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Clinical outcomes of deferred revascularisation using fractional flow reserve in diabetic patients
CARREV-01781; No of Pages 6 Cardiovascular Revascularization Medicine xxx (xxxx) xxx
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Cardiovascular Revascularization Medicine
Clinical outcomes of deferred revascularisation using fractional flow reserve in diabetic patients Mohammad Alkhalil a,⁎, Claire McCune a, Lisa McClenaghan a, Jonathan Mailey a, Patrick Collins a, Aileen Kearney a, Matthew Todd a, Peter McKavanagh a,b a b
Department of Cardiology, Royal Victoria Hospital, Belfast, UK Department of Cardiology, Ulster Hospital, Belfast, UK
a r t i c l e
i n f o
Article history: Received 27 October 2019 Received in revised form 10 December 2019 Accepted 13 December 2019 Available online xxxx Keywords: FFR Diabetes Deferred revascularisation
a b s t r a c t Background: Fractional flow reserve (FFR) is used to assess the functional significance of coronary artery lesions. Diabetic patients are associated with high burden of atherosclerosis and microvascular dysfunction. We studied the clinical outcomes of diabetic patients who underwent FFR-guided deferred revascularisation. Methods: Consecutive patients from a single large volume centre who underwent FFR assessment were included. Clinical endpoints were prospectively collected using the national electronic care records system. The primary endpoint was defined as the four-year risk of the vessel-oriented composite outcome of cardiac death, vesselrelated myocardial infarction (VMI), and vessel-related urgent revascularisation (VUR). Absolute FFR values groups (0.81 to 0.85; 0.86 to 0.90; and N0.90) were used to further stratify patient outcomes. Results: FFR-guided deferred revascularisation occurred in 860 patients (63%), of whom 159 were diabetic. The primary endpoint was significantly higher in the diabetic compared to the non-diabetic group [HR 1.76 (95%CI 1.08 to 2.88), P = 0.024]. The difference was driven from cardiac death (6.3% vs. 3.0%, P = 0.044) and VMI (5.0% vs. 1.7%, P = 0.012) but not VUR (8.8% vs. 5.1%, P = 0.07). There was a significant decrease in the incidence of the primary endpoint in the diabetic group according to FFR groups (23.6%, 12.3%, 2.4%, P = 0.001) with comparable clinical outcomes in the non-diabetic group (11.8%, 6.4%, 7.4%, P = 0.085). Conclusions: Our study demonstrated an increased risk of death and target vessel MI in diabetic patients undergoing FFR-guided deferred revascularisation compared to non-diabetic group. Nonetheless, FFR remained a useful tool to identify those at future risk, mainly in diabetic patients. © 2019 Elsevier Inc. All rights reserved.
1. Introduction Fractional flow reserve (FFR) is currently the standard of care to evaluate the functional significance of coronary arteries stenoses invasively [1]. FFR-guided percutaneous coronary intervention (PCI) significantly reduced major adverse events compared to angiography-based PCI and showed incremental benefits to medical therapy in patients with stable coronary artery disease [2,3]. Moreover, favourable clinical outcomes were also reported in patients with FFR-based deferred revascularisation in the DEFER and FAME 2 studies [3,4]. Diabetes mellitus is an independent risk factor of coronary artery disease. Diabetic patients have worse clinical outcomes irrespective of the presence or absence of established coronary artery disease [5].
⁎ Corresponding author at: Department of Cardiology, Royal Victoria Hospital, Belfast BT12 6BA, UK. E-mail address: [email protected] (M. Alkhalil).
Factors such as accelerated atherosclerosis, endothelial dysfunction, and impaired microvascular function are associated with diabetes and potentially contribute to its adverse clinical outcomes [6,7]. Microvascular dysfunction may impede the increase in coronary blood flow with pharmacological vasodilation, underestimating the degree of ischaemia using FFR [8,9]. This becomes more relevant since the number of diabetic patients whom had deferred FFR-guided PCI was remarkably small (11% in the DEFER and 27% in the FAME 2 studies). Therefore, any definitive conclusions regarding deferred revascularisation using FFR in diabetic patients may be challenged. Moreover, recent studies have demonstrated worse clinical outcomes in FFR-guided deferred revascularisation in diabetic patients [10,11]. These studies, however, were small in size to allow absolute decision regarding FFR in diabetic patients. Furthermore, a recent post hoc analysis from the DEFINEFLAIR trial reporting one-year follow up, demonstrated a numerically higher incidence of adverse clinical outcomes in deferred patients with diabetes compared to those without diabetes [12]. The aim of this study was to compare the long-term clinical outcomes of diabetic and non-diabetic patients who had FFR-guided
https://doi.org/10.1016/j.carrev.2019.12.019 1553-8389/© 2019 Elsevier Inc. All rights reserved.
Please cite this article as: M. Alkhalil, C. McCune, L. McClenaghan, et al., Clinical outcomes of deferred revascularisation using fractional flow reserve in diabetic patients, Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.12.019
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M. Alkhalil et al. / Cardiovascular Revascularization Medicine xxx (xxxx) xxx
medical management. Further consideration was given to the absolute FFR value obtained and how this affected study composite endpoints. 2. Methods 2.1. Study population Between January 2014 and December 2015, 1482 consecutive patients who underwent FFR at the Royal Victoria Hospital in Belfast were screened. In 42 (2.8%) patients, the absolute FFR value was not documented and rather a ‘positive’ or ‘negative’ functional assessment was reported. These patients were excluded from the current analysis alongside 35 (2.4%) patients who underwent instantaneous wave-free ratio (iFR) only (Fig. 1). Patients with positive FFR (≤0.8) requiring percutaneous or surgical revascularisation as per current guidelines were excluded from the analysis (Fig. 1) [1]. 2.2. Fractional flow reserve assessment Coronary artery lesions with angiographic 40–80% degree of stenosis were interrogated using FFR. Patients with multi-vessel disease who underwent multi-assessment using FFR and deemed non-functionally significant were also included. The lowest recorded value was used as the absolute FFR value in the current analysis. A 6 French guiding catheter was universally used for the functional assessment of coronary stenoses. A 0.014 intra-coronary pressuremonitoring guidewire was used (PressureWire Certus, St. Jude Medical or Combowire, Volcano Corp), calibrated, equalised, and positioned distal to the coronary lesion as previously described [8]. All procedures were performed using intra-arterial heparin (70 U/kg). Intra-venous adenosine was administered (140 μg/kg/min) to induce hyperaemia and minimal distal coronary pressure. Upon reaching stead-state hyperaemia, FFR was calculated as the ratio of the mean distal intra-coronary pressure to the mean arterial pressure as previously described [8].
