Outcomes of Fractional Flow Reserve-Based Deferral in Saphenous Vein Graft Narrowing

Accepted Manuscript

Outcomes of Fractional Flow Reserve-Based Deferral in Saphenous Vein Graft Narrowing Ahmed Almomani MD , Naga Venkata Pothineni MD , Mohan Edupuganti MD , Jason Payne MD , Shiv Agarwal MD , Barry Uretsky MD , Abdul Hakeem MD PII: DOI: Reference:

S0002-9149(18)31174-3 10.1016/j.amjcard.2018.05.002 AJC 23306

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The American Journal of Cardiology

Received date: Revised date: Accepted date:

10 January 2018 14 May 2018 18 May 2018

Please cite this article as: Ahmed Almomani MD , Naga Venkata Pothineni MD , Mohan Edupuganti MD , Jason Payne MD , Shiv Agarwal MD , Barry Uretsky MD , Abdul Hakeem MD , Outcomes of Fractional Flow Reserve-Based Deferral in Saphenous Vein Graft Narrowing, The American Journal of Cardiology (2018), doi: 10.1016/j.amjcard.2018.05.002

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Outcomes of Fractional Flow Reserve-Based Deferral in Saphenous Vein Graft Narrowing Ahmed Almomani,MDa, Naga Venkata Pothineni, MDa, Mohan Edupuganti, MDa, Jason

Central Arkansas VA Health System, Little Rock, AR, USA,

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Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ

Running Title: FFR in SVG lesions Conflicts: None

Corresponding Author:

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Abdul Hakeem MD

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Word count: 2566

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a

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Payne, MDa, Shiv Agarwal, MDa, Barry Uretsky,MDa, Abdul Hakeem, MDa,b

Associate Professor of Medicine & Staff Interventional Cardiologist

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Robert Wood Johnson Hospital, Rutgers University, New Brunswick, NJ [email protected]

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Phone- 608-695-3048

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125 Paterson St, New Brunswick, NJ 08901

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Abstract Fractional flow reserve (FFR) has been shown to improve clinical decision-making for revascularization in intermediate coronary stenosis in native coronary arteries of patients with stable coronary disease. However, its use for saphenous vein graft (SVG) lesions has not been

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well validated. We sought to determine the prognostic value of deferring intervention on lesions with FFR>0.8 in SVG lesions. Clinical, angiographic, hemodynamic variables and long-term outcomes were recorded in consecutive patients in whom PCI was deferred based on an FFR >0.8 for intermediate native coronary artery or SVG stenosis. Thirty-three patients underwent FFR of

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SVG lesions and were compared with 532 undergoing native vessel FFR during the same period. There were no differences in age [66.6 (IQR 63-76) vs. 65 (IQR 61-70) years; p=0.12], diabetes (41% vs. 50%; p=0.35), or hypertension (94% vs. 97%; p=0.71). During a median follow-up of 3.2 years (IQR 1.7-4.6 years) MACE was significantly higher in SVG group (36% vs. 21%; log

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rank p=0.01). Similarly, the rate of target vessel failure (TVF) was significantly higher in the SVG group (27% vs. 14%; p=0.01). Deferred SVG lesions had the worst survival free of TVF

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compared to deferred native lesions in both patients with and without prior CABG. An SVG lesion was an independent predictor of MACE on Cox proportional hazards analysis (HR 2.26; CI

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1.19, 4.28; p=0.01).In conclusion, non-ischemic FFR carries a significantly worse prognosis in

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SVG compared to non-SVG lesions. Caution is warranted in utilizing FFR for clinical decision-

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making in SVG lesions.

Key Words: Fractional flow reserve, saphenous vein graft, prognosis

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Background Fractional flow reserve (FFR) is an excellent modality for evaluating the significance of intermediate coronary artery stenosis in native coronary artery disease. Cumulative evidence over the past two decades has shown that FFR-guided percutaneous revascularization (PCI) or

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deferring PCI of native coronary stenosis based on FFR is associated with improved long-term clinical outcomes.(1-5) The use of FFR has been extrapolated to other subsets including saphenous vein grafts (SVG) lesions, presumably based on the assumption that the clinical and prognostic value of FFR in these subsets would mirror that of native coronary arteries.

