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The impact of age on fractional flow reserve-guided percutaneous coronary intervention: A FAME (Fractional Flow Reserve versus Angiography for Multivessel Evaluation) trial substudy
International Journal of Cardiology 177 (2014) 66–70
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
The impact of age on fractional flow reserve-guided percutaneous coronary intervention: A FAME (Fractional Flow Reserve versus Angiography for Multivessel Evaluation) trial substudy Hong-Seok Lim a,b, Pim A.L. Tonino c, Bernard De Bruyne d, Andy S.C. Yong a, Bong-Ki Lee a,e, Nico H.J. Pijls c, William F. Fearon a,⁎ a
Division of Cardiovascular Medicine, Stanford University Medical Center, Stanford, CA, United States Department of Cardiology, Ajou University School of Medicine, Suwon, Republic of Korea c Catharina Hospital, Eindhoven, The Netherlands d Cardiovascular Center, Aalst, Belgium e Division of Cardiology, Kangwon National University School of Medicine, Chuncheon, Republic of Korea b
a r t i c l e
i n f o
Article history: Received 2 June 2014 Received in revised form 23 August 2014 Accepted 15 September 2014 Available online 20 September 2014 Keywords: Fractional flow reserve Percutaneous coronary intervention Aging
a b s t r a c t Background: Fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) improved outcomes compared with an angiography-guided strategy in patients with multivessel coronary artery disease (CAD). However, the effect of age on FFR has not been well-studied. We aimed to evaluate the impact of age on the favorable results of routine FFR-guided PCI for multivessel CAD. Methods: We compared 1 year outcomes between FFR-guided PCI and angiography-guided PCI in the 512 patients enrolled in the FAME study b65 years old compared to the 493 patients ≥ 65 years old. We also evaluated the effect of age on the FFR result of varying degrees of visually estimated coronary stenosis. Results: The 1-year rate of death, myocardial infarction or repeat revascularization in the angiography-guided group tended to be higher than in the FFR-guided group for both those patients b 65 (17.2% vs. 12.0%, P = 0.098) and those ≥ 65 years old (19.7% vs. 14.3%, P = 0.111) with no significant interaction based on age (P = 0.920). Older patients had higher FFR in vessels with 50% to 70% stenosis (0.83 ± 0.11 vs. 0.80 ± 0.13, P = 0.028) and in vessels with 71% to 90% stenosis (0.69 ± 0.15 vs. 0.65 ± 0.16, P = 0.002). The proportion of functionally significant lesions (FFR ≤ 0.80) in vessels with 71% to 90% stenosis was significantly lower in elderly compared to younger patients (75.3% vs. 84.1%, P = 0.013). Conclusions: FFR-guided PCI is beneficial regardless of age, however, older patients have fewer functionally significant lesions, despite a similar angiographic appearance. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Despite remarkable advances in percutaneous coronary intervention (PCI) technique, including the development of drug-eluting stents (DES), and improvements in medical therapy, older patients continue to represent a high risk cohort with less favorable long-term prognosis [1–5]. However, with the increasing age of our population, the majority of PCI occurs in patients ≥65 years old [6]. For these reasons, it is important to demonstrate that any new strategy for improving PCI outcomes applies to older patients as well. Abbreviations: CAD, coronary artery disease; DES, drug-eluting stent(s); FFR, fractional flow reserve; MACE, major adverse cardiac event(s); MI, myocardial infarction; PCI, percutaneous coronary intervention. ⁎ Corresponding author at: Interventional Cardiology, H2103, 300 Pasteur Drive, Stanford University Medical Center, Stanford, CA 94305, United States. Tel.: +1 650 725 2621; fax: +1 650 725 6766. E-mail address: [email protected] (W.F. Fearon).
http://dx.doi.org/10.1016/j.ijcard.2014.09.010 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
The FAME (Fractional Flow Reserve versus Angiography for Multivessel Evaluation) trial demonstrated that measuring fractional flow reserve (FFR) to help guide the decision regarding the need for percutaneous coronary intervention (PCI) in patients with multivessel CAD improves outcomes and saves resources when compared to an angiography-guided strategy [7–9]. FFR is a coronary pressure wirebased method for assessing the ischemic potential of a stenosis [10]. The reliability of measuring FFR in older patients has not been previously studied. The primary goal of this substudy of the FAME trial is to evaluate whether the favorable results of FFR-guided PCI for multivessel CAD occur in older patients. 2. Methods 2.1. Study design and population To perform age-specific analysis using the original FAME study data [7], the patients were categorized into older (≥65 years old) and younger (b65 years old) groups because
H.-S. Lim et al. / International Journal of Cardiology 177 (2014) 66–70 2.4. Statistical analysis
Table 1 Baseline clinical characteristics.
Age, years Male Angina classificationa I II III IV Cardiovascular risk factors Hypertension Hypercholesterolemia Current smoker Diabetes Mellitus Family history Previous MI Previous PCI Left ventricular ejection fraction, % Medications Beta-blocker Calcium antagonist Nitrate Antianginal medicationsb, n ACE inhibitor or ARB Statin Aspirin Clopidogrel GP IIb/IIIa inhibitor EQ-5D score
67
b65 years old (n = 512)
≥65 years old (n = 493)
P
56.2 ± 6.4 425 (83.0)
73.1 ± 5.2 319 (64.7)
b0.001 b0.001 0.090
133 (26.0) 178 (34.8) 110 (21.5) 91 (17.8)
114 (23.1) 157 (31.8) 140 (28.4) 82 (16.6)
307 (60.0) 374 (73.0) 217(42.4) 117 (22.9) 227 (44.3) 214 (41.8) 160 (31.3) 57
332 (67.3) 354 (71.8) 77 (15.6) 131 (26.6) 168 (34.1) 153 (31.0) 115 (23.3) 58
0.015 0.660 b0.001 0.171 0.001 b0.001 0.005 0.077
392 (76.6) 95 (18.6) 150 (29.3) 1.2 ± 0.8 264 (51.6) 411 (80.3) 467 (91.2) 292 (57.0) 90 (17.6) 65.6 ± 19.0
380 (77.1) 122 (24.7) 196 (39.8) 1.4 ± 0.8 258 (52.3) 403 (81.7) 452 (91.7) 310 (62.9) 50 (10.1) 65.7 ± 18.6
0.846 0.017 b0.001 0.001 0.807 0.552 0.789 0.059 0.001 0.920
Values are mean ± SD or n (%).ACE indicates angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; EQ-5D, European Quality of Life-5 Dimensions; GP, glycoprotein; MI, myocardial infarction; and PCI, percutaneous coronary intervention. a Angina was assessed according to the Canadian Cardiovascular Society Functional Classification of Angina Pectoris. b Antianginal medications included beta-blockers, calcium-antagonists, and nitrates.