2.3. Study endpoints and follow up The primary endpoint was defined as the risk of the vessel-oriented composite outcome of cardiac death, vessel-related myocardial infarction, and vessel-related urgent revascularisation. The secondary endpoints were defined as the composite of all-cause mortality, myocardial infarction (which included both previously FFR-interrogated and noninterrogated arteries), and unplanned urgent revascularisation (which was combined previously FFR-assessed and non-assessed arteries), in addition, to the individual components of the primary endpoint. Patients were followed up for 4 years and clinical endpoints were prospectively collected and regularly updated using the national electronic care records system of Health and Social Care in Northern Ireland. Recorded information was crossed-checked by reviewing hospital admissions and general practitioners' records. 2.4. Statistical analysis Data were assessed using the Shapiro-Wilk test for normality of distribution. All variables were expressed as mean ± standard deviation (if data were normally distributed) or as median accompanied by interquartile range (IQR) for non-parametric data. Continuous variables were compared using unpaired t-test or Mann-Whitney U test as appropriate, while frequencies comparisons were made using Chi square test or Fisher's exact test, as appropriate. Kaplan–Meier and the associated log-rank test were performed to determine the differences in the primary and secondary endpoints. Cox regression model were used to calculate unadjusted and adjusted hazard ratio (HR) of the primary endpoint. All statistical analysis was performed using SPSS 22.0 (SPSS, Inc. Chicago, Illinois) and a P value b0.05 was considered statistically significant. 3. Results A total of 860 patients who underwent FFR-guided deferred revascularisation were included (Fig. 1). Average age was 66 ± 10 and
Fig. 1. Study flow chart.
Please cite this article as: M. Alkhalil, C. McCune, L. McClenaghan, et al., Clinical outcomes of deferred revascularisation using fractional flow reserve in diabetic patients, Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.12.019
M. Alkhalil et al. / Cardiovascular Revascularization Medicine xxx (xxxx) xxx Table 1 Clinical and procedural characteristics of patients stratified according to their diabetes status.
Age (mean ± SD) Male gender (n, %) Hypertension (n, %) Hypercholesteraemia (n, %) Family history of IHD (n, %) Active smoking (n, %) Previous MI (n, %) Previous PCI (n, %) Previous CABG (n, %) Normal renal function (n, %) Normal LVSF (n, %) Vessel interrogated (n, %) LAD LCX RCA Multi-vessel disease (n, %) FFR value (median, IQR)
Whole cohort
Diabetic (n = 159)
Non-diabetic (n = 701)
P value
66 ± 10 632 (74%) 522 (61%) 484 (56%) 552 (66%) 301 (35%) 300 (36%) 379 (45%) 33 (4%) 695 (81%) 646 (84%)
67 ± 9 116 (73%) 114 (72%) 90 (57%) 102 (67%) 60 (38%) 57 (38%) 76 (50%) 9 (6%) 118 (74%) 123 (86%)
66 ± 10 516 (74%) 408 (58%) 394 (56%) 450 (66%) 241 (34%) 243 (36%) 303 (44%) 24 (4%) 577 (83%) 523 (84%)
0.23 0.87 0.002 0.93 0.76 0.42 0.65 0.20 0.17 0.016 0.52
548 (64%) 252 (29%) 246 (29%) 166 (19%) 0.88 (0.84–0.91)
106 (67%) 50 (31%) 44 (28%) 39 (25%) 0.87 (0.85–0.91)
442 (63%) 202 (29%) 202 (29%) 127 (18%) 0.88 (0.84–0.91)
0.39 0.51 0.78 0.06 0.64
IHD: ischaemic heart disease, MI: myocardial infarction, PCI: percutaneous coronary intervention, CABG: coronary artery bypass graft, LVSF: left ventricle systolic function, LAD: left anterior descending, LCx: circumflex, RCA: right coronary artery, FFR: fractional flow reserve.
74% (632/860) were male. More than one third of patients had previous myocardial infarction and almost half of the cohort had previous revascularisation (Table 1). The median FFR value was 0.88 (0.84– 0.91) and the left anterior descending artery (LAD) was the most interrogated coronary artery (64%). Diabetes mellitus was present in 159 (18.5%) patients. There were no differences in age, gender and traditional clinical risk factors between diabetic and non-diabetic groups, except for hypertension which was more frequently reported in diabetic patients (72% vs. 58%, P = 0.002) (Table 1). The proportion of patients with normal renal unction was also lower in the diabetic group (74% vs. 83%, P = 0.016). The median FFR was comparable between the two groups with numerically higher proportion of multi-vessel disease in the diabetic
3
group (25% vs. 18%, P = 0.06), although this difference did not reach statistical significance. The primary endpoint occurred in 9.2% (79/860) patients over the 4 years follow up and was significantly higher in the diabetic compared to the non-diabetic group [HR 1.76 (95% CI 1.08 to 2.88), P = 0.024] (Fig. 2). The difference was driven from cardiac death (6.3% vs. 3.0%, P = 0.044) and target vessel myocardial infarction (5.0% vs. 1.7%, P = 0.012) (Table 2). Target vessel urgent revascularisations were higher in the diabetic group but this difference did not reach statistical significance (8.8% vs. 5.1%, P = 0.07) (Table 3). Similarly, the secondary endpoint of the composite of all-cause mortality, myocardial infarction (total) and urgent unplanned revascularisation, was significantly higher in the diabetic group [HR 1.79 (95% CI 1.25 to 2.56), P = 0.001] (Fig. 3A). Diabetic patients with deferred revascularisation had two-fold increased risk of death over 4 years follow up compared to non-diabetic patients [HR 2.01 (95% CI 1.24 to 3.25), P = 0.004] (Fig. 3B) (Table 2). When the cohort was stratified according to the absolute FFR value (0.81 to 0.85, 0.86 to 0.90, and N0.90), there was significant stepwise decrease in the incidence of the primary endpoint in the diabetic group (23.6%, 12.3%, 2.4%, P = 0.001 respectively) with comparable clinical outcomes in the non-diabetic group (11.8%, 6.4%, 7.4%, P = 0.085 respectively) (Fig. 4). Furthermore, for every 1 point percentage increase in FFR value there was 15% reduction of the primary endpoint in diabetic patients with deferred revascularisation, even after adjustment for multiple risk factors (HR 0.85, 95%CI 0.76 to 0.96, P = 0.007) (Table 3). 4. Discussion The main findings of this real-world study can be summarised as follow: (1) diabetic patients remain at an increased future risk compared to non-diabetic patients despite having functionally non-significant coronary artery disease, (2) this risk was mainly derived from cardiac death and target vessel myocardial infarction but not target vessel revascularisation, (3) the future risk was proportional to the degree of ischaemia as measured by FFR in the diabetic but not in the nondiabetic group.