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Furthermore, the concept of employing FFR for clinical decision-making in SVG lesions is intuitively attractive given the complex nature of these lesions and

higher risk of PCI

complications including distal embolization and post-procedure myocardial infarction (MI).(6) In some studies, intermediate SVG lesions have been associated with a two-fold increase in

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overall mortality independent of other comorbidities.(7-14). The recent appropriateness criteria document for percutaneous revascularization has specifically outlined the potential limitations of

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FFR in evaluating the hemodynamic significance and guiding PCI in SVG lesions noting the dearth of data in this regard.(15) In this study, we sought to determine the prognostic value of

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FFR>0.8 in SVG lesions comparing it to native vessels in patients with and without prior history

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of coronary artery bypass grafting (CABG).

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Methods

Clinical, angiographic, hemodynamic variables and outcomes were recorded in

consecutive patients in whom PCI was deferred based on non-ischemic FFR for intermediate coronary artery or saphenous vein stenosis between January 2009 and September 2015 at our center. This study was approved by the Central Arkansas VA Health System’s institutional review board.

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FFR was performed using guide catheters without side holes with either the Volcano [San Diego, CA] or St Jude Medical [St. Paul, MN] pressure wire. The wire was positioned in the distal native artery once therapeutic anticoagulation was achieved. Intracoronary (IC) nitroglycerin was administered prior to FFR measurement. Maximum hyperemia was induced by

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either intravenous (IV) adenosine infusion at a rate of ≥ 140 μg/kg per minute or by IC adenosine at a dose of at least ≥ 60 μg. Severity of stenosis was recorded as visually estimated by the operators during the index procedure.

Data were collected using chart review from VA electronic record system called CPRS

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(Computerized Patient Record System). Follow-up period was defined as the time between the index FFR procedures to the last clinic visit or hospital admission recorded. The primary end point of this study was target vessel failure (TVF) defined as myocardial infarction (MI) and or target vessel revascularization (TVR) of the index FFR vessel. Secondary end point was major

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adverse cardiac events (MACE) defined as a composite of death, MI and TVR. TVR was defined

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as subsequent revascularization of the index vessel by either PCI or bypass grafting (CABG) of the target vessel. MI was defined as a rise in serum troponin I > 99th percentile of reference lab

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value in the presence of clinical symptoms or intracoronary thrombus in the target vessel with or without new EKG changes and did not include periprocedural MI.

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Patient groups (SVG and non-SVG) were compared using unpaired Student's t test for

continuous variables and the chi square test (χ2) for categorical or dichotomous variables.

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Unadjusted annual event rates were calculated through Kaplan-Meier (K-M) curves. Four different outcome analyses were conducted a) deferred SVG lesions vs. all deferred native coronary lesions b) deferred SVG lesions vs. SVG lesions who underwent PCI based on ischemic FFR c) deferred SVG lesions vs. deferred native coronary lesions without prior CABG and d) deferred SVG lesions vs deferred native coronary lesions in patients with prior CABG.

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Multivariate models were constructed using Cox proportional hazards analysis for MACE and TVF prediction. Backward stepwise elimination was used to eliminate non-significant variables to derive a final multivariate model (inclusion criteria P< 0.05; exclusion criteria P>0.10). All significant covariates met the proportionality assumption. The level of statistical

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significance was set a priori at 0.05, and a 2-sided probability value used for the analyses. All statistical calculations were performed using MedCalc Statistical Software version 15.2.1 (MedCalc Software, Ostend, Belgium; http://www.medcalc.org; 2015) and SPSS Statistics, version 13 (IBM, Armonk, New York).

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Results

Thirty-three patients with SVG and 532 patients with native coronary artery intermediate lesions, who underwent FFR measurement and in whom PCI was deferred based on a nonischemic FFR (>0.80) were studied. There was no difference between the two groups in age,

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diabetes, hypertension, left ventricular systolic dysfunction (ejection fraction < 40%) and

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smoking. Patients in the SVG group had higher prevalence of CKD (44% vs. 23%; p<0.0001) and were more likely to have had an acute coronary syndrome presentation (56% vs. 36%;

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p<0.02) .At the time of presentation SVG group was more likely to be on beta-blockers (91% vs. 74%; p=0.05), nitrates (56% vs. 34%; p=0.01) and clopidogrel (41% vs. 22%; p=0.03) (Table 1).