the mean and median ages of the population was 64.5 and 64.7 years old, respectively. The age of the entire patient population ranged from 32.0 to 89.8 years old with an interquartile range of 15.7 years. Details regarding the study design have been described previously [7]. In brief, FAME was a prospective, multicenter, randomized clinical trial including 1005 patients with multivessel CAD eligible for PCI with drug-eluting stents. Patients with coronary lesions with at least 50% diameter stenosis based on visual estimation in ≥2 major epicardial vessels were randomly assigned to either angiography-guided PCI or FFR-guided PCI. Patients assigned to angiography-guided PCI underwent stenting of all identified stenoses, while patients assigned to the FFR-guided PCI had FFR measured first, and stenting was only performed if the FFR across the lesion was ≤0.80. Exclusion criteria were significant left main CAD, prior coronary artery bypass graft surgery, a recent ST-segment elevation MI (b5 days), cardiogenic shock, or extremely tortuous or calcified coronary arteries. The study protocol was approved by each Institutional Review Board or Ethics Committee, and each patient provided informed written consent.
2.2. Treatment and FFR measurement The interventional treatment of patients in the FAME study has been described previously [11]. PCI was performed according to standard coronary interventional techniques with DES. The FFR was measured with a coronary pressure guidewire (St. Jude Medical, St. Paul, MN) at maximum hyperemia induced by intravenous adenosine at a rate of 140 μg/kg/min through a central vein [7,12]. FFR was defined as the ratio between the mean distal coronary pressure and the mean aortic pressure. All patients received dual antiplatelet therapy with aspirin and clopidogrel for at least 1 year after PCI and the use of glycoprotein IIb/IIIa antagonists was at the discretion of the operator.
2.3. Endpoints and the goal of analysis All adverse clinical events were centrally adjudicated by an independent Clinical Events Committee blinded to treatment assignment. The primary endpoint of this reanalysis was the same as that of the original FAME trial and was the occurrence of major adverse cardiac events (MACE), a composite of all-cause death, myocardial infarction (MI), or the need for repeat coronary revascularization at 1 year after the index procedure in each age group. Details on these definitions regarding MACE have been described previously [7,11]. A secondary goal of this analysis was to compare FFR values between younger and older patients with similar degrees of angiographic stenosis.
All patients were included for analysis and stratified by age group for statistical comparisons based on treatment method. Categorical variables, including the primary endpoint and its individual components, are expressed as numbers or percentages and between-group differences were compared with chi-square test or Fisher exact test, as appropriate. Continuous variables are presented as mean ± SD and differences in those variables were assessed using Student t test or the Mann–Whitney U test as appropriate. The interaction between age and treatment strategy was investigated using Breslow– Day test. Angiographic stenosis per category and the respective FFR value of each specific coronary lesion were plotted in a box-and-whisker plot using GraphPad Prism version 5.03 software (GraphPad Software Inc., La Jolla, CA) to show side-by-side comparison in both age groups. Kaplan–Meier curves are shown for the time-to-event distributions of MACE in all patients stratified according to age group and treatment strategy. A 2-sided P value b 0.05 was considered statistically significant. All statistical analyses were performed using commercially available software (SPSS version 18 for Windows, SPSS Inc., Chicago, IL).
3. Results 3.1. Baseline clinical characteristics The age criteria were defined as 65 years old based on the mean and median ages of 1005 patients enrolled in the FAME study. With that, 512 patients (50.9%) were b65 years old, of which 250 were randomized to FFR-guided PCI and 262 were randomized to angiography-guided PCI. Among the 493 patients ≥ 65 years old, 259 and 234 patients were randomly assigned to FFR-guided PCI and angiography-guided PCI, respectively. Baseline clinical characteristics are presented in Table 1. Patients ≥65 years old were less likely to be male (64.7% vs. 83.0%, P b 0.001), to smoke (15.6% vs. 42.4%, P b 0.001), to have a history of MI (31.0% vs. 41.8%, P b 0.001) or to have a history of PCI (23.3% vs. 31.3%, P = 0.005), but were more likely to have hypertension (67.3% vs. 60.0%, P = 0.015), to use calcium antagonists or nitrates (24.7% vs. 18.6%, P = 0.017; 39.8% vs. 29.3, P b 0.001, respectively) and to require antianginal medications (1.4 vs. 1.2 per patient, P = 0.001). Older patients also had higher Euro-scores at baseline (4.5 ± 1.8 vs. 1.5 ± 1.5, P b 0.001) and lower EQ-5D scores at 1-year (72.5 ± 16.1 vs. 75.7 ± 15.4, P = 0.003). Table 2 Angiographic and procedural findings.
Number of diseased vessels, n 2 3 Lesions intended to treat, n Extent of occlusion visual estimation 50 to 70% stenosis 71 to 90% stenosis 91 to 99% stenosis Total occlusion Patient with Total Occlusion Proximal LAD lesion Lesion segments 1, 2, 3, 6, 7, and 11 Quantitative coronary analysis Extent of stenosis, % Minimal luminal diameter, mm Reference diameter, mm Mean lesion length, mm Length of lesions per patient, mm SYNTAX score Procedural time, min Volume of contrast agent used, ml Total stented length per patient, mm Implanted stents per patient, n
b65 years old (n = 512)
≥65 years old (n = 493)
372 (72.7) 140 (27.3) 2.8 ± 1.0.
