High-risk population among patients who were deferred PCI based on FFR
The FAME trial concluded that FFR-guided PCI had an advantage over angiography-guided PCI in decreasing major adverse cardiac events for up to 2 years after the index procedure. (14) The DEFER trial reported that deferral of PCI for intermediate coronary stenosis based on an FFR ≥ 0.75 was associated with favorable outcomes during the very long-term follow-up period. (15) These trials established FFR measurement as a common tool for evaluating myocardial ischemia in a cath lab by a feasible and reproducible method with a clear cut-off point. Recently, the IRIS-FFR study analyzed the relationship between the FFR value and the HR for deferred versus revascularized lesions based on a multivariable model predicting major adverse cardiac events, including cardiac death, myocardial infarction, and repeat revascularization. The two lines intersected at an FFR value of 0.79. (5) An FFR of 0.75–0.80 is considered as a gray zone for the prognostic performance of PCI. Therefore, we adopted an FFR of 0.80 as the cut-off level for deferral of PCI, and patients with FFR > 0.80 were analyzed in this trial.
There is limited evidence to stratify the risk of MACCE development in patients with deferred PCI. To clarify the high-risk population among these patients, we performed further stratification of patients with FFR > 0.80. We adopted a cut-off value of 0.85 with regard for MACCE based on the results from the IRIS-FFR registry. The registry reported that the HR of major adverse cardiac events was 2.48 (95% CI:1.47–4.20) in lesions with an FFR of 0.81–0.85 and 1.60 (95% CI:0.91–2.80) in lesions with an FFR of 0.86–0.90, in comparison to lesions with an FFR of 0.91-1.0. (5) Our results showing that the MACCE rate was higher in patients with an FFR of 0.81–0.85 than in patients with an FFR > 0.85 were consistent with the results from the IRIS-FFR registry. Multivariate analysis also showed that FFR values could be predictor of MACCE in patients whose PCI was deferred on the basis of the FFR value. These results suggested that patients with an FFR of 0.81–0.85 were a high-risk population among patients whose PCI was deferred on the basis of FFR values, and that these patients should be followed up closely even after deferral of PCI.
Lipid-lowering therapy in patients with deferred PCI on the basis of FFR
Secondary prevention of cardiovascular events by lipid control in patients who underwent PCI has been established based on evidence from various studies; (6, 10) however, treatment guidelines for patients with deferred PCI based on FFR measurement have not been established. In real clinical settings, some patients, especially those without a history of PCI, fall out of monitoring by cardiologists and do not receive sufficient lipid-lowering therapy. Indeed, the present study, which assessed real-world LDL-C management after FFR measurement, revealed that the mean LDL-C level at 1 year after FFR measurement was far from the target LDL-C level for secondary prevention. Of course, at this point, LDL-C level should be controlled under 70 mg/dL as a target level for secondary prevention in patients at high risk for cardiovascular events. However, in the real clinical settings, the numbers of patients with LDL-C level were very limited. Therefore, we adopted 100 mg/dL as a cut-off value of LDL-C in this study. In addition, patients did not receive sufficient lipid-lowering therapy regardless of the FFR value in the present study. There was no statistical difference in LDL-C values at 1 year after FFR measurement between patients with an FFR of 0.81–0.85 and those with FFR > 0.85.
In the current study, we reported the different prognostic effects of LDL-C management according to the patients’ FFR values. An uncontrolled LDL-C level was associated with a higher MACCE rate in patients with an FFR of 0.81–0.85, who were at a relatively higher risk of MACCE among patients whose PCI was deferred. In contrast, the LDL-C level was not associated with the MACCE rate in patients with FFR > 0.85, who were at a relatively lower risk of MACCE among patients whose PCI was deferred. Multivariate Cox regression analysis showed that the LDL-C level was an independent predictor even after adjusting for covariates in patients with an FFR of 0.81–0.85, but not in patients with FFR > 0.85. Additionally, the interaction between the FFR population (FFR of 0.81–0.85 or FFR > 0.85) and LDL-C groups (lower or higher LDL-C groups) was statistically significant. These results indicate the importance of LDL-C control, especially in patients with an FFR of 0.81–0.85. Of note, these results do not indicate that LDL-C management is less important in patients with FFR > 0.85. All patients with intermediate coronary stenosis, which were performed FFR measurement, should be received intensive LDL-C management. However, as shown in this study, LDL-C management have been insufficient after FFR measurement in real clinical practice. Therefore, as the first step, the risk stratification presented in this study is an important new perspective.
A close correlation has been reported between achieved LDL-C levels and the changes in the atheroma volume in a prior trial using intravascular ultrasound. (16) According to the GLAGOV randomized trial, an intensive LDL-C-lowering therapy with PCSK9i resulted in a greater decrease in the percent atheroma volume than a normal control. (17) One report described LDL-C control and FFR values for lesions after PCI, and showed that an LDL-C value over 70 mg/dL was associated with an increased FFR value for the target vessel at 18 months after PCI. (18) Since insufficient LDL-C control was associated with a high MACCE rate in patients with an FFR of 0.81–0.85 but not in those with FFR > 0.85, insufficient LDL-C could cause an atheroma volume increase or a destabilization of lipid plaque, leading to myocardial ischemia. These results suggest that patients whose PCI was deferred on the basis of an FFR of 0.81–0.85 should be followed up closely and should receive sufficient lipid-lowering therapy.
This study has several limitations that should be acknowledged. First, this was a retrospective observational study performed in a single center with a relatively small number of patients. Second, the cut-off LDL-C value was 100 mg/dL in our study, although the guidelines recommended LDL-C < 70 mg/dL as the target for patients with a very high cardiovascular event risk, such as patients with previous acute coronary syndrome and familial hypercholesterolemia. (10) The reason was mentioned in discussion part. However, the average LDL-C value in the lower LDL-C group was approximately 74 mg/dL in both FFR groups. Thus, LDL-C control in the lower LDL-C group nearly achieved the strict target under the guideline recommendations. Third, our study excluded patients with multiple intermediate stenoses that required separate FFR measurements because they could not be allocated into subgroup based on FFR value. Therefore, patients with a relatively lower severity of atherosclerosis may have been selected for analysis in the current study. Considering the lower-the-better strategy for LDL-C management, a randomized controlled study to verify the impact of strict LDL-C management in high-risk patients with deferred PCI is warranted.