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In the SVG group, the native artery was 100% occluded proximal to graft insertion in 26

(78.8%) cases and severely narrowed (>90%) in the remaining 7 (22%) patients. The median graft

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age was 12 years (IQR 5-15 years). SVG grafts were to the posterior descending/RCA circulation in 42%, left circumflex/obtuse marginal system in 30%, and LAD/diagonal/intermediate ramus in 28%. There was no significant difference between SVG and non-SVG lesion in the severity of percent diameter stenosis [50% (IQR 33-60) vs. 50% (IQR 40-60); p=0.34], baseline gradient [0.98 (IQR 0.95-1.0) vs. 0.97 (IQR 0.94-1.0); p=0.23], or FFR [0.87 (IQR 0.83-0.91) vs. 0.89

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(IQR 0.85-0.92); p=0.08]. IV adenosine was used in 17 (53%) of the SVG lesions and 264 (50%) of the non-SVG lesions (p=0.92) (Table 2). The median dose of IC adenosine The SVG cohort was 130 mcg (IQR 120-216).Median dose in grafts to RCA was 72 mcg (IQR 51-138) and 140 ( 120-230) in grafts to the left coronary system. Further, there was no difference in the IC

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adenosine dose for SVG lesions that were ischemic and non-ischemic. During a median follow up of 3.2 years (IQR 1.7-4.6 years), target vessel failure was significantly higher in the SVG group (27% vs. 14%; p=0.01) (Figure 1). Similarly, MACE was significantly higher in SVG group (36% vs. 21%; p=0.01) (Figure 2). Similarly, the rate of TVR

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was significantly higher in the SVG group (27% vs. 13%; p=0.001). (Figure 3). Table 3 depicts the difference in individual end points of death, MI, TVR and TVF between SVG and non-SVG groups. SVG lesion was an independent predictor of MACE (HR 2.26; 95% CI 1.19, 4.28; p =0.01) and TVF (HR 3.3; 95% CI 1.4, 7.4; p=0.004) on Cox proportional hazards analysis.

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(Tables 4A and 4B)

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Subgroup analyses were conducted comparing deferred SVG lesions (n=33 patients) to deferred non-SVG lesions in patients with previous CABG (n=79 patients) and deferred non-

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SVG lesion in patients without history of CABG (N=453 patients). The results showed significantly higher rates of TVF in the SVG group (27% vs 20% vs 16%; p = 0.04) (Figure 4).

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Moreover, when comparing the deferred SVG patients (N=33) with revascularized SVG lesion patients (N=27) based on abnormal FFR guidance (mean FFR 0.66+0.14), deferred SVG patients

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showed a trend toward worse long-term outcome over the same follow-up period (27% vs 11%; p = 0.16) (Figure 5). Discussion

The main finding of this study is that deferring revascularization based on non-ischemic FFR value for intermediate SVG lesions is associated with worse outcome and higher rate of

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MACE when compared to deferred native coronary artery lesions. The data also suggest that deferral may be worse than SVG lesions with lower (ischemic) FFR who underwent PCI. These findings suggest that FFR in SVG lesions, using a threshold derived from native coronary arteries, may not be appropriate.

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The angiographic evaluation of stenosis severity is more difficult in SVGs than in native arteries. Therefore, the use of another modality to evaluate the significance of the stenosis is crucial. However, it is not clear whether FFR of SVG lesion can serve this purpose by reliably ruling out ischemia, especially considering that multiple factors may affect FFR assessment in an

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SVG lesion including the (1) presence of residual ante grade flow in the grafted native coronary artery, (2) collaterals from long-standing native coronary occlusion, and (3) chronic microvascular and fibrotic changes related to chronic ischemia.(16) A small study by Aqel et al. in 10 patients with SVGs undergoing FFR and myocardial perfusion imaging (MPI) found the

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sensitivity, specificity, positive and negative predictive values and accuracy of FFR <0.75 for detecting ischemia on MPI was 50%, 75%, 33%, 85%, and 70% respectively.(17) However, the

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presentation of such a small number of data points cannot be statistically or clinically reliable, and larger studies are needed.

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Di Serafino et al. in a retrospective analysis of 223 patients with intermediate graft

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lesions compared the outcomes between FFR-guided (n=65; 29%) vs. angiography-guided percutaneous coronary intervention (PCI) to bypass grafts (including both, venous and arterial).