369 (74.8) 124 (25.2) 2.7 ± 0.9
603 (42.7) 551 (39.0) 212 (15.0) 46 (3.3)
571 (42.2) 532 (39.3) 197 (14.6) 52 (3.8)
44 (8.6) 207 (40.4) 472 (92.2)
47 (9.5) 189 (38.3) 468 (94.9)
0.604 0.497 0.077
60.5 ± 16.6 1.01 ± 0.44 2.51 ± 0.65 12.9 ± 6.7 32.2 ± 18.6 14.6 ± 9.3 71.5 ± 43.6 295.2 ± 136.0 46.9 ± 27.9 2.4 ± 1.3
59.8 ± 17.3 1.01 ± 0.45 2.46 ± 0.61 12.4 ± 6.4 30.7 ± 16.4 14.4 ± 8.1 68.9 ± 43.2 278.6 ± 124.8 42.7 ± 26.2 2.3 ± 1.3
0.331 0912 0.051 0.052 0.155 b0.001 0.347 0.045 0.015 0.071
P 0.430
0.742 0.844
Values are mean ± SD or n (%). EuroSCORE indicates European System for Cardiac Operative Risk Evaluation; LAD, left anterior descending artery; and SYNTAX, Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery.
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H.-S. Lim et al. / International Journal of Cardiology 177 (2014) 66–70
Table 3 Outcome at 1 year of patients stratified to age and treatment strategy. b65 years old (n = 512)
Composite of MACE Death MI Repeat revascularization Death or MI
≥65 years old (n = 493)
FFR-guided (n = 250)
Angiography-guided (n = 262)
Pa
RRRb
FFR-guided (n = 259)
Angiography-guided (n = 234)
Pa
RRRb
Breslow– Day Pc
30 (12.0) 3 (1.2) 13 (5.2) 14 (5.6) 16 (6.4)
45 (17.2) 5 (1.9) 24 (9.2) 25 (9.5) 28 (10.7)
0.098 0.725 0.084 0.093 0.084
0.30 (−0.06 to 0.66) 0.37 (−0.95 to 1.74) 0.87 (0.47 to 1.33) 0.41 (−0.08 to 0.91) 0.40 (−0.06 to 0.87)
37 (14.3) 6 (2.3) 16 (6.2) 19 (7.3) 21 (8.1)
46 (19.7) 10 (4.3) 19 (8.1) 22 (9.4) 27 (11.5)
0.111 0.221 0.402 0.407 0.199
0.27 (−0.06 to 0.61) 0.46 (−0.31 to 1.31) 0.24 (−0.33 to 0.83) 0.22 (−0.31 to 0.76) 0.30 (−0.16 to 0.77)
0.920 0.858 0.530 0.522 0.706
Values are n (%). FFR indicates fractional flow reserve; MACE, major adverse cardiac events; and MI, myocardial infarction. a P value represents comparison between FFR-guided versus angiography-guided percutaneous coronary intervention (PCI) for clinical outcomes at 1 year. b Relative risk reductions (RRR) by using FFR for both patients b65 and ≥65 years old is shown. Interaction between age groups and treatment for the different outcomes are also shown. c Breslow–Day indicates Breslow–Day test for heterogeneity of odds ratio of FFR-guided PCI versus the odds ratio of angiography-guided PCI within each age subgroup.
3.2. Angiographic and procedural results Table 2 shows angiographic findings and procedural results. Patients ≥65 years old had lower SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) scores (14.4 ± 8.1 vs. 14.6 ± 9.3, P b 0.001), a tendency to smaller reference diameters (2.46 ± 0.61 mm vs. 2.51 ± 0.65 mm, P = 0.051) and shorter lesion lengths (12.4 ± 6.4 mm vs. 12.9 ± 6.7 mm, P = 0.052). The total stented length per patient was shorter in those ≥ 65 years old (42.7 ± 26.2 mm vs. 46.9 ± 27.9 mm, P = 0.015), and there was less contrast used per patient (278.6 ± 124.8 ml vs. 295.2 ± 136.0 ml, P = 0.045). 3.3. Clinical outcomes at 1 year When comparing the benefit of FFR-guided PCI in patients b 65 years old to those ≥65 years old, there was a similar relative risk reduction in the primary endpoint of death, MI and the need for repeat revascularization and there was no evidence for heterogeneity in the benefit based on age (Table 3). Kaplan–Meier curves for survival free from MACE based on FFR or angiography guidance and age above or below 65 years are presented in Fig. 1. The composite of death, MI, and repeated revascularization occurred in 14.6% of all patients b65 years old versus 16.8% of patients ≥65 years old (P = 0.341). 3.4. Angiographic versus functional stenosis severity In the FFR-guided arm of the FAME study, a total of 1414 lesions were noted in 509 patients. Of these, the FFR was measured successfully
in 1,329 lesions which were available for comparison with angiographic lesion severity [12]. Mean FFR value obtained from older patients was significantly higher than that in younger patients (0.72 ± 0.17 vs. 0.70 ± 0.18, P = 0.043). By visual estimation, the lesions were prospectively categorized as 50% to 70%, 71% to 90%, or 91% to 99% diameter stenosis. Angiographic lesion severity per category and its respective FFR values are presented in Fig. 2. The mean FFR values of patients ≥ 65 years old, compared with those of patients b65 years old, were significantly higher in vessels with 50% to 70% (0.83 ± 0.11 vs. 0.80 ± 0.13, P = 0.028) and 71% to 90% stenosis (0.69 ± 0.15 vs. 0.65 ± 0.16, P = 0.002). Older patients had a significantly lower proportion of lesions with functional significance (FFR ≤ 0.80) than younger patients in the 71% to 90% stenosis category (75.3% vs. 84.1%, P = 0.013).
