses of the ASTEROID IVUS data.
Dr Ballantyne has received research grants from Abbott, ActivBiotics, Gene Logic, GlaxoSmithKline, Integrated Therapeutics, Merck, Pfizer, Schering-Plough, Sanofi-Synthelabo, and Takeda; has served on the speakers’ bureau for AstraZeneca, Merck, Abbott, Pfizer, Reliant, and Schering-Plough; and has served as a consultant or on an advisory board for Merck, Reliant, Abbott, AstraZeneca, Atherogenics, GlaxoSmithKline, Merck/Schering-Plough, Novartis, Pfizer, Schering-Plough, Sanofi-Synthelabo, and Takeda. Dr Raichlen is an employee of AstraZeneca. Dr Nicholls has received honoraria from Pfizer, AstraZeneca, Merck/Schering-Plough, and Takeda and has served as a consultant or on an advisory board for Pfizer, AstraZeneca, Roche, and Novo-Nordisk. Dr Erbel has served on the speakers’ bureau for Volcano and as a consultant or on an advisory board for Volcano. Dr Tardif has received research support and lectured for AstraZeneca and Pfizer. Dr Brener has received research grants from Proctor and Gamble (APEX trial), served on the speakers’ bureau for Medicines Company and BSC, received honoraria from Eli Lilly, and served as a consultant or on an advisory board for Sanofi and Lilly. V.A. Cain is an employee of AstraZeneca. Dr Nissen has received research grants from AstraZeneca, Eli Lilly, Takeda, Sankyo, Sanofi-Aventis, and Pfizer (all reimbursement is directed to the Cardiovascular Coordinating Center at the Cleveland Clinic; no personal reimbursement is accepted for directing or participating in clinical trials); has been on the speakers’ bureau for AstraZeneca and Pfizer (companies are directed to pay any honoraria related to lecturing directly to charity; no reimbursement is paid to Dr Nissen, and no tax deduction is involved); and served as a consultant or on an advisory board for AstraZeneca, Abbott, Atherogenics, Bayer, Lipid Sciences, Wyeth, Novartis, Pfizer, Sankyo, Haptogard, Hoffman-LaRoche, Kemia, Takeda, Kowa, Sanofi-Aventis, Protevia, Novo-Nordisk, Eli Lilly, Kos Pharmaceuticals, GlaxoSmithKline, Forbes Medi-tech, Vasogenix, Vascular Biogenics, Isis Pharmaceuticals, Viron Therapeutics, Roche, and Merck/Schering-Plough (companies are directed to pay any consulting fees directly to charity; no reimbursement is paid to Dr Nissen, and no tax deduction is involved).
Ballantyne CM, Raichlen JS, Nicholls SJ, Erbel R, Tardif J-C, Brener SJ, Cain VA, Nissen SE, for the ASTEROID Investigators. Effect of rosuvastatin therapy on coronary artery stenoses assessed by quantitative coronary angiography: A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound–Derived Coronary Atheroma Burden. Circulation. 2008; 117: 2458–2466.
Nissen SE, Nicholls SJ, Sipahi I, Libby P, Raichlen JS, Ballantyne CM, Davignon J, Erbel R, Fruchart JC, Tardif JC, Schoenhagen P, Crowe T, Cain V, Wolski K, Goormastic M, Tuzcu EM, for the ASTEROID Investigators. Effect of very high- intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006; 295: 1556–1565.
Herd JA, Ballantyne CM, Farmer JA, Ferguson JJ III, Jones PH, West MS, Gould KL, Gotto AM Jr, for the LCAS Investigators. Effects of fluvastatin on coronary atherosclerosis in patients with mild to moderate cholesterol elevations (Lipoprotein and Coronary Atherosclerosis Study [LCAS]). Am J Cardiol. 1997; 80: 278–286.