Clinical Decision-Making for the Hemodynamic "Gray Zone" (FFR 0.75-0.80) and Long-Term Outcomes

Abstract: Background. Fractional flow reserve (FFR) value between 0.75 and 0.80 is considered the “gray zone” and outcomes data relative to treatment strategy (revascularization vs medical therapy alone [deferral]) are limited for this group. Methods and Results. A total of 238 patients (64.3 ± 8.6 years; 97% male; 45% diabetic) with gray-zone FFR were followed for the primary endpoint of major adverse cardiovascular event (MACE), defined as a composite of death, myocardial infarction (MI), and target-vessel revascularization. Mean follow-up duration was 30 ± 17 months. Deferred patients (n = 48 [20%]) had a higher prevalence of smoking and chronic kidney disease compared with the percutaneous coronary intervention (PCI) group (n = 190 [80%]; P<.05). Patients who underwent PCI had significantly lower MACE compared with the deferred patients (16% vs 40%; log rank P<.01). While there was a trend toward a decrease in all-cause mortality (8% vs 19%; log rank P=.06), the composite of death or MI was significantly lower in the PCI group (9% vs 27%; P<.01). On multivariate Cox proportional hazards regression analysis, PCI was associated with lower MACE (hazard ratio, 0.5; 95% confidence interval, 0.27-0.95; P=.03). Conclusion. Revascularization for patients with gray-zone FFR was associated with a significantly reduced risk of MACE compared with medical therapy alone. 

J INVASIVE CARDIOL 2017;29(11):371-376. Epub 2017 April 15.

Key words: coronary artery disease, percutaneous coronary intervention, major adverse cardiovascular event

Fractional flow reserve (FFR)-guided revascularization using a cut-off value ≤0.80 has been shown to be clinically and economically effective as demonstrated by the landmark FAME (Fractional flow reserve versus Angiography for Multivessel Evaluation) trial.¹ This threshold has been endorsed by the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA)/Society for Cardiovascular Angiography and Interventions (SCAI) and European Society of Cardiology/European Association for Cardio-Thoracic Surgery in their guideline documents on percutaneous coronary intervention (PCI).^2,3 However, original validation studies had identified a FFR value of <0.75 to be the best correlate of inducible ischemia on non-invasive tests.^4,5 Subsequently, the DEFER study showed the safety and efficacy of deferring PCI for up to 15 years in patients with FFR ≥0.75.⁶ The FAME trials used an FFR value of ≤0.80 to guide PCI,^1,7 and PCI was superior to medical therapy alone using this cut-off in the FAME 2 trial.⁷ A recent meta-analysis has suggested the outcome-derived FFR threshold for intervention to be somewhere in the 0.75-0.80 range.⁸ Hence, FFR values between 0.75 and 0.80 are considered to constitute a “gray zone” for clinical decision-making, with studies showing conflicting results on the benefits of revascularization.^9-11 Therefore, we sought to compare the impact of PCI with medical therapy alone on long-term outcomes among real-world patients with FFR values in the gray zone. 

Methods

Study population. We retrospectively evaluated all patients who were referred for coronary angiography between January 2009 and December 2014. Consecutive patients with FFR in the gray zone (0.75-0.80) were included in the analysis. The study was approved by the institutional review board of the Central Arkansas Veterans Healthcare System.

Measurement of FFR. FFR was performed using guide catheters without side holes with either the Volcano or St. Jude Medical pressure-wire system. The wire was positioned in the distal artery for FFR measurement. Intracoronary (IC) nitroglycerin was administered prior to FFR measurement. Maximal hyperemia was induced by either intravenous (IV) adenosine infusion at a rate of ≥140 µg/kg/min (50%) or by IC adenosine at a dose ≥60 µg (50%). The decision to perform PCI or defer the patient for medical management was at the operator’s discretion.

Data collection and clinical endpoints. We reviewed inpatient and outpatient electronic records in the Computerized Patient Record System (CPRS) and Veterans Affairs Information System Technology and Architecture (VISTA) databases. Clinical, angiographic, and PCI data were manually extracted after reviewing all the available records. 

