Relation between fractional flow reserve value of coronary lesions with deferred revascularization and cardiovascular outcomes in non-diabetic and diabetic patients

    Relation between fractional flow reserve value of coronary lesions with deferred revascularization and cardiovascular outcomes in non-diabetic and diabetic patients Zhi Liu, Yasushi Matsuzawa, Joerg Herrmann, Jing Li, Ryan J. Lennon, Daniel J. Crusan, Taek-Geun Kwon, Ming Zhang, Tao Sun, Shiwei Yang, Rajiv Gulati, Malcolm R. Bell, Lilach O. Lerman, Amir Lerman PII: DOI: Reference:

S0167-5273(16)30936-6 doi: 10.1016/j.ijcard.2016.05.032 IJCA 22588

To appear in:

International Journal of Cardiology

Received date: Revised date: Accepted date:

3 March 2016 3 May 2016 12 May 2016

Please cite this article as: Liu Zhi, Matsuzawa Yasushi, Herrmann Joerg, Li Jing, Lennon Ryan J., Crusan Daniel J., Kwon Taek-Geun, Zhang Ming, Sun Tao, Yang Shiwei, Gulati Rajiv, Bell Malcolm R., Lerman Lilach O., Lerman Amir, Relation between fractional flow reserve value of coronary lesions with deferred revascularization and cardiovascular outcomes in non-diabetic and diabetic patients, International Journal of Cardiology (2016), doi: 10.1016/j.ijcard.2016.05.032

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Relation between fractional flow reserve value of coronary lesions with deferred

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Short title: Deferred lesion FFR and outcomes in diabetes

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revascularization and cardiovascular outcomes in non-diabetic and diabetic patients

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*Zhi Liu, MD1,2, *Yasushi Matsuzawa, MD, PhD1, Joerg Herrmann, MD1, Jing Li, MD2, Ryan J Lennon , MS3, Daniel J Crusan , BS3,Taek-Geun Kwon, MD, PhD1, Ming Zhang, MD1, Tao Sun,

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MD1, Shiwei Yang, MD1, Rajiv Gulati, MD, PHD1, Malcolm R. Bell, MD1, Lilach O. Lerman, MD, PhD4, and Amir Lerman, MD1

Division of Cardiovascular Diseases, 3Department of Health Sciences Research, and 4Division

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Division of Cardiology, Xuanwu Hospital Capital Medical University, Beijing 100053, China

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of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.

* These authors contributed equally to the work. Address for correspondence: Amir Lerman MD,

Division of Cardiovascular Disease and Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA Phone: 507-255-4152, Fax: 507-255-2550, e-mail address: [email protected] This work was supported by the National Institute of Health (NIH Grant HL-92954 and AG31750 to A.L.). Conflict of interest: All authors have nothing to declare. Keywords fractional flow reserve, deferred revascularization, diabetes mellitus, prognosis

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Abstract Background

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FFR of deferred PCI lesions can predict future cardiovascular events. However, the prognostic

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utility of FFR remains unclear in diabetic patients in view of the potential impact of the diffuse nature of vascular disease process. We aimed to study the relation between fractional flow

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reserve (FFR) values and long-term outcomes of diabetic and non-diabetic patients with deferred

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percutaneous coronary intervention (PCI). Methods

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Patients with FFR assessment and deferred PCI (n=630) were enrolled and stratified according to diabetes mellitus (DM) status and FFR values. Patients were followed over a median of 39

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months. Cox proportional hazard regression models were used to analyze the association between clinical endpoints and clinical factors such as DM and FFR.

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Results

In non-diabetics (n=450), higher FFR values were associated with less cardiovascular events (hazard ratio (HR) for death and myocardial infarction (MI) [95% confidence interval (CI)], 0.61[0.44 to 0.86] per 0.1 increase in FFR, p=0.007; HR for revascularization [95%CI], 0.66[0.49 to 0.9] per 0.1 increase in FFR, p=0.006). In diabetics (n=180), there was no difference in death and MI across the range of FFR values. Among those patients with an FFR>0.85, diabetics had a more than two-fold higher risk of death and MI than non-diabetics (HR [95% CI], 2.20 [1.19 to 4.01], p = 0.015). Conclusion Among non-diabetic patients with deferred PCI, a higher FFR was associated with lower rates of death, MI and revascularization. On the contrary in diabetic patients with deferred revascularization, FFR was not able to differentiate the risk of cardiovascular events.