4. Discussion The principle finding of this study is that FFR-guided PCI as compared to angiography-guided PCI in patients with multivessel CAD is equally beneficial in older patients, those ≥ 65 years old, as it is in younger ones. An important second finding is that for any given stenosis, the FFR is less likely to be abnormal in older patients. Not surprisingly, older patients tended to have worse overall outcomes with PCI, regardless of strategy, when compared to younger patients. The FAME trial showed that in patients with multivessel CAD undergoing PCI with DES, FFR guidance resulted in a lower rate of MACE (death, MI and the need for repeat revascularization) when compared to the traditional angiography-guided PCI [7]. In this substudy from FAME, we found that FFR-guided PCI was equally beneficial in older
Fig. 1. Kaplan–Meier curves for survival free from MACE at 1 year stratified to age and treatment strategy. Kaplan–Meier curves for the percentage survival free from major adverse cardiac events (MACE) at 1 year in the 4 groups stratified by age and treatment. Relative risk reduction (RRR) of MACE by fractional flow reserve (FFR)-guided percutaneous coronary intervention is indicated in b65 year-old and ≥65 year-old patients.
H.-S. Lim et al. / International Journal of Cardiology 177 (2014) 66–70
69
Fig. 2. FFR values according to angiographic stenosis severity. Box-and-whisker plot showing the fractional flow reserve (FFR) values of all lesions in both b65 and ≥65 age groups according to the categories of 50% to 70%, 71% to 90%, and 91% to 99% diameter stenosis. The dotted horizontal line represents FFR cut-off value for myocardial ischemia.
patients, as it was in younger ones. It is important to note that although the older cohort had higher rates of MACE after PCI compared to younger patients (Table 3), those who were randomized to FFR-guided PCI had a similar reduction in MACE compared to the younger cohort, both in absolute and relative terms (Fig. 1). These data are reassuring because changes in cardiac function which occur with aging might affect the reliability of FFR [13,14]. Microvascular dysfunction resulting from long-standing hypertension, left ventricular hypertrophy and/or diastolic dysfunction occurs more frequently in older patients [14,15]. FFR relies on achieving maximal hyperemia through vasodilation of the microvasculature. One might be concerned that the increased microvascular dysfunction in older patients could lead to lower peak flow down the vessel, a lower translesional gradient and an overestimation of FFR for a given stenosis. However, even in the setting of microvascular dysfunction, FFR remains a reliable indicator of the functional significance of an epicardial stenosis. It still informs the operator regarding the expected increase in coronary flow that will be achieved with PCI [16]. Indeed, an important secondary finding in this substudy is that in older patients a moderate stenosis is less likely to be associated with an abnormal FFR when compared to the same stenosis in a younger patient (Fig. 2). Presumably, this is a result of greater degrees of microvascular dysfunction present in older patients [13,14], although other differences between older and younger patients, such as lesion length and reference diameter might have contributed. This finding highlights the importance of using a physiologic index to assess the need for PCI, as opposed to angiography or intravascular imaging, particularly in older patients.
4.1. Study limitations This study is limited by its post hoc nature and because it was a subanalysis of patients in the FAME study. Therefore, it is underpowered to show superiority of the FFR-guided strategy over the angiographyguided strategy in each age subgroup and should be interpreted as hypothesis generating. In this respect, longer-term follow-up might be informative. A substudy of the FAME trial reported the 2-year followup, however, we decided to make the 1-year analysis the primary endpoint of this age substudy to avoid performing a substudy of another
substudy. The age cutoff of 65 years is arbitrary, but we believe it is reasonable, given that it represents the mean age of patients enrolled in the study. The interpretation of the coronary stenoses was based on visual inspection of the angiogram at the time of study enrolment and not core laboratory quantitative coronary angiography. However, we believe this is more reflective of clinical practice. 5. Conclusions In patients with multivessel CAD, FFR-guided PCI is beneficial regardless of age. However, older patients have fewer functionally significant lesions, despite a similar angiographic appearance. Funding sources The FAME study was sponsored by St. Jude Medical. Disclosures William F. Fearon receives an institutional research support from St. Jude Medical. Bernard De Bruyne and Nico H.J. Pijls are consultants for St. Jude Medical. The other authors report no conflicts relevant to the contents of this paper to disclose. Conflict of interest Dr. Pijls and Dr. De Bruyne are consultants for St. Jude Medical. Dr. Fearon receives research support from St. Jude Medical. All other authors have no relevant conflicts. References [1] Rao SV, Hess CN, Dai D, Green CL, Peterson ED, Douglas PS. Temporal trends in percutaneous coronary intervention outcomes among older patients in the United States. Am Heart J 2013;166:273–281 e4. [2] Varani E, Aquilina M, Balducelli M, Vecchi G, Frassineti V, Maresta A. Percutaneous coronary interventions in octogenarians: acute and 12 month results in a large single-centre experience. Catheter Cardiovasc Interv 2009;73:449–54. [3] Vlaar PJ, Lennon RJ, Rihal CS, et al. Drug-eluting stents in octogenarians: early and intermediate outcome. Am Heart J 2008;155:680–6.
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[4] Du R, Zhang RY, Zhang Q, et al. Assessment of the relation between IVUS measurements and clinical outcome in elderly patients after sirolimus-eluting stent implantation for de novo coronary lesions. Int J Cardiovasc Imaging 2012;28:1653–62. [5] Hassani SE, Wolfram RM, Kuchulakanti PK, et al. Percutaneous coronary intervention with drug-eluting stents in octogenarians: characteristics, clinical presentation, and outcomes. Catheter Cardiovasc Interv 2006;68:36–43. [6] Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation 2013;127:e6-245. [7] Tonino PA, De Bruyne B, Pijls NH, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360:213–24. [8] Pijls NH, Fearon WF, Tonino PA, et al. 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;56:177–84. [9] Fearon WF, Bornschein B, Tonino PA, et al. Economic evaluation of fractional flow reserve-guided percutaneous coronary intervention in patients with multivessel disease. Circulation 2010;122:2545–50. [10] 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;334:1703–8.