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Of the 65 grafts, 38 had an SVG graft, less than half deferred. The study reported that for patients with arterial graft stenosis, the rate of MACE and TVF was lower in the FFR-guided group. On the contrary, for patients with SVG stenosis no significant differences were observed for both MACE and TVF between the 2 groups.(18) The pathophysiology of SVG disease is different from native coronary arteries and is composed of three discrete processes: thrombosis, intimal hyperplasia, and atherosclerosis. These

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processes, although more or less temporally distinct, are interlinked pathophysiologically.(19-21) Beyond the first year after CABG , atherosclerosis is the dominant process underlying the attrition

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recurrence

of

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symptoms.(20) .Typically, SVG lesions have more rapid progression compared with native

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coronary arteries, which is likely related to the nature of SVG atherosclerosis and the shear stress on walls of the vein.(22) An example from our cohort is presented in Figure 6, which shows the rapid progression of SVG intermediate lesion in less than 12 months.

In the Stenting Of Saphenous vein graft (SOS) trial, 28% of the intermediate lesion had

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progressed to severe lesions by 1 year and 47% by 2 years.(23) In the POST Coronary Artery Bypass Graft (POST-CABG) trial, patients with intermediate SVG lesions at follow-up angiography had higher incidence of MACE (35% vs. 18%), compared with angiographically normal SVGs. The VELETI (Moderate VEin Graft LEsion Stenting With the Taxus stent and

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Intravascular ultrasound) trial, showed that atherosclerotic disease progressed very rapidly in old grafts (as found in our study) and moderately diseased SVG despite lipid-lowering therapy. The

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trial suggested that prophylactic stenting of intermediate SVG lesions with a paclitaxel-eluting stent may provide improved outcomes compared to medical therapy alone.(13) These findings

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were, however, not borne out by the VELETI II trial, which failed to demonstrate a difference

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between the two groups at extended follow-up of 4 years. The authors attributed this to a “catchup” phenomenon after 2 years in the stented group.(24)

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In contrast to the outcome in native coronary arteries, our cohort showed that SVG

lesions may tend to have better long-term outcome after revascularization compared with deferred SVG lesions with negative FFR. This rapid progression and the nature of SVG atherosclerosis provide additional explanation for the short “warranty” period provided by non-significant FFR for SVG lesions compared to native coronaries. Although the lesions may not be causing ischemia at the time of FFR, the disease process may progress rapidly to severely ischemic

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lesions. In addition, 56% of patients who underwent SVG lesion FFR evaluation had a clinical presentation of ACS-NSTEMI compared with 35% of non-SVG patients (p=0.02). We have recently demonstrated that FFR based deferral alone in this population may not yield the same prognosis as stable angina patients.(25)

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Our findings have important implications. The failure of non-ischemic FFR to predict good clinical outcome in intermediate SVG lesions suggests FFR not be useful for clinical decision-making. Given the relatively high-risk nature of SVG interventions,(26), larger studies are needed to evaluate the role of PCI in such subsets. More importantly, while flow may be

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normal as measured by FFR, given the aggressive nature of SVG disease and vulnerability for subsequent clinical events (physiologically insignificant but anatomically significant), further evaluation of the lesion morphology with intracoronary imaging such as with optical coherence tomography or intravascular ultrasound may be helpful in clinical decision-making. This point is

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particularly relevant to the SVG subset who present with an ACS. Furthermore, regardless of the physiological significance, the limited longevity of SVG grafts in general should prompt planning

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towards revascularization of the native coronary bed including CTOs, which are frequent in this

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population, which is associated with less risk of short- and long-term adverse effects.(6,27)

The limitations of this study are primarily related to the retrospective single-center design

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and small sample size; however, it should be noted that this series is the largest evaluating FFR based deferral in SVG lesions. The subjects were predominantly male veterans with a high

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prevalence of CKD and CAD risk factors. All the patients included in the study had FFR evaluation for intermediate lesion, which may lead to selection bias, since we have no data on patient with intermediate lesions who did not undergo FFR evaluation.

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In conclusion, Non-ischemic FFR using a threshold derived from native coronary arteries carries a significantly worse prognosis in SVG compared to non-SVG lesions. Caution is

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warranted in utilizing FFR for clinical decision-making in such patients.

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Figure legends

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Figure 1: Rate of target vessel failure in the SVG group vs. non-SVG group (27% vs. 14%; p=0.01).