The primary study endpoint was major adverse cardiac event (MACE), defined as a composite of death, myocardial infarction (MI) not related to intervention, and target-vessel revascularization (TVR). MI was defined as a clinical syndrome of ischemic symptoms and a rise in serum troponin >99th percentile of the reference value or IC thrombus in the target vessel with or without new ischemic ST and T changes.¹²TVR was defined as subsequent revascularization of the index vessel by either PCI (additional stent or angioplasty) or coronary artery bypass graft of the target vessel. Target-vessel failure (TVF) was defined as a combination of target-lesion revascularization (TLR)/TVR or MI attributed to the target vessel. Clinical outcomes were adjudicated independently by a review committee blinded to the patient’s clinical information. In case of more than one event, only the first event was counted for the Kaplan-Meier analysis.

Statistical analysis. Patient groups (PCI and deferred) were compared using the independent Student’s t-test or one-way ANOVA for continuous variables and the Chi² test for categorical or dichotomous variables. Unadjusted annual event rates were calculated by first estimating overall event rates through calculation of Kaplan-Meier curves, then dividing the event rate by the mean follow-up time for each group. Stepwise multivariate Cox proportional hazards regression was used to identify independent predictors of MACE and TVF. Statistically significant variables in the univariate model and potential predictors of adverse outcomes were selected and included in the multivariate model. The number of covariates entered into the model was restricted to maintain ≥10 events per degree of freedom at each step with only significant variables (<.05) carried further in the analysis. The level of statistical significance was set at .05, and a two-sided probability value was used for the analyses. All statistical calculations were performed using MedCalc Statistical Software version 15.2.1 (MedCalc Software) and IBM SPSS Statistics version 23.

Results

Patient characteristics. A total of 1135 patients (1460 lesions) underwent FFR evaluation between January 2009 and December 2014. A total of 238 patients (251 lesions) with FFR values in the gray zone (0.75-0.80) were included in the analysis; 190 patients (80%) underwent PCI and 48 patients (20%) were deferred for medical therapy alone. 

Baseline clinical and angiographic characteristics of the gray-zone groups based on treatment strategy are listed in Table 1. The deferred group had more clinical risk factors including smoking (56% vs 27%; P<.01), chronic kidney disease (29% vs 14%; P<.01), and use of statin (94% vs 82%; P=.04). Patients in the PCI group had a higher stenosis rate (63.9 ± 13.3% vs 52.1 ± 13.0%; P<.01) and lower FFR value (0.78 ± 0.02 vs 0.79 ± 0.02; P<.01), while the deferred group had a higher prevalence of multivessel disease (54% vs 37%; P=.03). Drug-eluting stent (DES) was used among 160 patients (84%) in the PCI group (Table 1).

Events at follow-up. Fifty patients (21%) in the gray zone had 55 MACEs during a follow-up of period of 30 ± 17 months. There were 24 all-cause deaths (48%), 6 MIs (12%), 25 TVRs (50%), and 26 patients with TVF (52%, or 47% of all MACEs). There were 5 patients (10%) with both MI and TVR (Table 2). 

On Kaplan-Meier survival analysis, PCI patients had significantly lower MACE rate vs the deferred group (16% vs 40%; log rank P<.01) (Figure 1). Similarly, TVF (8% vs 21%; log rank P=.02) (Figure 2) and MI (1% vs 8.3%; P<.01) (Figure 3) rates were lower in the PCI group vs the deferred group. However, there was only a trend toward a decrease in TVR (8% vs 19%; log rank P=.06) (Figure 4) and all-cause mortality (8% vs 19%; log rank P=.06) (Figure 5). The composite of death or MI was also significantly lower in the PCI group vs the deferred group (9% vs 27%; P<.01) (Figure 6).

Predictors of MACE in patients with gray-zone FFR. Clinical and angiographic characteristics of patients with and without MACE are listed in Table 3. Patients with MACE (vs non-MACE) were older (66.8 ± 9.8 years vs 63.6 ± 8.1 years; P=.02), more likely to be smokers (50% vs 31%; P=.01), and less likely to be treated with PCI (62% vs 85%; P<.01). In the stepwise multivariate Cox proportional hazards regression model, with MACE as the outcome variable, age (hazard ratio [HR], 1.04; 95% confidence interval [CI], 1.01-1.08; P<.01), smoking (HR, 1.9; 95% CI, 1.05-3.36; P=.03), and PCI (HR, 0.5; 95% CI, 0.27-0.95; P=.03) were found to be independently predictive of MACE. Other variables that were not significant included chronic kidney disease (HR, 0.61; 95% CI, 0.26-1.42; P=.30) and acute coronary syndromes (HR, 1.24; 95% CI, 0.68-2.26; P=.50). 