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Introduction Large clinical trials have reported that fractional flow reserve (FFR) guided-percutaneous

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coronary intervention (PCI) leads to superior outcomes compared with angiography guidedPCI.1,2 Even in patients with stable coronary artery disease (CAD), FFR guidance may yield

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better outcomes than medical therapy alone.3,4 The difference is particularly evident with FFR

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values< 0.80, which are associated with future cardiovascular events (mortality, acute coronary

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syndrome, and revascularization) in conservative management patients with intermediate lesions. 5

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Diffuse vascular disease involving the coronary epicardial and microvasculature may alter this equation, for instance in patients with diabetes mellitus (DM).6-8 Diffuse disease can produce

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an ischemic FFR despite the fact there are no focal areas in which to provide mechanical relief. Furthermore, microvascular disease may not allow for the coronary microvasculature to relax

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maximally and thus lead to an underestimation of the hemodynamic severity of CAD in patients with DM. Accordingly, the diffuse nature of ischemic heart disease in patients with DM may pose a particular challenge in terms of management and related outcomes. 9,10 For these very reasons, the optimal FFR threshold to guide treatment decisions may not be clear in patients with DM. Even in non-diabetic patients, deferral of PCI in the presence of FFR values in the range of 0.75 to 0.80 or 0.81 to 0.85 was equally inferior compared with a threshold of> 0.85.11 Furthermore to consider is the fact that measurement certainty of a single FFR result exceeds 95% when the FFR value is> 0.85 but diminishes to< 80% for FFR values between 0.75 to 0.85. As a consequence, there is a reasonable chance that management decisions change with repeated FFR measurements when values are in the range of 0.75 to 0.85.12

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The aim of this study was to compare the cardiovascular outcomes between diabetic and non-diabetic patients with deferred PCI based on FFR assessment. Due to the fact that FFR

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values in the range of 0.8 to 0.85 are near the borderline, especial uncertain for DM, we chose to

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pursue a stratification in three FFR ranges: ≤ 0.8, 0.8-0.85, ＞ 0.85.

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Methods

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Study population

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This was a registry-based study of patients treated at Mayo Clinic, Rochester MN, USA. The study was approved by the institutional review committee of Mayo Clinic and the subjects gave

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informed consent. Consecutive patients with angina pectoris and deferred PCI based on FFR

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assessment were included from October 2002 to December 2009. In patients with several FFR deferred lesions, we classified the patients according to the minimum deferred FFR value. The

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exclusion criteria included: referral to coronary artery bypass surgery (CABG), severe valvular disease, cancer, and patients who declined to allow use of their records for research.

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Patients were divided into six groups according to DM status and FFR values 0.8 and 0.85 (Figure 1). Patients who were treated with anti-diabetic agents including insulin were considered

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diabetic. A diagnosis of DM in patients not meeting these criteria was based on blood testing in keeping with the diagnostic criteria of the American Diabetes Association: ① fasting plasma glucose≥ 7.0mmol/liter (126mg/dL); or ② 2-hour plasma glucose≥ 11.1mmol/liter (200mg/dL) during standardized 75 g oral glucose tolerance test; or ③ symptoms of hyperglycemia plus nonfasting plasma glucose≥ 11.1mmol/liter (200mg/dL); or ④ glycosylated hemoglobin A1c≥ 6.5%.13 All the baseline and procedural information was collected from the Mayo Clinic medical records. Coronary angiography Coronary angiography was performed according to standard practice by 5-7 French catheters through femoral or radial artery approaches and the diameter stenosis of lesions were assessed

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visually. Intracoronary nitroglycerine 200 µg was administered to get the maximal coronary vasodilation for the calculation of stenosis severity.14

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FFR measurement

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Intracoronary pressure was measured by using a 0.014-inch pressure monitoring guidewire (Wave Wire, Volcano, Rancho Cordova, CA, USA, or Pressure Wire, Radi Medical, Uppsala,

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Sweden), as previously reported.14 In brief, the pressure wire was introduced via a 5F-7F

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guiding catheter and advanced distal to the stenosis in question. Thereafter, FFR was calculated as a ratio of mean distal coronary pressure of lesion to mean aortic pressure after the