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Figure 2: At a median follow up of 3.2 years (IQR 1.7-4.6 years), MACE was significantly higher in SVG group vs. non-SVG group (36% vs. 21%; p=0.01)

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Figure 3: Rate of target vessel revascularization in the SVG group vs. non-SVG group (27% vs. 13% p=0.001)

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Figure 4: Rate of target vessel failure in the SVG group (black) at 5 years was significantly higher when compared to non-SVG lesions in patient with history of CABG (gray) and non-SVG lesion in patient without history of CABG (yellow) (27% vs 20% vs 16%; p = 0.04)

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Figure 5: Deferred SVG lesion showed a trend (p=0.16) toward worse outcome (27%) when compared with revascularized SVG lesion based on ischemic FFR (11%).

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Figure 6: This example demonstrates rapid angiographic progression of an intermediate lesion. Fig 6A: SVG with intermediate lesion in the ostium of the graft Fig 6B: FFR was 0.94 was measured and PCI was deferred. Fig 6C: 10 months later, the same graft lesion showed rapid progression resulted in severe flow limiting (TIMI II) ostial lesion.

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Table 1 – Baseline characteristics

SVG (N=33)

Non SVG (N=532)

P value

Age (years)

66.6(IQR 63-76)

65(IQR 61-70)

0.12

Diabetes

13(41%)

265(50%)

0.35

Hypertension

30(94%)

514(97%)

0.71

Smoking

11(34%)

260(49%)

0.13

CKD

14(44%)

123(23%)

0.01

Prior revascularization

33(100%)

240(45%)

<0.01

Prior MI

26(79%)

EF<40%

8(25%)

ACS

18(56%)

AN US

CR IP T

Variable

M

Medications

148(28%)

<0.01

118(24%)

0.87

191 (35%)

0.02

471(89%)

0.24

31(97%)

Beta blockers

29(91%)

392(74%)

0.05

27(84%)

418(78%)

0.57

18(56%)

182(34%)

0.01

9(28%)

143(27%)

0.95

22(69%)

314(58%)

0.36

ED

Aspirin

Nitrates CCB

PT

Statins

CE

ACE inhibitors

AC

13(41%) 119(22%) 0.03 Clopidogrel ACE- angiotensin converting enzyme; ACS- acute coronary syndrome; CKD- chronic kidney disease; CCB- calcium channel blockers; EF- ejection fraction; IQR- interquartile range; MImyocardial infarction; SVG- saphenous vein graft

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Table 2 - Lesion characteristics

SVG

Non SVG

P value

% stenosis

50 (IQR 33-60)

50 (IQR40-60)

0.34

IV adenosine

17(53%)

264(50%)

0.92

Pd/Pa

0.98(IQR 0.95-1)

0.97(IQR 0.94-1)

CR IP T

Variable

0.23

AC

CE

PT

ED

M

AN US

0.87(IQR 0.83-0.91) 0.89(IQR 0.85-0.92) 0.08 FFR IV- intravenous ; FFR- fractional flow reserve; IQR- interquartile range; SVG- saphenous vein graft; Pd-distal pressure; Pa- aortic pressure; SVG- saphenous vein graft;

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Table 3. Long-term outcomes of patients deferred from intervention based on non-ischemic FFR

Native(N=532) 60(11.2%) 35(6.5%)

Log rank p value 0.006 0.22

9(27%)

72(13%)

0.001

9(27%)

74(14%)

CR IP T

SVG(N=33) 8(27%) 4 (12%)

AC

CE

PT

ED

M

AN US

Outcome Death Myocardial infarction Target vessel revascularization Target vessel failure

0.01

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Table 4- Cox Proportional Hazards Model for a) TVF b) MACE

AN US

B. MACE

HR 1.72 (1.16 to 2.55) 1.44(0.98 to 2.09) 2.26(1.19 to 4.28) 1.42(1.0002 to 2.03) 0.001(0.000 to 0.04) 1.54(1.02 to 2.30)

M

Covariate Prior MI/revascularization ACS SVG Smoking FFR EF<40%

CE

PT

ED

Variables not included in the model: Age, diabetes, chronic kidney disease and diffuse disease Abbreviations as in Tables 1and 2

AC

P 0.004 0.0003 0.004 0.0005

CR IP T

Covariate HR 2.54 (1.33 to 4.8) Prior MI/revascularization 2.6(1.55 to 4.31) ACS 3.3(1.4 to 7.4) SVG 0.0005(0.000 to 0.01) FFR Variables not included in the model age, diabetes, chronic kidney disease, , smoking, ejection fraction <40% and diffuse disease A. TVF

P 0.006 0.05 0.01 0.04 0.0005 0.03