Key Points:
- Adverse cardiovascular events can still occur from atherosclerotic events in non-culprit coronary arteries
- Evidence suggests lipid lowering therapy can significantly reduce the burden of disease in these segments, but analyses are lacking that investigate these effects on high-risk, high plaque burden segments of coronary arteries
- The FITTER study investigated PCSK-9 inhibitor therapy vs placebo on the background of high-intensity to treat high-risk non-culprit lesions identified in the setting of ACS in patients with multivessel coronary artery disease
- Though LDL was more reduced in the PCSK-9 inhibitor group, there were no significant differences between groups in either physiologic or imaging-based anatomic primary outcomes or secondary outcomes, perhaps in part due to study size, treatment effect, and/or short study length
Though many successful treatments exist for atherosclerotic cardiovascular disease (ASCVD), many patients still experience adverse cardiovascular events. Numerous studies suggest that this residual cardiovascular risk is largely due to non-culprit lesions in coronary artery segments that are left untreated at times that an acute lesion is being treated. In the past few decades, notable trials using intracoronary imaging evaluation have demonstrated that aggressive lipid lowering therapy can reduce total atheroma burden and lower lipid content for patients with coronary artery disease (CAD). In particular, PCSK-9 inhibitors demonstrate reduced LDL and improved plaque composition and lipid content post-acute coronary syndrome (ACS). However, questions remain as to the viability of aggressive lipid-lowering therapy as a treatment for non-culprit coronary lesions in the setting of ACS, even as a replacement for additional PCI. As such, the FITTER study aimed to determine the effect of PCSK-9 inhibitor therapy with evolocumab in addition to high-intensity statin therapy (HIST) on non-culprit coronary lesions as measured by fractional flow reserve (FFR) and multimodality intracoronary imaging.
The FITTER study was a multicenter double-blind placebo controlled randomized clinical trial among ACS patients that demonstrated multivessel disease (MVD) on coronary angiogram with successful culprit PCI but also had at least one non-culprit lesion with FFR 0.67-0.85. After screening 2406 patients with ACS, 150 participants were enrolled and either randomized to 12 weeks of PCSK-9 inhibitor therapy with evolocumab or placebo, with both groups on HIST in the background. Notable exclusion criteria included complications in infarct-related artery (IRA) treatment, prior CABG, untreated left main (LM) stenosis, LVEF < 30%, DAPT contraindication, known severe cardiac valve dysfunction, kidney disease (eGFR < 30), severe liver disease, or pregnancy or upcoming desire for pregnancy. Primary outcomes included a physiologic parameter, change in FFR at 12 weeks, and an imaging-based parameter, change in lipid core burden index 4mm (maxLCBI4mm) using intravascular ultrasound-near infrared spectroscopy (IVUS-NIRS) at 12 weeks. Secondary outcomes included change in percent atheroma volume (PAV), normalized total atheroma volume (TAV), maximum plaque burden (PB), and minimum lumen area (MLA).
A total of 2406 patients were screened but only 150 enrolled, 75 to high intensity statins and evolocumab and 76 to high intensity statins plus placebo. The primary analysis included 69 patients in the FFR and 45 in the IVUS/NIRS. Patient groups were overall balanced with respect to age, sex, and morbidities, though 82% of patients enrolled overall were men. Notably, 27% of patients included were on any statin therapy and 10% of patients overall on HIST at baseline. Regarding ACS presentation, 35.3% were STEMI, 60.0% were NSTEMI, and 4.7% were unstable angina.
The evolocumab group showed a significantly larger reduction in LDL-C compared to placebo (-2.8 mmol/L vs –1.6 mmol/L; p < 0.001). Regarding primary outcomes, there was no significant change in FFR over 12 weeks nor were there significant difference between groups (baseline vs 12-week FFR: 0.78 ± 0.05 vs 0.78 ± 0.07); similarly, there was no significant change in maxLCBI4mm over 12 weeks nor were there significant difference between groups (baseline vs 12-week maxLCBI4mm: 358.5 ± 175.5 vs 321.3 ± 170.5). Regarding secondary outcomes, change in baseline vs 12-week nTAV and max PB started to approach significance (nTAV: -9.00 [95% CI: -18.09 to 0.09]; p = 0.05) (max PB: -0.81 [95% CI: -1.64 to 0.02]; p = 0.05). However, none of the secondary outcomes showed significant difference between the evolocumab group vs placebo.
Ultimately, the study authors note multiple conclusions. There were no ischemic events associated with coronary lesions in this study within this high-risk study population. Notably, with intensive lipid-lowering therapy post-ACS, non-culprit lesion lipid content decreased within 12 weeks. However, there were no differences in both primary outcomes of change in FFR nor maxLBCI4mm after 12 weeks of intense lipid-lowering therapy.
These results may be due to limitations as acknowledged by the study authors. This was a smaller study overall with wide confidence intervals. There were a high percentage of statin naive patients (75%) with already large treatment effect on HIST only (LDL-C reduction of 50%). Lastly, the study was run over a short treatment period (12 weeks). Ultimately, the study does raise important questions of the utility of high-intensity lipid lowering therapy as an approach to high-risk non-culprit lesions identified in the context of ACS.