Fig. 2. Primary endpoint in patients with deferred revascularisation stratified according to their diabetes status. Kaplan-Meier curves comparing cumulative incidence of four-year vesseloriented composite endpoints (cardiac death, vessel-related myocardial infarction, and vessel-related urgent revascularisation) in patients with diabetes versus non-diabetes.
Please cite this article as: M. Alkhalil, C. McCune, L. McClenaghan, et al., Clinical outcomes of deferred revascularisation using fractional flow reserve in diabetic patients, Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.12.019
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Table 2 Incidence rate of primary and secondary clinical outcomes.
Primary endpoint (cardiac death, target vessel myocardial infarction, target vessel revascularisation) Secondary endpoint (death, myocardial infarction, urgent revascularisation) All-cause mortality Cardiac death Myocardial infarction (total) Target vessel myocardial infarction Urgent revascularisation Target vessel urgent revascularisation
Diabetic (n = 159)
Non-diabetic (n = 701)
P value
22 (13.8%)
57 (8.1%)
0.025
42 (26.4%)
107 (15.3%)
0.001
24 (15.1%) 10 (6.3%) 12 (7.5%) 8 (5.0%) 19 (11.9%) 14 (8.8%)
54 (7.7%) 21 (3.0%) 25 (3.6%) 12 (1.7%) 48 (6.8%) 36 (5.1%)
0.003 0.044 0.026 0.012 0.03 0.07
The decision to defer intervention in FFR-measured functionally non-significant coronary stenosis in patients with diabetes has been recently challenged [10,11]. The presence of small vessel disease was initially thought to influence the measurement of FFR and subsequently affecting ischaemia assessment [8,9]. Diabetic patients have worse microvascular dysfunction as measured by index microcirculatory resistance when compared to non-diabetic patients [13]. Nonetheless, such difference may not necessarily translate into a clinically meaningful difference in FFR measurements [14]. In fact, other work has suggested that there are no differences between FFR values of diabetic and nondiabetic patients who had coronary lesions with similar degree of stenosis and irrespective of the reference vessel diameter [14]. The separation of the Kaplan-Meier curves in our study did not support the concept that ischaemia was merely underestimated using FFR. Indeed, the curves run parallel for more than half of the study duration with clinically significant events accruing after the third year of follow up. The same trend was mirrored in the separation Kaplan-Meier curves of the secondary endpoint, which included total myocardial infarction alongside urgent revascularisation. This phenomenon may reflect the atherosclerosis process in diabetic patients leading to more vulnerable plaques and inevitably acute cardiac events and may suggest that native disease takes precedent over FFR, particular in diabetic patients. Previous studies of multi-vessel interrogations using optical coherent tomography (OCT) compared the atherosclerotic burden between diabetic and non-diabetic patients using [6]. Larger lipid area and higher prevalence of thin-cap fibro atheroma were identified in diabetic patients [6]. Similar findings were also reported from the PROSPECT study using intra-vascular ultrasound (IVUS) [15]. It is widely recognised that diabetes is a systemic disease with altered metabolic cellular profile and increased inflammation promoting thrombosis [16]. Nonetheless, the true mechanisms by which diabetes is associated with accelerated atherosclerosis remains unknown. FFR is a reliable surrogate of myocardial ischaemia [17,18]. The use of a cut-off to dichotomise a continuous variable such as FFR and subsequently ischaemia may remove a significant proportion of its information content [19]. However, Barbato et al. [17] reported a non-linear
relationship between FFR and major adverse events in patients who were managed without revascularisation. Interestingly, the risk of adverse events steeply increased when FFR value dropped below 0.80. The relationship was almost linear in lesions with FFR N 0.8, while there was a plateau of clinical events when FFR dropped below 0.60 [17]. This is important as patients with negative FFR (i.e. FFR N 0.80) remained at risk of future cardiac events. Moreover, this risk, albeit is small, was proportional to the degree of ischaemia as quantified by FFR. Our data illustrated a linear increase in the primary endpoint in patients with FFR N 0.80. This correlation was particularly pronounced in diabetic patients. Furthermore, we demonstrated that the risk associated with FFR deferred strategy was continuous and for every one point percentage increase in FFR value, there was 15% reduction in future cardiac events. In fact, almost 1 in 4 diabetic patients with FFR value of 0.81–0.85 sustained an event compared to b3% in diabetic patients with FFR N 0.90. This reinforces the concept that ischaemia assessment using FFR is a spectrum not a binary phenomenon and patients with FFR value N0.80 should not be dismissed as no risk but rather low future risk. In fact, in the IRIS-FFR Registry (Interventional Cardiology Research Incooperation Society Fractional Flow Reserve), FFR value showed linear association with future cardiovascular risk in deferred coronary lesions [20]. Similarly, a recent secondary analysis from the DEFINE-FLAIR study reported cardiac event rate of 5.1% at 12 months in the FFR-deferred diabetic group (177 patients) [12]. In a study evaluating the association between physiological stenosis severity using FFR and plaque vulnerability using coronary computed tomography angiography, Lee et al. [21], reported the differential prognostic implications of plaque vulnerability according to FFR. The authors highlighted the significant role of using plaque characteristics to identify high risk patients in particularly in patients with FFR N 0.80. Interestingly, alongside high-risk plaque features, diabetes status had more than three times the likelihood of developing adverse cardiac events even after adjusting for plaque vulnerability. In fact, diabetes was the strongest predictor of clinical outcomes in patients with FFR N 0.80. Importantly, our study used the same vessel oriented clinical endpoints to truly identify events derived from the interrogated coronary vessel. This contrasts with a recent study by Liu et al. [22], reporting that FFR was not able to differentiate the risk of cardiovascular events in diabetic patients. However, the clinical endpoints were not tailored towards the FFR-assessed coronary artery, making any comparison with our study very difficult. The explanation for our findings that patients with DM have lower risk than non-diabetic in the group of FFR N 0.9 is not clear. The demographic profile and clinical risks were comparable between the two groups. Likewise, the FFR value and the proportion of multivessel disease were also similar. We speculate that this may be related to the fact that these subsets were subgroup of subgroups with relatively small sample size. Our data were derived from a single centre which could be considered as a limitation. Nevertheless, we provided large real-world dataset from a high volume centre. Our study did not include resting Pd/Pa and therefore its prognostic role in diabetic versus non-diabetic cannot be
Table 3 Unadjusted and adjusted predictors of primary endpoint predictors in diabetic patients.
