Very Long-Term Clinical Follow-up After Fractional Flow Reserve-Guided Coronary Revascularization
- Volume 24 - Issue 7 - July 2012
- Posted on: 6/29/12
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Baseline laboratory measurements and use of medications were similar between both groups (Table 2). Following index cardiac catheterization, use of all medication classes increased in comparison to presentation with the exception of nitrates and calcium channel blockers. The proportion of patients using clopidogrel on discharge was significantly higher in the initial revascularization group (85.7%) compared to the deferred group (38.7%; P<.001).
Follow-up was complete in all but 3 patients (97%). All 3 patients with unknown follow-up status were in the deferred group. The mean length of follow-up was 5.9 years in the initial revascularization group and 6.2 years in the deferred group (P=.50). During the follow-up period, death occurred in 20 patients (35.1%) in the initial revascularization group and 21 patients (22.3%) in the deferred group (P=.13; Table 3). The cause of death was unknown in most cases in the initial revascularization group, while a non-cardiac cause of death was most common in the deferred group. Survival in both groups is shown by means of Kaplan-Meier curves, and no significant difference was noted (P=.30; Figure 1).
Subsequent MI occurred in 15 patients (26.3%) in the initial revascularization group, and 23 patients (24.5%) in the deferred group (P=.80). Late revascularization of the index lesion was subsequently performed in 7 patients (12.3%) in the initial revascularization group and 10 patients (11.7%) in the deferred group (P=.84). At the end of follow-up, 59.6% of patients in the initial revascularization group were alive and free of angina, compared to 64.9% of patients in the deferred group (P=.64). Revascularization status of the index lesion at the time of FFR was not a predictor of death, MI, or late revascularization when examined in a univariate analysis or multivariate model.
In addition, 39 patients had a total of 40 lesions with an FFR measurement in the so-called FFR “grey zone,” between 0.75 and 0.80. Initial revascularization was performed on 20 of these patients and 19 were deferred. Of the 20 patients who underwent initial revascularization, 17 (85%) underwent PCI; the remaining 3 patients (15%) underwent CABG. The mean length of follow-up in this small subgroup was 5.7 years, though 2 of the patients had an unknown clinical status at the end of follow-up. Long-term clinical outcomes in this small group of patients were similar to those of the overall cohort, and no significant differences between the initial revascularization and deferred groups were noted (Table 4).
Randomized clinical trials have shown that an FFR-guided revascularization strategy is safe, effective, and reduces overall healthcare costs in the short-term (1-2 years).8-10 Our data obtained in a non-randomized, real-world setting suggest that there are no adverse long-term outcomes associated with use of an FFR-guided revascularization strategy for intermediate-severity coronary lesions. We believe our cohort has one of the longest follow-up periods of patients undergoing FFR-based revascularization, and includes a higher-risk patient population than most prior analyses.14-17
The two largest randomized trials evaluating the use of FFR are the FAME study and the Deferral of Percutaneous Coronary Intervention (DEFER) study. In the FAME study, lesions with >50% stenosis were first identified as targets for percutaneous intervention based on angiography, and patients were then randomized to a routine angiography-guided intervention or an FFR-guided approach.8 In the DEFER study, stable patients with intermediate coronary lesions (>50% stenosis) and no evidence of reversible ischemia were randomized to deferral or performance of PCI, and FFR was used to guide therapy in the deferral arm only.9 While these two trials compare the use of an FFR-guided strategy to the usual angiography-guided care, our analysis examines long-term outcomes when the FFR-guided PCI strategy supported by these studies is applied to patients in a non-randomized fashion.
In comparison to FAME and DEFER, our overall cohort is most similar to the FFR arm of FAME: all patients in this group underwent FFR evaluation and PCI was performed on lesions with FFR ≤0.80. The deferred group in our study is most similar to the deferred group in DEFER: all patients in this group also underwent FFR evaluation, and no PCI was performed based on the results (FFR ≥0.75). It must be acknowledged that the patients enrolled in FAME were scheduled for coronary intervention, whereas our patients were referred for both diagnostic studies and PCI. Long-term clinical outcomes from FAME, DEFER, and other studies are available, with varied results. In FAME, 2-year rates of death, MI, and CABG or PCI in the FFR arm of the study were 2.6%, 6.1%, and 10.6%, respectively.14 In DEFER, 5-year rate of both cardiac and non-cardiac death was 3.3% in the deferred group. Target vessel revascularization was performed in 8.9% in this group, and no Q-wave or non-Q wave MIs were noted.15 When compared to these trials, our cohort had a much higher rate of death and MI, regardless of whether revascularization was performed or deferred, though the rate of subsequent revascularization was similar.
