Long-Term Patient-Related and Lesion-Related Outcomes After Real-World Fractional Flow Reserve Use

Abstract: Background. Long-term clinical outcomes of real-world use of fractional flow reserve (FFR), including the decisions against FFR, have not been fully evaluated in the era of drug-eluting stent (DES) implantation. Methods. A total of 1294 patients who underwent FFR measurement for de novo coronary lesions were included. FFR measured lesions (n = 1628) were divided into FFR-defer or FFR-stent lesions according to the treatment strategy selected after FFR measurement. Clinical outcomes were assessed by patient-related major adverse cardiac event (a composite of all-cause death, myocardial infarction, and any revascularization) and target-lesion related event (target-lesion related myocardial infarction and revascularization). Results. Mean FFR was 0.80 ± 0.12, and FFR was ≤0.8 in 728 lesions (44.7%). Five-year cumulative all-death rate was 6.3%, myocardial infarction rate was 1.5%, and rate of any revascularization was 12.5%. Among 797 deferred lesions, 105 lesions had FFR ≤0.8 and those lesions had a higher risk of 5-year target-lesion related events than the lesions with FFR >0.8 (21.2% vs 6.6%, respectively; P=.03). By multivariate analyses, the determinant for the 1-year target-lesion related events was the presence of diabetes (hazard ratio, 3.74; 95% confidence interval, 1.45-9.67; P=.01), while the determinant for delayed events at 1-5 years was FFR ≤0.8 (hazard ratio, 4.50; 95% confidence interval, 1.65-12.28; P=.01). Angiographic lesion severity was not an independent predictor for clinical events during follow-up among deferred lesions. Conclusion. The deferral of stenting according to FFR was associated with favorable long-term outcomes. Presence of diabetes and low FFR (≤0.8) increased the risk of clinical events in deferred lesions. 

J INVASIVE CARDIOL 2015;27(9):410-415

Key words: coronary, stenosis, fractional flow reserve, outcome

___________________________

Fractional flow reserve (FFR) is an invasive physiologic index that can be easily measured in the cardiac catheterization laboratory to assess the presence of myocardial ischemia or the need for revascularization.^1-4 Recent randomized trials showed that an FFR-guided revascularization strategy was better than angiography-guided drug-eluting stent (DES) implantation, and DES implantation for functionally significant stenosis reduced the need for urgent revascularization compared with medical therapy alone.^5-7 Therefore, the use of FFR is increasing in daily clinical practice. 

In real-world practice, FFR is measured for angiographically intermediate or ambiguous lesions and revascularization is performed without FFR when there is a clinically-indicated culprit lesion.⁸ In those cases, the outcome of a patient is determined by both FFR-measured lesions and stented lesions without FFR.⁹ Furthermore, the decision to perform revascularization is sometimes made by the clinical and anatomical information as well as FFR value. As residual stenosis after revascularization is reported to be associated with increased risk of future cardiovascular events,^10-12 some operators believe that the clinical judgment against FFR may improve patient outcomes, especially when second-generation DESs are used. However, long-term clinical outcomes of real-world FFR use, including the decisions against FFR, have not been fully evaluated in the DES era.

We performed this study to comprehensively evaluate the long-term patient-related and target-lesion related clinical outcomes after FFR use in real-world clinical practice in four Korean centers. 

Methods

Patient population. This study was a multicenter registry conducted in four Korean centers. Eligible patients had at least one de novo lesion located in major epicardial coronary arteries in which FFR could be successfully measured. Patients with planned or previous bypass surgery, cardiomyopathies, balloon angioplasty only, and congenital coronary anomaly were excluded. In patients who had a clinically indicated culprit lesion(s), the culprit lesion was revascularized without FFR measurement followed by FFR measurement for the other stenoses.

Study procedure. The target vessel was engaged using a 5-7 Fr guiding catheter. Angiographic images were acquired after intracoronary administration of 100-200 µg of nitroglycerin. FFR was measured using a 0.014˝ pressure guidewire (PressureWire [St. Jude Corporation] or ComboWire [Volcano Corporation]), as previously described.¹ Hyperemia was induced with an intracoronary bolus (80 µg in left coronary artery, 40 µg in right coronary artery; n = 471), intracoronary continuous infusion of adenosine (240 µg/min; n = 443), or intravenous continuous infusion of adenosine (140 µg/kg/min; n = 380).^13-15 The decision to perform additional invasive tests and whether to treat the target lesion was left to operator discretion after FFR measurement. The FFR-measured lesions (FFR-lesions) were divided into FFR-defer (deferral of stenting after FFR measurement regardless of FFR value) or FFR-stent lesions (stenting after FFR measurement regardless of FFR value) according to the treatment strategy selected after FFR measurement regardless of FFR values. Sirolimus-eluting and paclitaxel-eluting stents were classified as first-generation DESs, while zotarolimus-eluting, everolimus-eluting, and biolimus-eluting stents were classified as second-generation DESs.