Age Male gender Hypertension Active smoking Previous MI Previous revascularisation Estimated glomerular filtration rate (eGFR) Normal LVSF LAD artery Multi-vessel disease FFR valuea a
HR (unadjusted)
95% CI
P value
1.04 0.93 1.80 1.70 1.89 1.27 0.97 3.26 2.28 1.10 0.85
0.99 to 1.10 0.36 to 2.36 0.61 to 5.31 0.74 to 3.93 0.80 to 4.45 0.53 to 3.01 0.94 to 1.00 0.44 to 24.27 0.77 to 6.75 0.43 to 2.82 0.75 to 0.95
0.10 0.87 0.29 0.21 0.15 0.59 0.05 0.25 0.14 0.84 0.006
HR (adjusted)
95% CI
P value
0.97
0.95 to 1.00
0.08
0.85
0.76 to 0.96
0.007
For every one percentage change in FFR value. MI: myocardial infarction, LVSF: left ventricle systolic function, FFR: fractional flow reserve.
Please cite this article as: M. Alkhalil, C. McCune, L. McClenaghan, et al., Clinical outcomes of deferred revascularisation using fractional flow reserve in diabetic patients, Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.12.019
M. Alkhalil et al. / Cardiovascular Revascularization Medicine xxx (xxxx) xxx
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Fig. 3. Secondary endpoints in patients with deferred revascularisation stratified according to their diabetes status. Panel (A), Kaplan-Meier curves comparing cumulative incidence of allcause mortality, myocardial infarction and urgent revascularisation according to patients' diabetes status. Panel (B), Kaplan-Meier curves demonstrating worse survival in diabetic patients during the study follow up.
ascertained. While Pd/Pa has been shown to correlate with FFR [23,24], it is not clinically used to guide treatment for intermediate coronary artery stenosis. The ongoing LIPSIASTRATEGY study (NCT03497637) is currently testing this hypothesis. Moreover, patients with deferred revascularisation did not undergo intra vascular imaging assessment to evaluate whether future cardiac events could be predicted using certain plaque characteristics such as large plaque burden and/or lipid core.
Further research to assess whether OCT or IVUS are useful tools to delineate risk in diabetic patients with FFR N 0.80 are needed. In conclusion our study demonstrated an increased risk of death and target vessel MI in diabetic patients undergoing FFR-guided deferred revascularisation compared to non-diabetic group. Nonetheless, FFR remained a useful tool to identify those at future risk in particularly in diabetic patients.
Fig. 4. The incidence of the primary endpoint according to the FFR value between diabetic and non-diabetic patients. There was a stepwise increase in vessel-oriented composite endpoints according to the FFR value. This linear relationship was more marked in the diabetic group.
Please cite this article as: M. Alkhalil, C. McCune, L. McClenaghan, et al., Clinical outcomes of deferred revascularisation using fractional flow reserve in diabetic patients, Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.12.019
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Authors' contributions Conceptualization, data curation, project administration and formal analysis (MA). Investigation, methodology, software and resources (MA, CM, LM, JM, PC, AK, MT, PM). Writing original draft and preparation of full manuscript (MA, PM). Writing review and editing (MA, CM, LM, JM, PC, AK, MT, PM). Funding None. Declaration of competing interest None. Acknowledgments None. References [1] Neumann FJ, Sousa-Uva M, Ahlsson A, Alfonso F, Banning AP, Benedetto U, et al. ESC/ EACTS guidelines on myocardial revascularization. Eur Heart J 2018:2018. [2] Tonino PA, De Bruyne B, Pijls NH, Siebert U, Ikeno F, van’t Veer M, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360:213–24. [3] De Bruyne B, Pijls NH, Kalesan B, Barbato E, Tonino PA, Piroth Z, et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med 2012;367:991–1001. [4] Pijls NH, van Schaardenburgh P, Manoharan G, Boersma E, Bech JW, van’t Veer M, et al. Percutaneous coronary intervention of functionally nonsignificant stenosis: 5-year follow-up of the DEFER study. J Am Coll Cardiol 2007;49:2105–11. [5] Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229–34. [6] Kato K, Yonetsu T, Kim SJ, Xing L, Lee H, McNulty I, et al. Comparison of nonculprit coronary plaque characteristics between patients with and without diabetes: a 3vessel optical coherence tomography study. JACC Cardiovasc Interv 2012;5:1150–8. [7] Di Carli MF, Janisse J, Grunberger G, Ager J. Role of chronic hyperglycemia in the pathogenesis of coronary microvascular dysfunction in diabetes. J Am Coll Cardiol 2003;41:1387–93. [8] Pijls NH, De Bruyne B, Peels K, Van Der Voort PH, Bonnier HJ, Bartunek JKJJ, et al. Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses. N Engl J Med 1996;334:1703–8.