[11] Fearon WF, Tonino PA, De Bruyne B, Siebert U, Pijls NH, Investigators FS. Rationale and design of the Fractional Flow Reserve versus Angiography for Multivessel Evaluation (FAME) study. Am Heart J 2007;154:632–6. [12] Tonino PA, Fearon WF, De Bruyne B, et al. Angiographic versus functional severity of coronary artery stenoses in the FAME study fractional flow reserve versus angiography in multivessel evaluation. J Am Coll Cardiol 2010;55: 2816–21. [13] Uren NG, Camici PG, Melin JA, et al. Effect of aging on myocardial perfusion reserve. J Nucl Med 1995;36:2032–6. [14] Galderisi M, Rigo F, Gherardi S, et al. The impact of aging and atherosclerotic risk factors on transthoracic coronary flow reserve in subjects with normal coronary angiography. Cardiovasc Ultrasound 2012;10:20. [15] Galderisi M, Cicala S, Caso P, et al. Coronary flow reserve and myocardial diastolic dysfunction in arterial hypertension. Am J Cardiol 2002;90:860–4. [16] Pijls NH, De Bruyne B. Coronary pressure. 2nd ed. The Netherlands: Kluwer Academic Publishers; 2000 [Chapter 13].
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
The impact of age on fractional flow reserve-guided percutaneous coronary intervention: A FAME (Fractional Flow Reserve versus Angiography for Multivessel Evaluation) trial substudy Hong-Seok Lim a,b, Pim A.L. Tonino c, Bernard De Bruyne d, Andy S.C. Yong a, Bong-Ki Lee a,e, Nico H.J. Pijls c, William F. Fearon a,⁎ a
Division of Cardiovascular Medicine, Stanford University Medical Center, Stanford, CA, United States Department of Cardiology, Ajou University School of Medicine, Suwon, Republic of Korea c Catharina Hospital, Eindhoven, The Netherlands d Cardiovascular Center, Aalst, Belgium e Division of Cardiology, Kangwon National University School of Medicine, Chuncheon, Republic of Korea b
a r t i c l e
i n f o
Article history: Received 2 June 2014 Received in revised form 23 August 2014 Accepted 15 September 2014 Available online 20 September 2014 Keywords: Fractional flow reserve Percutaneous coronary intervention Aging
a b s t r a c t Background: Fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) improved outcomes compared with an angiography-guided strategy in patients with multivessel coronary artery disease (CAD). However, the effect of age on FFR has not been well-studied. We aimed to evaluate the impact of age on the favorable results of routine FFR-guided PCI for multivessel CAD. Methods: We compared 1 year outcomes between FFR-guided PCI and angiography-guided PCI in the 512 patients enrolled in the FAME study b65 years old compared to the 493 patients ≥ 65 years old. We also evaluated the effect of age on the FFR result of varying degrees of visually estimated coronary stenosis. Results: The 1-year rate of death, myocardial infarction or repeat revascularization in the angiography-guided group tended to be higher than in the FFR-guided group for both those patients b 65 (17.2% vs. 12.0%, P = 0.098) and those ≥ 65 years old (19.7% vs. 14.3%, P = 0.111) with no significant interaction based on age (P = 0.920). Older patients had higher FFR in vessels with 50% to 70% stenosis (0.83 ± 0.11 vs. 0.80 ± 0.13, P = 0.028) and in vessels with 71% to 90% stenosis (0.69 ± 0.15 vs. 0.65 ± 0.16, P = 0.002). The proportion of functionally significant lesions (FFR ≤ 0.80) in vessels with 71% to 90% stenosis was significantly lower in elderly compared to younger patients (75.3% vs. 84.1%, P = 0.013). Conclusions: FFR-guided PCI is beneficial regardless of age, however, older patients have fewer functionally significant lesions, despite a similar angiographic appearance. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Despite remarkable advances in percutaneous coronary intervention (PCI) technique, including the development of drug-eluting stents (DES), and improvements in medical therapy, older patients continue to represent a high risk cohort with less favorable long-term prognosis [1–5]. However, with the increasing age of our population, the majority of PCI occurs in patients ≥65 years old [6]. For these reasons, it is important to demonstrate that any new strategy for improving PCI outcomes applies to older patients as well. Abbreviations: CAD, coronary artery disease; DES, drug-eluting stent(s); FFR, fractional flow reserve; MACE, major adverse cardiac event(s); MI, myocardial infarction; PCI, percutaneous coronary intervention. ⁎ Corresponding author at: Interventional Cardiology, H2103, 300 Pasteur Drive, Stanford University Medical Center, Stanford, CA 94305, United States. Tel.: +1 650 725 2621; fax: +1 650 725 6766. E-mail address: [email protected] (W.F. Fearon).
http://dx.doi.org/10.1016/j.ijcard.2014.09.010 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
The FAME (Fractional Flow Reserve versus Angiography for Multivessel Evaluation) trial demonstrated that measuring fractional flow reserve (FFR) to help guide the decision regarding the need for percutaneous coronary intervention (PCI) in patients with multivessel CAD improves outcomes and saves resources when compared to an angiography-guided strategy [7–9]. FFR is a coronary pressure wirebased method for assessing the ischemic potential of a stenosis [10]. The reliability of measuring FFR in older patients has not been previously studied. The primary goal of this substudy of the FAME trial is to evaluate whether the favorable results of FFR-guided PCI for multivessel CAD occur in older patients. 2. Methods 2.1. Study design and population To perform age-specific analysis using the original FAME study data [7], the patients were categorized into older (≥65 years old) and younger (b65 years old) groups because
H.-S. Lim et al. / International Journal of Cardiology 177 (2014) 66–70 2.4. Statistical analysis
Table 1 Baseline clinical characteristics.