Quantitative coronary angiography (QCA). QCA was performed by independent core laboratories at Seoul National University Cardiovascular Center and Ajou University Cardiovascular Center, by experienced observers who were blinded to the FFR values and clinical data. Using the guiding catheter for calibration and an edge-detection system (CAAS 5.7 QCA system; Pie Medical), the reference diameter, minimal lumen diameter, and lesion length were measured, and the percent diameter stenosis was calculated. Lesion location was determined according to the American Heart Association classification.¹⁶

Follow-up and outcome analysis. Clinical follow-up data were obtained from a web-based reporting system. Additional information was obtained from hospital records and telephone contact, if needed. An independent study monitor verified all information on electronic case report forms. Clinical outcomes included all-cause death, cardiac death, myocardial infarction (MI), target-lesion revascularization (TLR), any revascularization, patient-based major adverse cardiac event (MACE, a composite of all-cause death, MI, and any revascularization) and target-lesion related event (target-lesion related MI and revascularization). Revascularization was defined as ischemia-driven if there was stenosis of at least 50% of the diameter and documented ischemia (positive functional study, ischemic changes on electrocardiogram [ECG], ischemic symptoms, or FFR ≤0.8), or if there was stenosis of at least 70% as assessed by QCA. FFR-lesion during the index procedure was considered to be a target lesion. All deaths were considered cardiac unless there was a clear non-cardiac cause. MI was defined as an elevated cardiac enzyme with ischemic symptoms or new pathologic Q-waves on ECG. Periprocedural MI was not included. All clinical events were adjudicated by a clinical events committee in a blind fashion using original source documents and angiographic images. 

The study protocol was approved by the ethics committee at each participating center. Due to the retrospective nature of this study, the Institutional Review Board waived the need for written informed consent from the participants. 

Statistical analysis. Data are presented as mean ± standard deviation for continuous variables and frequency for categorical variables. Comparisons of continuous and categorical variables between the two groups were performed by generalized estimating equations to consider correlation among several lesions in a patient. Time-to-event data were presented as Kaplan-Meier estimates and comparisons between groups were performed by log-rank test in patient-level analyses and by Cox regression considering the clustering effect using robust sandwich covariance matrix estimate in lesion-level analyses. To find the determinants of target-lesion related events, multivariable Cox regression analysis was performed with a forward selection method (entry criteria P<.05). Significant variables at the level of .20 by univariate analysis were included. Statistical analyses were performed using SAS version 9.2 (SAS Institute), and a P-value <.05 was considered statistically significant. All P-values and confidence intervals were 2-sided. 

Results

Between 2003 April and 2011 March, a total of 1963 patients with successful FFR measurement were considered eligible for this study. After excluding the patients with post-stent FFR (n = 247), side-branch FFR (n = 212), in-stent restenosis lesion (n = 93), and others (Figure 1), a group of 1294 patients who underwent successful FFR measurement for at least one de novo lesion located at major epicardial vessels was included in this study.

Baseline characteristics. Baseline characteristics of patients and lesions are shown in Tables 1 and 2. FFR was measured in 1628 lesions and the mean FFR was 0.80 ± 0.12. FFR was ≤0.8 in 728 lesions (44.7%). Stent implantation without FFR measurement was performed in 401 severe lesions.

Lesions with FFR ≤0.8 had more severe stenosis and longer lesion length than those with FFR >0.8 (Table 2). Compared to stented lesions without FFR measurement, minimal lumen diameter was larger than FFR-lesions (1.3 ± 0.5 mm vs 0.8 ± 0.5 mm; P<.001) and percent diameter stenosis was lower in FFR-lesions (55.9 ± 15.2% vs 75.6 ± 15.3%; P<.001). 

Patient-oriented clinical outcomes. Clinical follow-up was available in 1285 patients (99.3%). With the use of the Korean health system’s unique identification numbers, the vital status was confirmed in all patients. During a median follow-up of 30 months (interquartile range, 15.8-53.5 months), 176 MACE occurred in 114 patients. Among the events, all death, cardiac death, and MI occurred in 31 patients, 18 patients, and 6 patients, respectively. MI was due to FFR-lesion in 2 patients, stenting without FFR in 2 patients, new lesion in 1 patient, and indeterminate lesion in 1 patient. Five-year cumulative all-death rate was 6.3%, MI rate was 1.5%, any revascularization rate was 12.5%, and MACE rate was 14.9% (Figure 2). 