[9] Meuwissen M, Chamuleau SA, Siebes M, Schotborgh CE, Koch KT, de Winter RJ, et al. Role of variability in microvascular resistance on fractional flow reserve and coronary blood flow velocity reserve in intermediate coronary lesions. Circulation 2001;103:184–7. [10] Kennedy MW, Kaplan E, Hermanides RS, Fabris E, Hemradj V, Koopmans PC, et al. Clinical outcomes of deferred revascularisation using fractional flow reserve in patients with and without diabetes mellitus. Cardiovasc Diabetol 2016;15:100. [11] Dominguez-Franco AJ, Jimenez-Navarro MF, Munoz-Garcia AJ, Alonso-Briales JH, Hernandez-Garcia JM, de Teresa Galvan E. Long-term prognosis in diabetic patients in whom revascularization is deferred following fractional flow reserve assessment. Rev Esp Cardiol 2008;61:352–9. [12] Investigators D-FT, Lee JM, Choi KH, Koo BK, Dehbi HM, Doh JH, et al. Comparison of major adverse cardiac events between instantaneous wave-free ratio and fractional flow reserve-guided strategy in patients with or without type 2 diabetes: a secondary analysis of a randomized clinical trial. JAMA Cardiol 2019;4(9):857–64. https:// doi.org/10.1001/jamacardio.2019.2298. [13] Leung M, Leung DY. Coronary microvascular function in patients with type 2 diabetes mellitus. EuroIntervention 2016;11:1111–7. [14] Sahinarslan A, Kocaman SA, Olgun H, Kunak T, Kiziltunc E, Ozdemir M, et al. The reliability of fractional flow reserve measurement in patients with diabetes mellitus. Coron Artery Dis 2009;20:317–21. [15] Stone GW, Maehara A, Lansky AJ, de Bruyne B, Cristea E, Mintz GS, et al. A prospective natural-history study of coronary atherosclerosis. N Engl J Med 2011;364: 226–35. [16] Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 2002;287:2570–81. [17] Barbato E, Toth GG, Johnson NP, Pijls NH, Fearon WF, Tonino PA, et al. A prospective natural history study of coronary atherosclerosis using fractional flow reserve. J Am Coll Cardiol 2016;68:2247–55. [18] van de Hoef TP, Meuwissen M, Escaned J, Davies JE, Siebes M, Spaan JA, et al. Fractional flow reserve as a surrogate for inducible myocardial ischaemia. Nat Rev Cardiol 2013;10:439–52. [19] Harrell Jr FE, Lee KL, Califf RM, Pryor DB, Rosati RA. Regression modelling strategies for improved prognostic prediction. Stat Med 1984;3:143–52. [20] Ahn JM, Park DW, Shin ES, Koo BK, Nam CW, Doh JH, et al. Fractional flow reserve and cardiac events in coronary artery disease: data from a prospective IRIS-FFR registry (Interventional Cardiology Research Incooperation Society Fractional Flow Reserve). Circulation 2017;135:2241–51. [21] Lee JM, Choi KH, Koo BK, Park J, Kim J, Hwang D, et al. Prognostic implications of plaque characteristics and stenosis severity in patients with coronary artery disease. J Am Coll Cardiol 2019;73:2413–24. [22] Liu Z, Matsuzawa Y, Herrmann J, Li J, Lennon RJ, Crusan DJ, et al. Relation between fractional flow reserve value of coronary lesions with deferred revascularization and cardiovascular outcomes in non-diabetic and diabetic patients. Int J Cardiol 2016;219:56–62. [23] De Luca G, Verdoia M, Barbieri L, Marino P, Suryapranata H. Resting Pd/Pa and haemodynamic relevance of coronary stenosis as evaluated by fractional flow reserve. Coron Artery Dis 2018;29:138–44. [24] Mamas MA, Horner S, Welch E, Ashworth A, Millington S, Fraser D, et al. Resting Pd/ Pa measured with intracoronary pressure wire strongly predicts fractional flow reserve. J Invasive Cardiol 2010;22:260–5.
Please cite this article as: M. Alkhalil, C. McCune, L. McClenaghan, et al., Clinical outcomes of deferred revascularisation using fractional flow reserve in diabetic patients, Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.12.019
Contents lists available at ScienceDirect
Cardiovascular Revascularization Medicine
Clinical outcomes of deferred revascularisation using fractional flow reserve in diabetic patients Mohammad Alkhalil a,⁎, Claire McCune a, Lisa McClenaghan a, Jonathan Mailey a, Patrick Collins a, Aileen Kearney a, Matthew Todd a, Peter McKavanagh a,b a b
Department of Cardiology, Royal Victoria Hospital, Belfast, UK Department of Cardiology, Ulster Hospital, Belfast, UK
a r t i c l e
i n f o
Article history: Received 27 October 2019 Received in revised form 10 December 2019 Accepted 13 December 2019 Available online xxxx Keywords: FFR Diabetes Deferred revascularisation
a b s t r a c t Background: Fractional flow reserve (FFR) is used to assess the functional significance of coronary artery lesions. Diabetic patients are associated with high burden of atherosclerosis and microvascular dysfunction. We studied the clinical outcomes of diabetic patients who underwent FFR-guided deferred revascularisation. Methods: Consecutive patients from a single large volume centre who underwent FFR assessment were included. Clinical endpoints were prospectively collected using the national electronic care records system. The primary endpoint was defined as the four-year risk of the vessel-oriented composite outcome of cardiac death, vesselrelated myocardial infarction (VMI), and vessel-related urgent revascularisation (VUR). Absolute FFR values groups (0.81 to 0.85; 0.86 to 0.90; and N0.90) were used to further stratify patient outcomes. Results: FFR-guided deferred revascularisation occurred in 860 patients (63%), of whom 159 were diabetic. The primary endpoint was significantly higher in the diabetic compared to the non-diabetic group [HR 1.76 (95%CI 1.08 to 2.88), P = 0.024]. The difference was driven from cardiac death (6.3% vs. 3.0%, P = 0.044) and VMI (5.0% vs. 1.7%, P = 0.012) but not VUR (8.8% vs. 5.1%, P = 0.07). There was a significant decrease in the incidence of the primary endpoint in the diabetic group according to FFR groups (23.6%, 12.3%, 2.4%, P = 0.001) with comparable clinical outcomes in the non-diabetic group (11.8%, 6.4%, 7.4%, P = 0.085). Conclusions: Our study demonstrated an increased risk of death and target vessel MI in diabetic patients undergoing FFR-guided deferred revascularisation compared to non-diabetic group. Nonetheless, FFR remained a useful tool to identify those at future risk, mainly in diabetic patients. © 2019 Elsevier Inc. All rights reserved.
1. Introduction Fractional flow reserve (FFR) is currently the standard of care to evaluate the functional significance of coronary arteries stenoses invasively [1]. FFR-guided percutaneous coronary intervention (PCI) significantly reduced major adverse events compared to angiography-based PCI and showed incremental benefits to medical therapy in patients with stable coronary artery disease [2,3]. Moreover, favourable clinical outcomes were also reported in patients with FFR-based deferred revascularisation in the DEFER and FAME 2 studies [3,4]. Diabetes mellitus is an independent risk factor of coronary artery disease. Diabetic patients have worse clinical outcomes irrespective of the presence or absence of established coronary artery disease [5].
⁎ Corresponding author at: Department of Cardiology, Royal Victoria Hospital, Belfast BT12 6BA, UK. E-mail address: [email protected] (M. Alkhalil).