Age, years Male Angina classificationa I II III IV Cardiovascular risk factors Hypertension Hypercholesterolemia Current smoker Diabetes Mellitus Family history Previous MI Previous PCI Left ventricular ejection fraction, % Medications Beta-blocker Calcium antagonist Nitrate Antianginal medicationsb, n ACE inhibitor or ARB Statin Aspirin Clopidogrel GP IIb/IIIa inhibitor EQ-5D score
67
b65 years old (n = 512)
≥65 years old (n = 493)
P
56.2 ± 6.4 425 (83.0)
73.1 ± 5.2 319 (64.7)
b0.001 b0.001 0.090
133 (26.0) 178 (34.8) 110 (21.5) 91 (17.8)
114 (23.1) 157 (31.8) 140 (28.4) 82 (16.6)
307 (60.0) 374 (73.0) 217(42.4) 117 (22.9) 227 (44.3) 214 (41.8) 160 (31.3) 57
332 (67.3) 354 (71.8) 77 (15.6) 131 (26.6) 168 (34.1) 153 (31.0) 115 (23.3) 58
0.015 0.660 b0.001 0.171 0.001 b0.001 0.005 0.077
392 (76.6) 95 (18.6) 150 (29.3) 1.2 ± 0.8 264 (51.6) 411 (80.3) 467 (91.2) 292 (57.0) 90 (17.6) 65.6 ± 19.0
380 (77.1) 122 (24.7) 196 (39.8) 1.4 ± 0.8 258 (52.3) 403 (81.7) 452 (91.7) 310 (62.9) 50 (10.1) 65.7 ± 18.6
0.846 0.017 b0.001 0.001 0.807 0.552 0.789 0.059 0.001 0.920
Values are mean ± SD or n (%).ACE indicates angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; EQ-5D, European Quality of Life-5 Dimensions; GP, glycoprotein; MI, myocardial infarction; and PCI, percutaneous coronary intervention. a Angina was assessed according to the Canadian Cardiovascular Society Functional Classification of Angina Pectoris. b Antianginal medications included beta-blockers, calcium-antagonists, and nitrates.
the mean and median ages of the population was 64.5 and 64.7 years old, respectively. The age of the entire patient population ranged from 32.0 to 89.8 years old with an interquartile range of 15.7 years. Details regarding the study design have been described previously [7]. In brief, FAME was a prospective, multicenter, randomized clinical trial including 1005 patients with multivessel CAD eligible for PCI with drug-eluting stents. Patients with coronary lesions with at least 50% diameter stenosis based on visual estimation in ≥2 major epicardial vessels were randomly assigned to either angiography-guided PCI or FFR-guided PCI. Patients assigned to angiography-guided PCI underwent stenting of all identified stenoses, while patients assigned to the FFR-guided PCI had FFR measured first, and stenting was only performed if the FFR across the lesion was ≤0.80. Exclusion criteria were significant left main CAD, prior coronary artery bypass graft surgery, a recent ST-segment elevation MI (b5 days), cardiogenic shock, or extremely tortuous or calcified coronary arteries. The study protocol was approved by each Institutional Review Board or Ethics Committee, and each patient provided informed written consent.
2.2. Treatment and FFR measurement The interventional treatment of patients in the FAME study has been described previously [11]. PCI was performed according to standard coronary interventional techniques with DES. The FFR was measured with a coronary pressure guidewire (St. Jude Medical, St. Paul, MN) at maximum hyperemia induced by intravenous adenosine at a rate of 140 μg/kg/min through a central vein [7,12]. FFR was defined as the ratio between the mean distal coronary pressure and the mean aortic pressure. All patients received dual antiplatelet therapy with aspirin and clopidogrel for at least 1 year after PCI and the use of glycoprotein IIb/IIIa antagonists was at the discretion of the operator.
2.3. Endpoints and the goal of analysis All adverse clinical events were centrally adjudicated by an independent Clinical Events Committee blinded to treatment assignment. The primary endpoint of this reanalysis was the same as that of the original FAME trial and was the occurrence of major adverse cardiac events (MACE), a composite of all-cause death, myocardial infarction (MI), or the need for repeat coronary revascularization at 1 year after the index procedure in each age group. Details on these definitions regarding MACE have been described previously [7,11]. A secondary goal of this analysis was to compare FFR values between younger and older patients with similar degrees of angiographic stenosis.
All patients were included for analysis and stratified by age group for statistical comparisons based on treatment method. Categorical variables, including the primary endpoint and its individual components, are expressed as numbers or percentages and between-group differences were compared with chi-square test or Fisher exact test, as appropriate. Continuous variables are presented as mean ± SD and differences in those variables were assessed using Student t test or the Mann–Whitney U test as appropriate. The interaction between age and treatment strategy was investigated using Breslow– Day test. Angiographic stenosis per category and the respective FFR value of each specific coronary lesion were plotted in a box-and-whisker plot using GraphPad Prism version 5.03 software (GraphPad Software Inc., La Jolla, CA) to show side-by-side comparison in both age groups. Kaplan–Meier curves are shown for the time-to-event distributions of MACE in all patients stratified according to age group and treatment strategy. A 2-sided P value b 0.05 was considered statistically significant. All statistical analyses were performed using commercially available software (SPSS version 18 for Windows, SPSS Inc., Chicago, IL).
3. Results 3.1. Baseline clinical characteristics The age criteria were defined as 65 years old based on the mean and median ages of 1005 patients enrolled in the FAME study. With that, 512 patients (50.9%) were b65 years old, of which 250 were randomized to FFR-guided PCI and 262 were randomized to angiography-guided PCI. Among the 493 patients ≥ 65 years old, 259 and 234 patients were randomly assigned to FFR-guided PCI and angiography-guided PCI, respectively. Baseline clinical characteristics are presented in Table 1. Patients ≥65 years old were less likely to be male (64.7% vs. 83.0%, P b 0.001), to smoke (15.6% vs. 42.4%, P b 0.001), to have a history of MI (31.0% vs. 41.8%, P b 0.001) or to have a history of PCI (23.3% vs. 31.3%, P = 0.005), but were more likely to have hypertension (67.3% vs. 60.0%, P = 0.015), to use calcium antagonists or nitrates (24.7% vs. 18.6%, P = 0.017; 39.8% vs. 29.3, P b 0.001, respectively) and to require antianginal medications (1.4 vs. 1.2 per patient, P = 0.001). Older patients also had higher Euro-scores at baseline (4.5 ± 1.8 vs. 1.5 ± 1.5, P b 0.001) and lower EQ-5D scores at 1-year (72.5 ± 16.1 vs. 75.7 ± 15.4, P = 0.003). Table 2 Angiographic and procedural findings.