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administration of incremental doses of intracoronary adenosine (up to 42 µg for the right coronary artery and up to 72 µg for the left coronary artery) or intravenous adenosine at a rate of

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140 μg/kg/min to achieve maximal hyperemia.15 In general, PCI was performed in patients with FFR≤ 0.8, and deferred in those with FFR＞ 0.8. However, the decision to perform PCI

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remained at the operator’s discretion on basis of patients’ clinical condition. Clinical follow-up

Patients were followed up for cardiac events by a questionnaire and medical records review. The cardiac events included all-cause death, nonfatal spontaneous myocardial infarction (MI, excluding periprocedural MI) and coronary revascularization (2). Myocardial infarction was defined as: detection of rise of cardiac biomarkers (preferably troponin) with at least one value above the 99th percentile of the upper reference limit together with evidence of myocardial ischaemia with at least one of the following: Symptoms of ischaemia; electrocardiogram change indicative of new ischemia (new ST-T changes, or new left bundle branch block); development of pathological Q waves in electrocardiogram; imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.16

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Statistical analysis Statistical analysis was performed independently by statisticians of Mayo Clinic using JMP

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version 9.0.0 (SAS Institute, Inc. Cary, NC). Continuous variables were presented as mean ±

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standard deviation, or median values for those with a skewed distribution. Discrete variables were summarized as absolute numbers and percentages. Inter-group comparisons were tested

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with independent t-test for normally distributed continuous variables and Wilcoxon rank sum test

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for skewed continuous variables, and Pearson’s χ2 test was used for categorical variables. Cumulative event rates were estimated with the Kaplan-Meier method and differences were

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tested with a log-rank test. The Cox proportional hazard regression models were used to explore the association between the survival of patients and multiple clinical factors. We built

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multivariable models by adjusting for age, gender, hypertension, dyslipidemia, body mass index

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(BMI), prior CAD (prior MI, coronary artery bypass grafting, and PCI), stent implantation in

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other lesions, number of vessel disease, current smoking, cerebral vascular disease (CVD), peripheral vascular disease (PVD), infusion method of adenosine. All significance tests were two-tailed. Statistical significance was defined as a P value less than 0.05.

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Results

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Baseline characteristics of non-DM and DM patients

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Between 2002 and 2009, there were 732 patients with deferred PCI after FFR measurement. One hundred-and-two patients were excluded: 12 were referred to CABG, 8 had severe valvular

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disease, 11 had cancer, 13 refused their records for research, and 58 patients were lost to follow-

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up (19 (32.8%) were diabetes). The final patient cohort consisted of 450 non-diabetic and 180 diabetic patients (Figure 1). The median follow-up time was 39 months (interquartile range 18 to

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66). Age, gender, and clinical presentation were similar for patients with and without DM. Likewise, percentages of patients in both groups underwent stent implantation of other coronary

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arteries were similar. Diabetic patients had higher BMI and more extensive CAD and atherosclerotic disease in general compared with non-diabetic patients (Supplementary table).

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There were 12 DM patients and 18 non-DM patients were administrated intravenous adenosine (4.76% vs 4.0%, p = 0.17). There were 10 DM patients and 22 non-DM patients with FFR< 0.75 in patients with FFR≤0.8 (23.8% vs 28.9%, p = 0.55). FFR median (interquartile range) was 0.86 (0.81 to 0.90) in diabetic group, which was lower than 0.87 (0.82 to 0.92) in non-diabetic group (p = 0.007). The prevalence of deferred lesions with FFR≤ 0.80 was comparable between diabetic and non-diabetic patients (16.9% vs 23.3%, p = 0.07). One hundred ninety six patients experienced adverse events during follow-up (death, MI, or coronary revascularization). DM was a significant risk factor for death and MI independent of traditional risk factors (age, gender, hypertension, BMI, current smoking), history of coronary artery disease, and medications (adjusted hazard ratio (HR) 1.59, 95% confidence interval (CI) 1.01 to 2.45, p = 0.041), but not

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for coronary revascularization (adjusted HR 1.33, 95% CI 0.90 to 1.93, p = 0.15). Furthermore, the association between DM and death/MI was independent of the FFR value.