Factors such as accelerated atherosclerosis, endothelial dysfunction, and impaired microvascular function are associated with diabetes and potentially contribute to its adverse clinical outcomes [6,7]. Microvascular dysfunction may impede the increase in coronary blood flow with pharmacological vasodilation, underestimating the degree of ischaemia using FFR [8,9]. This becomes more relevant since the number of diabetic patients whom had deferred FFR-guided PCI was remarkably small (11% in the DEFER and 27% in the FAME 2 studies). Therefore, any definitive conclusions regarding deferred revascularisation using FFR in diabetic patients may be challenged. Moreover, recent studies have demonstrated worse clinical outcomes in FFR-guided deferred revascularisation in diabetic patients [10,11]. These studies, however, were small in size to allow absolute decision regarding FFR in diabetic patients. Furthermore, a recent post hoc analysis from the DEFINEFLAIR trial reporting one-year follow up, demonstrated a numerically higher incidence of adverse clinical outcomes in deferred patients with diabetes compared to those without diabetes [12]. The aim of this study was to compare the long-term clinical outcomes of diabetic and non-diabetic patients who had FFR-guided
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Please cite this article as: M. Alkhalil, C. McCune, L. McClenaghan, et al., Clinical outcomes of deferred revascularisation using fractional flow reserve in diabetic patients, Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.12.019
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medical management. Further consideration was given to the absolute FFR value obtained and how this affected study composite endpoints. 2. Methods 2.1. Study population Between January 2014 and December 2015, 1482 consecutive patients who underwent FFR at the Royal Victoria Hospital in Belfast were screened. In 42 (2.8%) patients, the absolute FFR value was not documented and rather a ‘positive’ or ‘negative’ functional assessment was reported. These patients were excluded from the current analysis alongside 35 (2.4%) patients who underwent instantaneous wave-free ratio (iFR) only (Fig. 1). Patients with positive FFR (≤0.8) requiring percutaneous or surgical revascularisation as per current guidelines were excluded from the analysis (Fig. 1) [1]. 2.2. Fractional flow reserve assessment Coronary artery lesions with angiographic 40–80% degree of stenosis were interrogated using FFR. Patients with multi-vessel disease who underwent multi-assessment using FFR and deemed non-functionally significant were also included. The lowest recorded value was used as the absolute FFR value in the current analysis. A 6 French guiding catheter was universally used for the functional assessment of coronary stenoses. A 0.014 intra-coronary pressuremonitoring guidewire was used (PressureWire Certus, St. Jude Medical or Combowire, Volcano Corp), calibrated, equalised, and positioned distal to the coronary lesion as previously described [8]. All procedures were performed using intra-arterial heparin (70 U/kg). Intra-venous adenosine was administered (140 μg/kg/min) to induce hyperaemia and minimal distal coronary pressure. Upon reaching stead-state hyperaemia, FFR was calculated as the ratio of the mean distal intra-coronary pressure to the mean arterial pressure as previously described [8].
2.3. Study endpoints and follow up The primary endpoint was defined as the risk of the vessel-oriented composite outcome of cardiac death, vessel-related myocardial infarction, and vessel-related urgent revascularisation. The secondary endpoints were defined as the composite of all-cause mortality, myocardial infarction (which included both previously FFR-interrogated and noninterrogated arteries), and unplanned urgent revascularisation (which was combined previously FFR-assessed and non-assessed arteries), in addition, to the individual components of the primary endpoint. Patients were followed up for 4 years and clinical endpoints were prospectively collected and regularly updated using the national electronic care records system of Health and Social Care in Northern Ireland. Recorded information was crossed-checked by reviewing hospital admissions and general practitioners' records. 2.4. Statistical analysis Data were assessed using the Shapiro-Wilk test for normality of distribution. All variables were expressed as mean ± standard deviation (if data were normally distributed) or as median accompanied by interquartile range (IQR) for non-parametric data. Continuous variables were compared using unpaired t-test or Mann-Whitney U test as appropriate, while frequencies comparisons were made using Chi square test or Fisher's exact test, as appropriate. Kaplan–Meier and the associated log-rank test were performed to determine the differences in the primary and secondary endpoints. Cox regression model were used to calculate unadjusted and adjusted hazard ratio (HR) of the primary endpoint. All statistical analysis was performed using SPSS 22.0 (SPSS, Inc. Chicago, Illinois) and a P value b0.05 was considered statistically significant. 3. Results A total of 860 patients who underwent FFR-guided deferred revascularisation were included (Fig. 1). Average age was 66 ± 10 and
Fig. 1. Study flow chart.
Please cite this article as: M. Alkhalil, C. McCune, L. McClenaghan, et al., Clinical outcomes of deferred revascularisation using fractional flow reserve in diabetic patients, Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.12.019
M. Alkhalil et al. / Cardiovascular Revascularization Medicine xxx (xxxx) xxx Table 1 Clinical and procedural characteristics of patients stratified according to their diabetes status.
Age (mean ± SD) Male gender (n, %) Hypertension (n, %) Hypercholesteraemia (n, %) Family history of IHD (n, %) Active smoking (n, %) Previous MI (n, %) Previous PCI (n, %) Previous CABG (n, %) Normal renal function (n, %) Normal LVSF (n, %) Vessel interrogated (n, %) LAD LCX RCA Multi-vessel disease (n, %) FFR value (median, IQR)
Whole cohort
Diabetic (n = 159)
Non-diabetic (n = 701)
P value
66 ± 10 632 (74%) 522 (61%) 484 (56%) 552 (66%) 301 (35%) 300 (36%) 379 (45%) 33 (4%) 695 (81%) 646 (84%)
67 ± 9 116 (73%) 114 (72%) 90 (57%) 102 (67%) 60 (38%) 57 (38%) 76 (50%) 9 (6%) 118 (74%) 123 (86%)
66 ± 10 516 (74%) 408 (58%) 394 (56%) 450 (66%) 241 (34%) 243 (36%) 303 (44%) 24 (4%) 577 (83%) 523 (84%)
0.23 0.87 0.002 0.93 0.76 0.42 0.65 0.20 0.17 0.016 0.52
548 (64%) 252 (29%) 246 (29%) 166 (19%) 0.88 (0.84–0.91)
106 (67%) 50 (31%) 44 (28%) 39 (25%) 0.87 (0.85–0.91)
442 (63%) 202 (29%) 202 (29%) 127 (18%) 0.88 (0.84–0.91)
0.39 0.51 0.78 0.06 0.64
IHD: ischaemic heart disease, MI: myocardial infarction, PCI: percutaneous coronary intervention, CABG: coronary artery bypass graft, LVSF: left ventricle systolic function, LAD: left anterior descending, LCx: circumflex, RCA: right coronary artery, FFR: fractional flow reserve.