Number of diseased vessels, n 2 3 Lesions intended to treat, n Extent of occlusion visual estimation 50 to 70% stenosis 71 to 90% stenosis 91 to 99% stenosis Total occlusion Patient with Total Occlusion Proximal LAD lesion Lesion segments 1, 2, 3, 6, 7, and 11 Quantitative coronary analysis Extent of stenosis, % Minimal luminal diameter, mm Reference diameter, mm Mean lesion length, mm Length of lesions per patient, mm SYNTAX score Procedural time, min Volume of contrast agent used, ml Total stented length per patient, mm Implanted stents per patient, n
b65 years old (n = 512)
≥65 years old (n = 493)
372 (72.7) 140 (27.3) 2.8 ± 1.0.
369 (74.8) 124 (25.2) 2.7 ± 0.9
603 (42.7) 551 (39.0) 212 (15.0) 46 (3.3)
571 (42.2) 532 (39.3) 197 (14.6) 52 (3.8)
44 (8.6) 207 (40.4) 472 (92.2)
47 (9.5) 189 (38.3) 468 (94.9)
0.604 0.497 0.077
60.5 ± 16.6 1.01 ± 0.44 2.51 ± 0.65 12.9 ± 6.7 32.2 ± 18.6 14.6 ± 9.3 71.5 ± 43.6 295.2 ± 136.0 46.9 ± 27.9 2.4 ± 1.3
59.8 ± 17.3 1.01 ± 0.45 2.46 ± 0.61 12.4 ± 6.4 30.7 ± 16.4 14.4 ± 8.1 68.9 ± 43.2 278.6 ± 124.8 42.7 ± 26.2 2.3 ± 1.3
0.331 0912 0.051 0.052 0.155 b0.001 0.347 0.045 0.015 0.071
P 0.430
0.742 0.844
Values are mean ± SD or n (%). EuroSCORE indicates European System for Cardiac Operative Risk Evaluation; LAD, left anterior descending artery; and SYNTAX, Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery.
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Table 3 Outcome at 1 year of patients stratified to age and treatment strategy. b65 years old (n = 512)
Composite of MACE Death MI Repeat revascularization Death or MI
≥65 years old (n = 493)
FFR-guided (n = 250)
Angiography-guided (n = 262)
Pa
RRRb
FFR-guided (n = 259)
Angiography-guided (n = 234)
Pa
RRRb
Breslow– Day Pc
30 (12.0) 3 (1.2) 13 (5.2) 14 (5.6) 16 (6.4)
45 (17.2) 5 (1.9) 24 (9.2) 25 (9.5) 28 (10.7)
0.098 0.725 0.084 0.093 0.084
0.30 (−0.06 to 0.66) 0.37 (−0.95 to 1.74) 0.87 (0.47 to 1.33) 0.41 (−0.08 to 0.91) 0.40 (−0.06 to 0.87)
37 (14.3) 6 (2.3) 16 (6.2) 19 (7.3) 21 (8.1)
46 (19.7) 10 (4.3) 19 (8.1) 22 (9.4) 27 (11.5)
0.111 0.221 0.402 0.407 0.199
0.27 (−0.06 to 0.61) 0.46 (−0.31 to 1.31) 0.24 (−0.33 to 0.83) 0.22 (−0.31 to 0.76) 0.30 (−0.16 to 0.77)
0.920 0.858 0.530 0.522 0.706
Values are n (%). FFR indicates fractional flow reserve; MACE, major adverse cardiac events; and MI, myocardial infarction. a P value represents comparison between FFR-guided versus angiography-guided percutaneous coronary intervention (PCI) for clinical outcomes at 1 year. b Relative risk reductions (RRR) by using FFR for both patients b65 and ≥65 years old is shown. Interaction between age groups and treatment for the different outcomes are also shown. c Breslow–Day indicates Breslow–Day test for heterogeneity of odds ratio of FFR-guided PCI versus the odds ratio of angiography-guided PCI within each age subgroup.
3.2. Angiographic and procedural results Table 2 shows angiographic findings and procedural results. Patients ≥65 years old had lower SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) scores (14.4 ± 8.1 vs. 14.6 ± 9.3, P b 0.001), a tendency to smaller reference diameters (2.46 ± 0.61 mm vs. 2.51 ± 0.65 mm, P = 0.051) and shorter lesion lengths (12.4 ± 6.4 mm vs. 12.9 ± 6.7 mm, P = 0.052). The total stented length per patient was shorter in those ≥ 65 years old (42.7 ± 26.2 mm vs. 46.9 ± 27.9 mm, P = 0.015), and there was less contrast used per patient (278.6 ± 124.8 ml vs. 295.2 ± 136.0 ml, P = 0.045). 3.3. Clinical outcomes at 1 year When comparing the benefit of FFR-guided PCI in patients b 65 years old to those ≥65 years old, there was a similar relative risk reduction in the primary endpoint of death, MI and the need for repeat revascularization and there was no evidence for heterogeneity in the benefit based on age (Table 3). Kaplan–Meier curves for survival free from MACE based on FFR or angiography guidance and age above or below 65 years are presented in Fig. 1. The composite of death, MI, and repeated revascularization occurred in 14.6% of all patients b65 years old versus 16.8% of patients ≥65 years old (P = 0.341). 3.4. Angiographic versus functional stenosis severity In the FFR-guided arm of the FAME study, a total of 1414 lesions were noted in 509 patients. Of these, the FFR was measured successfully
in 1,329 lesions which were available for comparison with angiographic lesion severity [12]. Mean FFR value obtained from older patients was significantly higher than that in younger patients (0.72 ± 0.17 vs. 0.70 ± 0.18, P = 0.043). By visual estimation, the lesions were prospectively categorized as 50% to 70%, 71% to 90%, or 91% to 99% diameter stenosis. Angiographic lesion severity per category and its respective FFR values are presented in Fig. 2. The mean FFR values of patients ≥ 65 years old, compared with those of patients b65 years old, were significantly higher in vessels with 50% to 70% (0.83 ± 0.11 vs. 0.80 ± 0.13, P = 0.028) and 71% to 90% stenosis (0.69 ± 0.15 vs. 0.65 ± 0.16, P = 0.002). Older patients had a significantly lower proportion of lesions with functional significance (FFR ≤ 0.80) than younger patients in the 71% to 90% stenosis category (75.3% vs. 84.1%, P = 0.013).