Discussion 

Our study demonstrates that in an unselected population with gray-zone FFR, the risk of downstream adverse events was significantly higher in the deferred group vs patients treated with PCI. This risk not only included TVF (TVR + MI) but also “hard endpoints” including MI and composite of death/MI. 

Based on the DEFER study, stable patients with FFR >0.75 can safely be deferred to medical therapy without increase in adverse events.¹³ However, in the DEFER study, mean FFR was 0.86 ± 0.06 in the deferred arm and 0.87 ± 0.07 in the PCI arm, signifying a very low proportion of gray-zone patients. A few non-randomized studies^14-16 have suggested the safety of deferring gray-zone patients. These studies were relatively small, with low-risk patients who had predominantly single-vessel disease.^13-15 Subsequently, it has been suggested that revascularization may be safely deferred in various higher-risk groups with FFR >0.75 including acute coronary syndromes,¹⁷ multivessel disease,¹⁸ and left main disease.¹⁹ Similar to the DEFER trial, the major limitation in all these studies was that the mean FFR value of the deferred population was >0.85,^13-19 suggesting that the proportion of patients in the gray zone was relatively low. Our study exclusively evaluated patients with gray-zone FFR, demonstrating higher event rates with deferral (40%) vs those who underwent PCI (16%) at a follow up of 30 ± 17 months. Our study included complex patients with multiple cardiac risk factors, acute coronary syndromes, and multivessel disease.

The role of revascularization (combined coronary artery bypass graft surgery and PCI) in patients with gray-zone FFR was first retrospectively evaluated by Courtis et al, who followed 107 patients for 13.6 ± 7 months. They showed that MACE rates were significantly lower in the revascularization group vs the deferred group (8% vs 28%, respectively; P<.01) during the follow-up period. Events were primarily driven by TVR.⁹ Later, Lavi et al followed 281 patients with borderline FFR (defined as FFR 0.75-0.90) for a median duration of approximately 20 months.²⁰ They compared the outcomes between deferred group and two revascularization groups (bare-metal stent [BMS] and DES). Patients treated with DES (12%) had outcomes similar to the deferred group (16%). However, patients treated with BMS were likely to have more MACEs vs the deferred group (28% vs 16%; P=.04). A major limitation of the study is that the FFR in the deferred group was significantly higher than in the DES and BMS groups (0.85 vs 0.79 vs 0.78; P<.01).²⁰ They also showed that the event rates in the deferred group decreased as the FFR increased,²⁰ so it is plausible that if only patients with gray-zone FFR were included, the results of the DES group might have been similar to our study, where DES implantation (84%) was predominantly used during PCI.

In a recent study, 453 patients with gray-zone FFR were treated with either revascularization (187 patients) or deferred to medical therapy (266 patients) and followed for a median duration of 26 months and 25 months, respectively.¹¹ There was no significant difference in MACE rate between the revascularization and deferred groups in the study (11.2% vs 13.9%; P=.30). However, there was a strong trend toward lower rates of death or MI (4.8% vs 9.4%; P=.06) and overall death (3.2% vs 7.5%; P=.06). Additionally, the study showed that the deferred patients with gray-zone FFR had increased rates of death or MI (9.4% vs 4.6%; P=.03), overall death (7.5% vs 2.9%; P=.02), and cardiovascular death (2.3% vs 0.2%) compared with deferred patients with borderline FFR (defined as 0.81-0.85 in their study). Based on these results, the authors strongly advocated revascularization in patients with gray-zone FFR.¹¹ Our study supports revascularization in gray-zone FFR patients, as it is associated with lower rates of MACE, TVF, and MI. Our study also showed a strong trend toward decrease in overall death (8% vs 19%; P=.06). 