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Baseline characteristics were compared according to FFR value within non-diabetic and

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diabetic groups (Table 1). In non-diabetic patients, fewer were males, age was older, current

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smoking and dyslipidemia percentages were lower in the FFR＞ 0.85 group than the other two subgroups. In diabetic patients, cardiovascular risk factors were not significantly different

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between the three subgroups. Angiographic severity of coronary stenosis were higher in the

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FFR≤ 0.8 group than the FFR＞0.85 group in both diabetic and non-diabetic patients.

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Association between FFR value of deferred lesion and events in non-DM and DM patients

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The coronary events in non-diabetic and diabetic patients according to FFR quintiles (≤ 0.8,

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0.81-0.85, 0.85-0.89, 0.89-0.92, ＞ 0.92) were shown in Figure 2A and 2B. In non-DM, the coronary events decreased with increasing FFR value. In DM, the patients with FFR≤ 0.8 still had the most events, but the four else groups had not clear trend for FFR values. That means in conventional FFR safe range 0.8-1.0, diabetic patients with higher FFR value maybe haven’t lower rates of cardiovascular events. Figure 3 shows observed death, MI or revascularization rates at 3-year follow-up according to FFR values (≤ 0.80, 0.81 to 0.85, and ＞ 0.85). Higher FFR values were associated with lower event rates of MACE in non-diabetic patients, whereas the trend was not so clearly in DM patients. Even with FFR values >0.85, DM patients still had much more death and MI than non-DM (32.2% vs 18.2%, p = 0.007). In the multivariable Cox model, the adjusted HR of death, MI or revascularization for each group defined by FFR value and DM status were shown in Figure 4. Non-diabetic patients with FFR> 0.85 was as reference. Patients with FFR≤ 0.8,

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whether diabetic or non-diabetic, had a significantly higher risk of death, MI or revascularization than reference. But the HR of MACE in diabetic patients with FFR＞ 0.85 was a little higher

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than diabetic patients with FFR0.8-0.85 (HR [95% CI] 1.06 [0.85 to 1.40], p = 0.51). On the

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other hand, the HR of MACE in diabetic patients with FFR＞ 0.85 was higher than non-diabetic

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patients with FFR＞0.85 (HR [95% CI] 1.53 [1.01 to 2.42], p = 0.048). Among those with an FFR> 0.85, diabetic patients were at a significantly higher risk of death and MI than non-

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diabetics (HR [95% CI] 2.20 [1.19 to 4.01], p = 0.015).Thus, the outcomes were equally poor

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regardless of FFR in patients with DM and deferred PCI. The multivariable Cox hazard analysis revealed that FFR was a significant predictor for death, MI or revascularization in non-DM

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patients (HR [95% CI] per 0.1 increase in FFR for death and MI was 0.61 [0.44 to 0.86], p =

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0.007, for revascularization 0.66 [0.49 to 0.90], p = 0.006). Contrarily, in diabetic patients, FFR was only associated with revascularization (HR [95% CI] per 0.1 increase in FFR 0.53 [0.33 to

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0.85], p = 0.008), but not with death or MI (Table 2). Figure 5 (A, B, C, D) demonstrated Kaplan-Meier estimates of the probability of death/MI and revascularization according to the subgroups defined by DM and FFR. In non-diabetes, the event rate of patients with FFR≤ 0.8 was significantly higher than the other two groups. But in diabetes, the rates of death and MI were not significantly different between the three subgroups (p=0.11).

Discussion

The current study demonstrated that among patients with deferred PCI, FFR significantly predicted death, MI and coronary revascularization in non-diabetic patients, but not in DM

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patients except revascularization. Accordingly, these observations indicated that the risk for death and MI of DM patients with deferred revascularization was independent from FFR value,

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and more so, the predictive value of FFR may be different for DM and non-DM patients.

The utility of FFR to predict events

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FFR could reflect the extent of myocardial ischemia integrating the contributions of

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epicardial artery and collaterals.17 The extent of myocardial ischemia is a key factor in the management and prognosis of patients with stable CAD.18 Indeed, several studies have reported

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the prognostic utility of FFR in patients with deferred revascularization. Meuwissen et al. studied patients with deferred PCI with intermediate coronary stenosis, and demonstrated the significant

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association between low FFR and high major cardiovascular event rate.19 Similarly, another study of deferred PCI patients by Lavi et al. showed a 13% decrease in the risk for

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cardiovascular events per 0.01 increase in FFR.5 FFR has been suggested as a continuous marker of future events20, reflecting severity of epicardial coronary stenosis and myocardial ischemia. However, the difference in the predictive value of FFR between non-DM and DM has not fully been investigated.