4. Discussion The principle finding of this study is that FFR-guided PCI as compared to angiography-guided PCI in patients with multivessel CAD is equally beneficial in older patients, those ≥ 65 years old, as it is in younger ones. An important second finding is that for any given stenosis, the FFR is less likely to be abnormal in older patients. Not surprisingly, older patients tended to have worse overall outcomes with PCI, regardless of strategy, when compared to younger patients. The FAME trial showed that in patients with multivessel CAD undergoing PCI with DES, FFR guidance resulted in a lower rate of MACE (death, MI and the need for repeat revascularization) when compared to the traditional angiography-guided PCI [7]. In this substudy from FAME, we found that FFR-guided PCI was equally beneficial in older
Fig. 1. Kaplan–Meier curves for survival free from MACE at 1 year stratified to age and treatment strategy. Kaplan–Meier curves for the percentage survival free from major adverse cardiac events (MACE) at 1 year in the 4 groups stratified by age and treatment. Relative risk reduction (RRR) of MACE by fractional flow reserve (FFR)-guided percutaneous coronary intervention is indicated in b65 year-old and ≥65 year-old patients.
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Fig. 2. FFR values according to angiographic stenosis severity. Box-and-whisker plot showing the fractional flow reserve (FFR) values of all lesions in both b65 and ≥65 age groups according to the categories of 50% to 70%, 71% to 90%, and 91% to 99% diameter stenosis. The dotted horizontal line represents FFR cut-off value for myocardial ischemia.
patients, as it was in younger ones. It is important to note that although the older cohort had higher rates of MACE after PCI compared to younger patients (Table 3), those who were randomized to FFR-guided PCI had a similar reduction in MACE compared to the younger cohort, both in absolute and relative terms (Fig. 1). These data are reassuring because changes in cardiac function which occur with aging might affect the reliability of FFR [13,14]. Microvascular dysfunction resulting from long-standing hypertension, left ventricular hypertrophy and/or diastolic dysfunction occurs more frequently in older patients [14,15]. FFR relies on achieving maximal hyperemia through vasodilation of the microvasculature. One might be concerned that the increased microvascular dysfunction in older patients could lead to lower peak flow down the vessel, a lower translesional gradient and an overestimation of FFR for a given stenosis. However, even in the setting of microvascular dysfunction, FFR remains a reliable indicator of the functional significance of an epicardial stenosis. It still informs the operator regarding the expected increase in coronary flow that will be achieved with PCI [16]. Indeed, an important secondary finding in this substudy is that in older patients a moderate stenosis is less likely to be associated with an abnormal FFR when compared to the same stenosis in a younger patient (Fig. 2). Presumably, this is a result of greater degrees of microvascular dysfunction present in older patients [13,14], although other differences between older and younger patients, such as lesion length and reference diameter might have contributed. This finding highlights the importance of using a physiologic index to assess the need for PCI, as opposed to angiography or intravascular imaging, particularly in older patients.
4.1. Study limitations This study is limited by its post hoc nature and because it was a subanalysis of patients in the FAME study. Therefore, it is underpowered to show superiority of the FFR-guided strategy over the angiographyguided strategy in each age subgroup and should be interpreted as hypothesis generating. In this respect, longer-term follow-up might be informative. A substudy of the FAME trial reported the 2-year followup, however, we decided to make the 1-year analysis the primary endpoint of this age substudy to avoid performing a substudy of another
substudy. The age cutoff of 65 years is arbitrary, but we believe it is reasonable, given that it represents the mean age of patients enrolled in the study. The interpretation of the coronary stenoses was based on visual inspection of the angiogram at the time of study enrolment and not core laboratory quantitative coronary angiography. However, we believe this is more reflective of clinical practice. 5. Conclusions In patients with multivessel CAD, FFR-guided PCI is beneficial regardless of age. However, older patients have fewer functionally significant lesions, despite a similar angiographic appearance. Funding sources The FAME study was sponsored by St. Jude Medical. Disclosures William F. Fearon receives an institutional research support from St. Jude Medical. Bernard De Bruyne and Nico H.J. Pijls are consultants for St. Jude Medical. The other authors report no conflicts relevant to the contents of this paper to disclose. Conflict of interest Dr. Pijls and Dr. De Bruyne are consultants for St. Jude Medical. Dr. Fearon receives research support from St. Jude Medical. All other authors have no relevant conflicts. References [1] Rao SV, Hess CN, Dai D, Green CL, Peterson ED, Douglas PS. Temporal trends in percutaneous coronary intervention outcomes among older patients in the United States. Am Heart J 2013;166:273–281 e4. [2] Varani E, Aquilina M, Balducelli M, Vecchi G, Frassineti V, Maresta A. Percutaneous coronary interventions in octogenarians: acute and 12 month results in a large single-centre experience. Catheter Cardiovasc Interv 2009;73:449–54. [3] Vlaar PJ, Lennon RJ, Rihal CS, et al. Drug-eluting stents in octogenarians: early and intermediate outcome. Am Heart J 2008;155:680–6.
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