Target-lesion related events. At 1-year follow-up, target-lesion related events occurred in 2.6% and 4.0% in FFR-defer lesions and FFR-stent lesions, respectively. At 2.5-year follow-up, target-lesion related events occurred in 4.3% and 5.3% in FFR-defer lesions and FFR-stent lesions, respectively. Forty-two cases of revascularization and 1 case of MI were caused by the new lesions (Table 3). Among 902 lesions with FFR >0.8, a total of 208 lesions were stented and there was no difference in long-term target-lesion related outcomes between deferred and stented lesions (hazard ratio [HR], 1.783; 95% confidence interval [CI], 0.677-4.697; P=.24).

Clinical events in deferred lesions. Among 797 deferred lesions after FFR measurement, a total of 105 lesions had FFR ≤0.8. Compared with lesions that had FFR>0.8, those with FFR ≤0.8 had a higher risk of 5-year estimated target-lesion related events (21.2% vs 6.6%; P=.03). There was no difference in the 5-year cumulative rate of ischemia-driven target-lesion related events among deferred functionally insignificant lesions (FFR >0.8), first-generation DES, and second-generation DES implanted lesions (Figure 3). 

To find the short-term and long-term determinants for target-lesion related events in deferred lesions, multivariable regression analysis was performed with the variables of age, sex, presence of diabetes mellitus, use of statins, presence of stented lesion without FFR measurement, lesion location, vessel size, percent diameter stenosis, lesion length, and FFR ≤0.8. The determinant for the 1-year target-lesion related events was the presence of diabetes (HR, 3.74; 95% CI, 1.45-9.67; P=.01) while the determinant for the delayed events (1-5 years) was FFR ≤0.8 (HR, 4.50; 95% CI, 1.65-12.28; P=.01) (Table 4). Angiographic lesion severity was not an independent predictor for clinical events during follow-up among deferred lesions. 

Discussion

In this long-term outcome study after real-world use of FFR in the DES era, it was found that: (1) the deferral of stenting according to FFR was associated with favorable long-term outcomes; (2) the determinants of early and delayed events in deferred lesions were the presence of diabetes mellitus and FFR ≤0.8, respectively; and (3) angiographic lesion severity was not an independent predictor for clinical events during follow-up among deferred lesions.

Several studies proved the clinical benefit of an FFR-guided revascularization strategy.^1-7,17 However, long-term comprehensive patient-level and lesion-level outcomes after real-world use of FFR are not yet clearly defined in the DES era. In our registry, which included all patients in whom FFR was measured in at least one de novo lesion located in a major epicardial vessel, 5-year MACE rate was 14.8% in all patients, and 5-year target-lesion related event rate in FFR-guided deferred lesions (FFR>0.8 and defer) was 6.5%. These results are consistent with previous studies which showed favorable outcomes for an FFR-guided revascularization strategy. In 2-year follow-up results of the FAME study,⁶ the rates of TLR and MI in FFR-guided deferred lesions were 3.2% and 0.2%, respectively. In the DEFER study, 5-year target vessel revascularization rate of deferred lesions with FFR ≥0.75 was 8.9%.³

Residual stenosis after revascularization and the presence of coronary plaque are reported to be associated with increased risk of cardiovascular events.^10-12 Moses et al reported favorable outcomes after DES implantation without physiologic assessment in patients with intermediate stenosis.¹⁸ Therefore, some operators might believe that stenting functionally insignificant lesions with DES can improve patient outcomes. In the DEFER study, performed in the bare-metal stent era, there was no difference in 5-year event-free survival rate between defer and revascularization for functionally insignificant lesions (FFR ≥0.75).³ In our study, there was no difference in long-term target-lesion related outcomes between deferred and stented lesions among lesions with FFR >0.8 and angiographic lesion severity was not an independent predictor for clinical events in deferred lesions. These results suggest that the lesson learned from the DEFER study still applies in the DES era.

It is well known that coronary events can occur at the site of angiographically or functionally insignificant stenoses.^6,10,19 In our study, predictors of target-lesion related events among deferred lesions were the presence of diabetes for 1-year events and FFR ≤0.8 for delayed events. However, angiographic lesion severity was not an independent predictor for clinical events during follow-up among deferred lesions. This result is in agreement with the FAME II study and suggests that leaving the functionally significant stenosis, and not angiographically significant stenosis, is associated with higher risk of target-lesion related events during long-term follow-up. The different time interval from the FFR measurement and clinical event between the FAME II study and ours may be due to the difference in the degree of clinical and angiographic severity in deferred functionally significant stenosis. In our study, clinically indicated severe stenosis was treated without FFR measurement, reflective of real-world clinical practice.

