Author + information
- Hector M. Garcia-Garcia, MD, MSc, PhD†∗ (, )
- Carlos M. Campos, MD†,‡ and
- Patrick W. Serruys, MD, PhD†
- †Department of Interventional Cardiology, Erasmus University Medical Centre, Thoraxcenter, Rotterdam, the Netherlands
- ‡Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil
- ↵∗Reprint requests and correspondence:
Dr. Hector M. Garcia-Garcia, Thoraxcenter – Erasmus Medical Center, z120 Dr Molerwaterplein 40, 3015 GD Rotterdam, the Netherlands.
Women are under-represented (range from 8% to 68%) in most lipid-lowering randomized clinical trials. Meta-analysis data from 170,000 participants showed that women had a significant proportional risk reduction of 16% (99% confidence interval: 3% to 27%; p = 0.002 per 1.0 mmol/l decrease in low-density lipoprotein cholesterol [LDL-C]) of the combined endpoint of coronary death, nonfatal myocardial infarction coronary revascularization, and stroke (1). Is this because women had a greater change in intravascular ultrasound (IVUS) percentage atheroma volume (PAV) in progression/regression trials, as shown in this substudy of the SATURN (Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin) study (2)? This observation has not been proven to be a consistent one. In the ASTEROID (A Study To Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden) study, in which high dose rosuvastatin was administered, the findings were at variance with the current report (Table 1). Men had slightly larger regression than women. Of note, the IVUS analyses were performed under the same standard operating procedures in the same analysis core laboratory in both studies. Why did the differential impact of rosuvastatin and atorvastatin on plaque regression in women was not reproduced?
In the SATURN trial subgroup analysis, overall (taking both groups together: rosuvastatin- and atorvastatin-treated patients) women had a greater reduction in PAV (–1.52 ± 0.18% vs. –1.07 ± 0.10%, p = 0.03) (2), but only in cases with LDL-C levels <70 mg/dl. Interestingly, the percentage of women that achieved LDL-C levels <70 mg/dl was smaller compared to men (61.7% vs. 65.0%, respectively). Thus, women showed more regression despite that they were fewer achieving the target of LCL-C. Taken all together, it is interesting to see that even in the best-case scenario, namely in the context of a large randomized clinical trial, less than two-thirds of patients achieved the per protocol target (LDL-C levels <70 mg/dl).
Is percentage atheroma volume the best parameter to compare women versus men? The percent atheroma volume with as numerator atheroma volume and as denominator vessel volume, may mask the specific directional changes in its numerator and denominator (3) when used as primary endpoint to compare 2 pharmacological agents or 2 groups; it has, though, a lower variation (smaller SD) than atheroma volume and therefore has been used as a primary endpoint in many IVUS studies. In Table 2, it can be seen that, looking purely at the actual atheroma size changes without normalizing for the vessel volume, in all studies with the exception of the ASTEROID trial, women showed more atheroma volume regression than men.
Additional lessons learned from previous progression/regression trials, in general:
1. The larger the PAV at baseline is, the larger the regression in PAV is (4).
2. The larger the reduction in LDL-C is, the larger the regression in PAV is (5).
3. The higher the increase in high-density lipoprotein cholesterol (HDL-C) is, the larger the regression in PAV is (5).
4. The larger the reduction in C-reactive protein (CRP) levels is, the larger the regression in PAV is (6).
Yet, in this substudy from the SATURN trial, women had a larger regression in PAV compared to men, despite the fact that women had smaller plaques at baseline and they had on average higher levels of CRP. As mentioned previously, women, in lipid-lowering trials, had a reduction of the combined endpoint of coronary death, nonfatal myocardial infarction coronary revascularization and stroke. Moreover, in another substudy of the SATURN trial, the CRP levels were associated with major adverse cardiac events (MACE) (7), which makes it harder to dissect this complex interplay between women and CRP and their association with MACE.
Is it then the greater reduction in PAV in women related to the fact that they had on treatment lower LDL-C and higher HDL-C values? In this report (SATURN trial gender analysis), compared with men, women had higher HDL-C at baseline and follow-up. In the REVERSAL (Reversing Atherosclerosis with Aggressive Lipid Lowering) trial (8), the patients with HDL-C above the mean who were treated with atorvastatin had a regression of –1.5% (p = 0.97 for the comparison with baseline), but not their counterparts. At variance, in this SATURN trial gender analysis, irrespective of the baseline HDL-C (above or below the mean), there was a significant reduction in PAV. Thus, the association of atheroma changes and HDL-C need to be further elucidated.
Many of the lessons learned in previous progression/regression trials have been challenged in this gender report of the SATURN study. In order to get clarity on whether there is a differential impact of gender on coronary atheroma size or these changes in plaque size are due to other potential confounding factors, we would like to encourage the authors to pool the data of the SATURN, ASTEROID, and REVERSAL studies to further elucidate these observations.
↵∗ Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
All authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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- Puri R.,
- Nissen S.E.,
- Shao M.,
- et al.
- Van Mieghem C.A.,
- Bruining N.,
- Schaar J.A.,
- et al.
- Puri R.,
- Nissen S.E.,
- Libby P.,
- et al.