74% (632/860) were male. More than one third of patients had previous myocardial infarction and almost half of the cohort had previous revascularisation (Table 1). The median FFR value was 0.88 (0.84– 0.91) and the left anterior descending artery (LAD) was the most interrogated coronary artery (64%). Diabetes mellitus was present in 159 (18.5%) patients. There were no differences in age, gender and traditional clinical risk factors between diabetic and non-diabetic groups, except for hypertension which was more frequently reported in diabetic patients (72% vs. 58%, P = 0.002) (Table 1). The proportion of patients with normal renal unction was also lower in the diabetic group (74% vs. 83%, P = 0.016). The median FFR was comparable between the two groups with numerically higher proportion of multi-vessel disease in the diabetic
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group (25% vs. 18%, P = 0.06), although this difference did not reach statistical significance. The primary endpoint occurred in 9.2% (79/860) patients over the 4 years follow up and was significantly higher in the diabetic compared to the non-diabetic group [HR 1.76 (95% CI 1.08 to 2.88), P = 0.024] (Fig. 2). The difference was driven from cardiac death (6.3% vs. 3.0%, P = 0.044) and target vessel myocardial infarction (5.0% vs. 1.7%, P = 0.012) (Table 2). Target vessel urgent revascularisations were higher in the diabetic group but this difference did not reach statistical significance (8.8% vs. 5.1%, P = 0.07) (Table 3). Similarly, the secondary endpoint of the composite of all-cause mortality, myocardial infarction (total) and urgent unplanned revascularisation, was significantly higher in the diabetic group [HR 1.79 (95% CI 1.25 to 2.56), P = 0.001] (Fig. 3A). Diabetic patients with deferred revascularisation had two-fold increased risk of death over 4 years follow up compared to non-diabetic patients [HR 2.01 (95% CI 1.24 to 3.25), P = 0.004] (Fig. 3B) (Table 2). When the cohort was stratified according to the absolute FFR value (0.81 to 0.85, 0.86 to 0.90, and N0.90), there was significant stepwise decrease in the incidence of the primary endpoint in the diabetic group (23.6%, 12.3%, 2.4%, P = 0.001 respectively) with comparable clinical outcomes in the non-diabetic group (11.8%, 6.4%, 7.4%, P = 0.085 respectively) (Fig. 4). Furthermore, for every 1 point percentage increase in FFR value there was 15% reduction of the primary endpoint in diabetic patients with deferred revascularisation, even after adjustment for multiple risk factors (HR 0.85, 95%CI 0.76 to 0.96, P = 0.007) (Table 3). 4. Discussion The main findings of this real-world study can be summarised as follow: (1) diabetic patients remain at an increased future risk compared to non-diabetic patients despite having functionally non-significant coronary artery disease, (2) this risk was mainly derived from cardiac death and target vessel myocardial infarction but not target vessel revascularisation, (3) the future risk was proportional to the degree of ischaemia as measured by FFR in the diabetic but not in the nondiabetic group.
Fig. 2. Primary endpoint in patients with deferred revascularisation stratified according to their diabetes status. Kaplan-Meier curves comparing cumulative incidence of four-year vesseloriented composite endpoints (cardiac death, vessel-related myocardial infarction, and vessel-related urgent revascularisation) in patients with diabetes versus non-diabetes.
Please cite this article as: M. Alkhalil, C. McCune, L. McClenaghan, et al., Clinical outcomes of deferred revascularisation using fractional flow reserve in diabetic patients, Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.12.019
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Table 2 Incidence rate of primary and secondary clinical outcomes.
Primary endpoint (cardiac death, target vessel myocardial infarction, target vessel revascularisation) Secondary endpoint (death, myocardial infarction, urgent revascularisation) All-cause mortality Cardiac death Myocardial infarction (total) Target vessel myocardial infarction Urgent revascularisation Target vessel urgent revascularisation
Diabetic (n = 159)
Non-diabetic (n = 701)
P value
22 (13.8%)
57 (8.1%)
0.025
42 (26.4%)
107 (15.3%)
0.001
24 (15.1%) 10 (6.3%) 12 (7.5%) 8 (5.0%) 19 (11.9%) 14 (8.8%)
54 (7.7%) 21 (3.0%) 25 (3.6%) 12 (1.7%) 48 (6.8%) 36 (5.1%)
0.003 0.044 0.026 0.012 0.03 0.07
The decision to defer intervention in FFR-measured functionally non-significant coronary stenosis in patients with diabetes has been recently challenged [10,11]. The presence of small vessel disease was initially thought to influence the measurement of FFR and subsequently affecting ischaemia assessment [8,9]. Diabetic patients have worse microvascular dysfunction as measured by index microcirculatory resistance when compared to non-diabetic patients [13]. Nonetheless, such difference may not necessarily translate into a clinically meaningful difference in FFR measurements [14]. In fact, other work has suggested that there are no differences between FFR values of diabetic and nondiabetic patients who had coronary lesions with similar degree of stenosis and irrespective of the reference vessel diameter [14]. The separation of the Kaplan-Meier curves in our study did not support the concept that ischaemia was merely underestimated using FFR. Indeed, the curves run parallel for more than half of the study duration with clinically significant events accruing after the third year of follow up. The same trend was mirrored in the separation Kaplan-Meier curves of the secondary endpoint, which included total myocardial infarction alongside urgent revascularisation. This phenomenon may reflect the atherosclerosis process in diabetic patients leading to more vulnerable plaques and inevitably acute cardiac events and may suggest that native disease takes precedent over FFR, particular in diabetic patients. Previous studies of multi-vessel interrogations using optical coherent tomography (OCT) compared the atherosclerotic burden between diabetic and non-diabetic patients using [6]. Larger lipid area and higher prevalence of thin-cap fibro atheroma were identified in diabetic patients [6]. Similar findings were also reported from the PROSPECT study using intra-vascular ultrasound (IVUS) [15]. It is widely recognised that diabetes is a systemic disease with altered metabolic cellular profile and increased inflammation promoting thrombosis [16]. Nonetheless, the true mechanisms by which diabetes is associated with accelerated atherosclerosis remains unknown. FFR is a reliable surrogate of myocardial ischaemia [17,18]. The use of a cut-off to dichotomise a continuous variable such as FFR and subsequently ischaemia may remove a significant proportion of its information content [19]. However, Barbato et al. [17] reported a non-linear
relationship between FFR and major adverse events in patients who were managed without revascularisation. Interestingly, the risk of adverse events steeply increased when FFR value dropped below 0.80. The relationship was almost linear in lesions with FFR N 0.8, while there was a plateau of clinical events when FFR dropped below 0.60 [17]. This is important as patients with negative FFR (i.e. FFR N 0.80) remained at risk of future cardiac events. Moreover, this risk, albeit is small, was proportional to the degree of ischaemia as quantified by FFR. Our data illustrated a linear increase in the primary endpoint in patients with FFR N 0.80. This correlation was particularly pronounced in diabetic patients. Furthermore, we demonstrated that the risk associated with FFR deferred strategy was continuous and for every one point percentage increase in FFR value, there was 15% reduction in future cardiac events. In fact, almost 1 in 4 diabetic patients with FFR value of 0.81–0.85 sustained an event compared to b3% in diabetic patients with FFR N 0.90. This reinforces the concept that ischaemia assessment using FFR is a spectrum not a binary phenomenon and patients with FFR value N0.80 should not be dismissed as no risk but rather low future risk. In fact, in the IRIS-FFR Registry (Interventional Cardiology Research Incooperation Society Fractional Flow Reserve), FFR value showed linear association with future cardiovascular risk in deferred coronary lesions [20]. Similarly, a recent secondary analysis from the DEFINE-FLAIR study reported cardiac event rate of 5.1% at 12 months in the FFR-deferred diabetic group (177 patients) [12]. In a study evaluating the association between physiological stenosis severity using FFR and plaque vulnerability using coronary computed tomography angiography, Lee et al. [21], reported the differential prognostic implications of plaque vulnerability according to FFR. The authors highlighted the significant role of using plaque characteristics to identify high risk patients in particularly in patients with FFR N 0.80. Interestingly, alongside high-risk plaque features, diabetes status had more than three times the likelihood of developing adverse cardiac events even after adjusting for plaque vulnerability. In fact, diabetes was the strongest predictor of clinical outcomes in patients with FFR N 0.80. Importantly, our study used the same vessel oriented clinical endpoints to truly identify events derived from the interrogated coronary vessel. This contrasts with a recent study by Liu et al. [22], reporting that FFR was not able to differentiate the risk of cardiovascular events in diabetic patients. However, the clinical endpoints were not tailored towards the FFR-assessed coronary artery, making any comparison with our study very difficult. The explanation for our findings that patients with DM have lower risk than non-diabetic in the group of FFR N 0.9 is not clear. The demographic profile and clinical risks were comparable between the two groups. Likewise, the FFR value and the proportion of multivessel disease were also similar. We speculate that this may be related to the fact that these subsets were subgroup of subgroups with relatively small sample size. Our data were derived from a single centre which could be considered as a limitation. Nevertheless, we provided large real-world dataset from a high volume centre. Our study did not include resting Pd/Pa and therefore its prognostic role in diabetic versus non-diabetic cannot be
Table 3 Unadjusted and adjusted predictors of primary endpoint predictors in diabetic patients.