The outcomes of medical treatment and revascularization may differ between Westerners and Asians due to the difference in body and vessel size, risk factor profile, and regional differences in medical practice patterns and health-care policies.^20-24 However, our study revealed that the results of previous FFR studies can be applied to all patients with coronary artery disease, regardless of ethnicity.  

Study limitations. Our study has several limitations. First, this is a non-randomized study and therefore cannot overcome all limitations inherent in a registry study. Second, plaque vulnerability was not assessed in our study. Third, the frequency of FFR non-compliance in our study was 19% and higher than previous studies (17% in a study by Legalery et al²⁵ and 5% in a study by Muller et al²⁶). The main reason for this non-compliant strategy was frequent use of intravascular ultrasound (IVUS). Among 208 lesions with FFR >0.8 and stenting, a total of 82 lesions (39%) were stented due to the IVUS findings. Our study results again showed that an IVUS-guided strategy might result in more stent implantations without improvement in patient outcomes.^27-29 

Conclusion

The deferral of stenting according to FFR was associated with favorable long-term outcomes. Presence of diabetes and low FFR increased the risk of clinical events in deferred lesions.

References

1. Pijls NH, De Bruyne B, Peels K, et al. Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses. N Engl J Med. 1996;334:1703-1708.
2. Bech GJ, De Bruyne B, Pijls NH, et al. Fractional flow reserve to determine the appropriateness of angioplasty in moderate coronary stenosis: a randomized trial. Circulation. 2001;103:2928-2934.
3. Pijls NH, van Schaardenburgh P, Manoharan G, et al. Percutaneous coronary intervention of functionally nonsignificant stenosis: 5-year follow-up of the DEFER Study. J Am Coll Cardiol. 2007;49:2105-2111. 
4. Kim JE, Koo BK. Fractional flow reserve: the past, present and future. Korean Circ J. 2012;42:441-446.
5. Tonino PA, De Bruyne B, Pijls NH, et al; FAME Study Investigators. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med. 2009;360:213-224.
6. Pijls NH, Fearon WF, Tonino PA, et al; FAME Study Investigators. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention in patients with multivessel coronary artery disease: 2-year follow-up of the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) study. J Am Coll Cardiol. 2010;56:177-184.
7. De Bruyne B, Pijls NH, Kalesan B, et al; FAME 2 Trial Investigators. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med. 2012;367:991-1001.
8. Patel MR, Bailey SR, Bonow RO, et al. ACCF/SCAI/AATS/AHA/ASE/ASNC/HFSA/HRS/SCCM/SCCT/SCMR/STS 2012 appropriate use criteria for diagnostic catheterization: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, Society for Cardiovascular Angiography and Interventions, American Association for Thoracic Surgery, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society of Critical Care Medicine, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, Society of Thoracic Surgeons. J Thorac Cardiovasc Surg. 2012;144:39-71.
9. Berger A, Botman KJ, MacCarthy PA, et al. Long-term clinical outcome after fractional flow reserve-guided percutaneous coronary intervention in patients with multivessel disease. J Am Coll Cardiol. 2005;46:438-442.
10. Glaser R, Selzer F, Faxon DP, et al. Clinical progression of incidental, asymptomatic lesions discovered during culprit vessel coronary intervention. Circulation. 2005;111:143-149.
11. Zaman T, Agarwal S, Anabtawi AG, et al. Angiographic lesion severity and subsequent myocardial infarction. Am J Cardiol. 2012;110:167-172.
12. Farooq V, Serruys PW, Garcia-Garcia HM, et al. The negative impact of incomplete angiographic revascularization on clinical outcomes and its association with total occlusions: the SYNTAX (Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery) trial. J Am Coll Cardiol. 2013;61:282-294.
13. De Bruyne B, Pijls NH, Barbato E, et al. Intracoronary and intravenous adenosine 5’-triphosphate, adenosine, papaverine, and contrast medium to assess fractional flow reserve in humans. Circulation. 2003;107:1877-1883.
14. Yoon MH, Tahk SJ, Yang HM, et al. Comparison of the intracoronary continuous infusion method using a microcatheter and the intravenous continuous adenosine infusion method for inducing maximal hyperemia for fractional flow reserve measurement. Am Heart J. 2009;157:1050-1056.