The higher rate of adverse outcomes in our cohort is likely explained by the longer follow-up period, the high proportion of patients presenting with an acute coronary syndrome, and the high degree of medical co-morbidities present. DEFER was a study of patients with stable coronary disease and no ischemia on stress testing, and while a similar proportion of patients included in FAME presented with unstable angina, our patient group had a much higher incidence of diabetes and hypertension when compared with these trials.8,9 Also, as a non-randomized, real-world analysis, our study population likely includes patients with medical co-morbidities, such as cancer, chronic kidney disease, and severe heart failure, that might otherwise preclude patients from inclusion in a randomized controlled trial. Overall, our cohort represents a sicker population when compared with most studies of FFR, including previously reported results from other non-randomized cohorts.16,17
Study limitations. There are several limitations to our study. First, our analysis is a non-randomized observational cohort study: FFR of intermediate coronary lesions was performed according to operator discretion — not per protocol —as would be the case in a randomized controlled trial. As such, unrecognized confounders may have entered into the clinical decision to initially perform an FFR measurement, or in the ultimate decision regarding revascularization. Our inclusion of only a small number of lesions over a decade-long period suggests this is the case, despite the fact that the same operators performed the procedures over the entire course of the study period. Since we did not examine data on patients in whom FFR was not performed, it is difficult to discern the rationale behind FFR use in each case compared to those in which it was not performed.
One possibility is that these unmeasured confounders may have selected for a lower-risk patient group, as higher-risk patients may have been felt to have a greater need for aggressive revascularization without further ancillary coronary testing. Given the comparatively high burden of co-morbid conditions in our patient group, and the mortality rate of approximately 28% over a mean of 6 years, we feel this is unlikely to be true.
Certainly, operator comfort and expertise in performance and interpretation of FFR, as well as trends in the overall use of FFR, changed over the study period. As the accumulated data pool supporting the use of FFR has grown, so has the use of FFR in our laboratory, raising the possibility that there may also be unrecognized differences in FFR use among patients included in earlier and later parts of the study. Additionally, more recent trends in technique of FFR measurement, including utilization of increased adenosine doses for increased sensitivity, are not captured with our data.18
The ability to capture follow-up events that did not occur within our medical system was also limited. Although many of our patients exclusively receive medical care within the VA healthcare system, and significant hospitalizations and cardiac events were likely to be captured in the electronic medical record even when occurring outside of our system, it is possible that significant clinical events were missed. Likewise, while patient deaths occurring outside of the VA system are recorded in the medical record, data useful in determining a cause of death were limited. Follow-up was also incomplete in 3 patients. An additional analysis in which a “worst case scenario” of repeat revascularization, MI, and cardiac death was assigned to the 3 missing patients was performed and no significant alterations in the overall findings of this cohort study were found.
Our study began in the era prior to drug-eluting stents and concluded in 2005 when a large majority of procedures were done with these devices. It is possible that our results would have been different if all the procedures were done in the current era, but this limitation is inherent in any study evaluating very long-term outcomes since therapies change over time.
Finally, our study represents a small cohort of male patients at a single VA medical center. Though no significant differences in outcomes of interest were noted, the small sample size of our study limits our ability to detect such differences with certainty. As such, findings should be interpreted with caution. Further, the temptation to interpret our analysis as a comparison of initial revascularization and deferral of revascularization of equivalent lesions must be resisted: in our real-world analysis of our application of an FFR-guided revascularization strategy, we are only able to compare the long-term results of initial revascularization of hemodynamically significant lesions with deferral of those lesions that were angiographically suspicious yet ultimately hemodynamically insignificant as measured by FFR. Given that our results are largely consistent with those found in larger randomized trials, we believe that this analysis adds to the accumulating data supporting the use of FFR in guiding revascularization decision-making for lesions of intermediate angiographic severity in the cardiac catheterization laboratory.