Age Male gender Hypertension Active smoking Previous MI Previous revascularisation Estimated glomerular filtration rate (eGFR) Normal LVSF LAD artery Multi-vessel disease FFR valuea a
HR (unadjusted)
95% CI
P value
1.04 0.93 1.80 1.70 1.89 1.27 0.97 3.26 2.28 1.10 0.85
0.99 to 1.10 0.36 to 2.36 0.61 to 5.31 0.74 to 3.93 0.80 to 4.45 0.53 to 3.01 0.94 to 1.00 0.44 to 24.27 0.77 to 6.75 0.43 to 2.82 0.75 to 0.95
0.10 0.87 0.29 0.21 0.15 0.59 0.05 0.25 0.14 0.84 0.006
HR (adjusted)
95% CI
P value
0.97
0.95 to 1.00
0.08
0.85
0.76 to 0.96
0.007
For every one percentage change in FFR value. MI: myocardial infarction, LVSF: left ventricle systolic function, FFR: fractional flow reserve.
Please cite this article as: M. Alkhalil, C. McCune, L. McClenaghan, et al., Clinical outcomes of deferred revascularisation using fractional flow reserve in diabetic patients, Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.12.019
M. Alkhalil et al. / Cardiovascular Revascularization Medicine xxx (xxxx) xxx
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Fig. 3. Secondary endpoints in patients with deferred revascularisation stratified according to their diabetes status. Panel (A), Kaplan-Meier curves comparing cumulative incidence of allcause mortality, myocardial infarction and urgent revascularisation according to patients' diabetes status. Panel (B), Kaplan-Meier curves demonstrating worse survival in diabetic patients during the study follow up.
ascertained. While Pd/Pa has been shown to correlate with FFR [23,24], it is not clinically used to guide treatment for intermediate coronary artery stenosis. The ongoing LIPSIASTRATEGY study (NCT03497637) is currently testing this hypothesis. Moreover, patients with deferred revascularisation did not undergo intra vascular imaging assessment to evaluate whether future cardiac events could be predicted using certain plaque characteristics such as large plaque burden and/or lipid core.
Further research to assess whether OCT or IVUS are useful tools to delineate risk in diabetic patients with FFR N 0.80 are needed. In conclusion our study demonstrated an increased risk of death and target vessel MI in diabetic patients undergoing FFR-guided deferred revascularisation compared to non-diabetic group. Nonetheless, FFR remained a useful tool to identify those at future risk in particularly in diabetic patients.
Fig. 4. The incidence of the primary endpoint according to the FFR value between diabetic and non-diabetic patients. There was a stepwise increase in vessel-oriented composite endpoints according to the FFR value. This linear relationship was more marked in the diabetic group.
Please cite this article as: M. Alkhalil, C. McCune, L. McClenaghan, et al., Clinical outcomes of deferred revascularisation using fractional flow reserve in diabetic patients, Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.12.019
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Authors' contributions Conceptualization, data curation, project administration and formal analysis (MA). Investigation, methodology, software and resources (MA, CM, LM, JM, PC, AK, MT, PM). Writing original draft and preparation of full manuscript (MA, PM). Writing review and editing (MA, CM, LM, JM, PC, AK, MT, PM). Funding None. Declaration of competing interest None. Acknowledgments None. References [1] Neumann FJ, Sousa-Uva M, Ahlsson A, Alfonso F, Banning AP, Benedetto U, et al. ESC/ EACTS guidelines on myocardial revascularization. Eur Heart J 2018:2018. [2] Tonino PA, De Bruyne B, Pijls NH, Siebert U, Ikeno F, van’t Veer M, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360:213–24. [3] De Bruyne B, Pijls NH, Kalesan B, Barbato E, Tonino PA, Piroth Z, et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med 2012;367:991–1001. [4] Pijls NH, van Schaardenburgh P, Manoharan G, Boersma E, Bech JW, van’t Veer M, et al. Percutaneous coronary intervention of functionally nonsignificant stenosis: 5-year follow-up of the DEFER study. J Am Coll Cardiol 2007;49:2105–11. [5] Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229–34. [6] Kato K, Yonetsu T, Kim SJ, Xing L, Lee H, McNulty I, et al. Comparison of nonculprit coronary plaque characteristics between patients with and without diabetes: a 3vessel optical coherence tomography study. JACC Cardiovasc Interv 2012;5:1150–8. [7] Di Carli MF, Janisse J, Grunberger G, Ager J. Role of chronic hyperglycemia in the pathogenesis of coronary microvascular dysfunction in diabetes. J Am Coll Cardiol 2003;41:1387–93. [8] Pijls NH, De Bruyne B, Peels K, Van Der Voort PH, Bonnier HJ, Bartunek JKJJ, et al. Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses. N Engl J Med 1996;334:1703–8.
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Please cite this article as: M. Alkhalil, C. McCune, L. McClenaghan, et al., Clinical outcomes of deferred revascularisation using fractional flow reserve in diabetic patients, Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.12.019