15. Seo MK, Koo BK, Kim JH, et al. Comparison of hyperemic efficacy between central and peripheral venous adenosine infusion for fractional flow reserve measurement. Circ Cardiovasc Interv. 2012;5:401-405.
16. Austen WG, Edwards JE, Frye RL, et al. A reporting system on patients evaluated for coronary artery disease. Report of the Ad Hoc Committee for Grading of Coronary Artery Disease, Council on Cardiovascular Surgery, American Heart Association. Circulation. 1975;51(4 Suppl):5-40.
17. Li J, Elrashidi MY, Flammer AJ, et al. Long-term outcomes of fractional flow reserve-guided vs angiography-guided percutaneous coronary intervention in contemporary practice. Eur Heart J. 2013;34:1375-1383.
18. Moses JW, Stone GW, Nikolsky E, et al. Drug-eluting stents in the treatment of intermediate lesions: pooled analysis from four randomized trials. J Am Coll Cardiol. 2006;47:2164-2171.
19. Stone GW, Maehara A, Lansky AJ, et al; PROSPECT Investigators. A prospective natural-history study of coronary atherosclerosis. N Engl J Med. 2011;364:226-235.
20. Kohsaka S, Kimura T, Goto M, et al. Difference in patient profiles and outcomes in Japanese versus American patients undergoing coronary revascularization (collaborative study by CREDO-Kyoto and the Texas Heart Institute Research Database). Am J Cardiol. 2010;105:1698-1704.
21. Saito S, Nakamura S, Fujii K, et al. Mid-term results of everolimus-eluting stent in a Japanese population compared with a US randomized cohort: SPIRIT III Japan registry with harmonization by doing. J Invasive Cardiol. 2012;24:444-450.
22. Mentz RJ, Kaski JC, Dan GA, et al. Implications of geographical variation on clinical outcomes of cardiovascular trials. Am Heart J. 2012;164:303-312.
23. Blair JE, Zannad F, Konstam MA, et al; EVEREST Investigators. Continental differences in clinical characteristics, management, and outcomes in patients hospitalized with worsening heart failure; results from the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) program. J Am Coll Cardiol. 2008;52:1640-1648.
24. Hulten E, Villines TC, Cheezum MK, et al; CONFIRM Investigators. Usefulness of coronary computed tomography angiography to predict mortality and myocardial infarction among Caucasian, African, and East Asian Ethnicities (from the CONFIRM [Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter] registry). Am J Cardiol. 2013;111:479-485.
25. Legalery P, Schiele F, Seronde MF, et al. One-year outcome of patients submitted to routine fractional flow reserve assessment to determine the need for angioplasty. Eur Heart J. 2005;26:2623-2629.
26. Muller O, Mangiacapra F, Ntalianis A, et al. Long-term follow-up after fractional flow reserve-guided treatment strategy in patients with an isolated proximal left anterior descending coronary artery stenosis. JACC Cardiovasc Interv. 2011;4:1175-1182.
27. Koo BK, Yang HM, Doh JH, et al. Optimal intravascular ultrasound criteria and their accuracy for defining the functional significance of intermediate coronary stenoses of different locations.  JACC Cardiovasc Interv. 2011;4:803-811.
28. Nam CW, Yoon HJ, Cho YK, et al. Outcomes of percutaneous coronary intervention in intermediate coronary artery disease: fractional flow reserve-guided versus intravascular ultrasound-guided.  JACC Cardiovasc Interv. 2010;3:812-817.
29. Chieffo A, Latib A, Caussin C, et al. A prospective, randomized trial of intravascular-ultrasound guided compared to angiography guided stent implantation in complex coronary lesions: the AVIO trial. Am Heart J. 2013;165:65-72.

___________________________

^*Joint first authors. 

From the ¹Department of Medicine, Inje University Ilsan Paik Hospital, Goyang, Korea; ²Department of Medicine, Keimyung University Dongsan Medical Center, Daegu, Korea; ³Department of Medicine, Seoul National University Hospital, Seoul, Korea; ⁴Department of Medicine, Eulji University Hospital, Daejeon, Korea; ⁵Department of Medicine, Chungbuk National University Hospital, Cheongju, Korea; and ⁶Department of Medicine, Ajou University Medical Center, Suwon, Korea. 

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 September 16, 2014, provisional acceptance given October 22, 2014, final version accepted December 11, 2014.

Address for correspondence: Bon-Kwon Koo, MD, PhD, Professor, Department of Internal Medicine, Cardiovascular Center, Seoul National University Hospital, 101 Daehang-ro, Chongno-gu, Seoul, 110-744 Korea. Email: bkkoo@snu.ac.kr