There is one study with results at variance with those noted above; Lindsteadt et al¹⁰ reported on 97 patients with gray-zone FFR who were followed for 24.2 ± 16.6 months. The MACE rate in the revascularization group was significantly higher vs the deferred group (44.9% vs 18.8%; P<.01) despite similar symptoms among both groups (69.4% vs 77.1%; P=.39).¹⁰ One possible reason could be higher overall MACE reported by Lindsteadt et al (32%) compared with Courtis et al (15.9%),⁹ Adjedj et al (12.3%),¹¹ and our study (21%). This was possibly because they included any vessel revascularization in their definition of MACE,¹⁰ while others (including our study) included TVR.^9,11 At least 11% of MACEs were not associated with target vessel in their study. After excluding these events, the adverse event rate (20.6%) was similar to our study.

TVR rates were also different in previous studies, with only one study reporting a significant improvement in the TVR rates in the revascularization group vs the deferred group (23% vs 5%; P<.01),⁹ while the other two studies reported no significant difference.^10,11 In our study, even though there was no statistically significant difference, there was a trend toward decrease in TVR rates in the PCI group (8% vs 19%; P=.06). However, TVF, which was not reported in the previous studies^9-11 was significantly lower in the PCI group (8% vs 21%; P=.02). In most studies, including the FAME 2 trial, MACE is driven by reduction in the TVR^7,9 without any difference in mortality with revascularization,^7,9,10,20 except for our study and Adjedj et al,¹¹ where there was a trend toward reduction in overall death (P=.06). 

There were more active smokers and chronic kidney disease patients in the deferred group vs the PCI group. However, after multivariate analysis, only smoking was independently associated with adverse outcomes. Smoking has consistently been shown to predict adverse outcomes after revascularization²¹ and also in patients who have been treated medically.²² While smoking cessation has shown to improve the outcomes,²² data on smoking cessation rate in general practice are sparse. Importantly, in our analysis of gray-zone patients, PCI was associated with decreased adverse events even after adjusting for the smoking status in the Cox regression analysis. Another important factor is to understand that FFR has a continuous and independent relationship with adverse outcomes,²³ and an arbitrary cut-off of <0.80 has been validated in the FAME trial¹ and accepted by the ACCF/AHA and SCAI.²

The role of intravascular ultrasound (IVUS) to further refine the management strategy of patients in the gray zone was recently reported by Lin et al.²⁴ They showed that IVUS- guided PCI was similar to patients deferred based on IVUS, but superior to medical therapy deferred based on FFR alone. Patients who were deferred to medical therapy based on IVUS also had superior outcomes than patients deferred to medical therapy based on FFR alone. IVUS-guided PCI patients had higher plaque burden and lower minimal luminal diameter and area.²⁴ However, further studies are needed to confirm these results and also to elucidate the role of imaging modalities like IVUS to further risk stratify gray-zone FFR patients, and to identify those in whom PCI will be beneficial. 

Clinical implications. We have shown that in patients with FFR in the gray zone, compared with medical therapy alone, PCI was associated with a significantly lower rate of adverse events during extended follow-up. For symptomatic patients who are suitable candidates for revascularization (favorable risk-benefit ratio), PCI (in addition to optimal medical therapy) should be considered to reduce the risk of subsequent MACE. 

Study limitations. First, this is a retrospective, single-center, observational study of predominantly male patients. Second, selection bias might have been possible, especially regarding the gray zone, as the decision for PCI or medical therapy might not have been solely based on the FFR value. Third, angiograms were not reviewed by an independent core laboratory. Instead, they were evaluated by the operator who made clinical decision for PCI or medical therapy; this approach, however, is reflective of “real-world” practice. Another major limitation is the small patient population, especially of the deferred group. IC adenosine was used in one-half of the cases at doses of at least 60 µg. We do not have recorded information about the IC adenosine doses in all patients.

Conclusion

In an all-comer coronary artery disease population with gray-zone FFR, PCI was associated with lower incidence of adverse events (MACE, MI, and TVF) compared with medical therapy alone. These results suggest the value of PCI in this patient group. 

References

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From the ¹Division of Cardiovascular Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas; and ²Division of Cardiovascular Medicine, Central Arkansas for Veterans Healthcare System, Little Rock, Arkansas.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted October 11, 2016, provisional acceptance given November 21, 2016, final version accepted November 30, 2016.

Address for correspondence: Abdul Hakeem, MD, Division of Cardiovascular Medicine, Central Arkansas Veterans Health System, 4300 West Seventh Street, Little Rock AR 72205. Email: ahakeem@gmail.com