From our results, among patients with deferred PCI, diabetic patients had higher risk for death and MI than non-diabetic patients. Importantly, we demonstrated that FFR has no significantly discriminative value for the prediction of death and MI in patients with DM, indicating that their risk of events is to be defined in much more complex terms. Relative to nondiabetes, there are more non-cardiovascular death in diabetes. On the other hand, diabetes have more unstable coronary lesions which are non-flow limiting coronary stenosis but may rupture to

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induce AMI. Therefore, the current study suggests a different risk stratification strategy for

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diabetic and non-diabetic patients.

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Possible mechanisms for the difference in the association of FFR with events between nonDM and DM

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A number of factors may explain the current observation that FFR was not associated with death

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and MI in DM patients. One explanation is the potential impact of diffuse epicardial CAD and microvascular disease on FFR and the prognosis of patients with DM and CAD. 21-23 Individually

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non-flow-limiting lesions can result in a significant pressure in aggregation whereas structural and functional changes of the coronary microcirculation may not allow for sufficient flow

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acceleration to mount a significance pressure drop.24,25 Another explanation might be a difference in plaque vulnerability. Compared to patients

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without DM, DM patients have a larger plaque burden, larger amount of necrotic core, and more frequent thin-cap fibroatheromas.26,27 Coronary thrombotic complications often result from disruption of these unstable plaques.28 Furthermore, microvascular dysfunction might be predictive of future cardiovascular events in diabetic patients by itself.19,29-31 Thus, in addition to the risk derived from epicardial coronary stenosis (FFR related risk), non-FFR related risk including other vascular diseases, non-flow limiting coronary stenosis, and microvascular dysfunction may substantially contribute to patients’ vulnerability, and it could be higher in diabetic than non-diabetic patients. Some studies indicated that FFR-related risk exponentially decreases along with increasing FFR value in general patients with deferred PCI.5,20 That means non-FFR related risk has more impact on clinical outcomes in diabetic patients with normal FFR value.

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Limitations

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This was a single-center observational study, and the sample size was modest. In our follow up data, we could not exactly know if the late event occurred in the FFR lesions. We did not assess

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non-flow limiting coronary plaque. We can’t identify the cause of death in all the dead patients.

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In patients with DM, a combined measurement of FFR and CFR may provide more information

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cardiovascular events in patients with DM.

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of myocardial perfusion. A larger study is needed to determine the utility of in FFR in predicting

Conclusion

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Among non-diabetic patients with deferred PCI, higher FFR values were associated with a lower risk of death, MI and revascularization. On the contrary in diabetic patients with deferred PCI,

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FFR was not able to differentiate the risk of cardiovascular events. The risk for death and MI of diabetic patients was independent of the FFR value of the coronary lesion whose revascularization was deferred.

Acknowledgements

We would like to show our gratitude to Jonella M. Tilford for her organizing materials and thank Victoria K. Schultz for her checking and submitting the manuscript.

Disclosure None.

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Figure legends

Figure 1. Study flowchart

Registered coronary artery disease patients with deferred PCI based on FFR from 2002 to 2009 were divided into six groups according to DM and FFR value. FFR, fractional flow reserve; DM, diabetes mellitus; MI, myocardial infarction; PCI, percutaneous coronary intervention.

Figure 2A. Death, MI or revascularization in non-DM according to quintiles of FFR values

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In non-DM, the coronary events decreased with increasing FFR values.

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Figure 2B. Death, MI or revascularization in DM according to quintiles of FFR values In DM, the patients with FFR≤ 0.8 still had the most events, the four else groups had not clear

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trend according to FFR values.

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Figure 3. Death, MI or revascularization rate at 3-year follow-up according to 3 ranges of FFR

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value

DM and non-DM patients were separately divided into three groups according to FFR values

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(≤0.80, 0.8 to 0.85, and >0.85). Higher FFR values were associated with lower event rates in

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non-DM, whereas the trend did not exist between FFR 0.8 to 0.85 and >0.85 in DM patients.

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Figure 4. Adjusted hazard ratio for death, MI or coronary revascularization according to tertile FFR value and DM status

Adjusted for age, gender, hypertension, dyslipidemia, body mass index, prior CAD (prior MI, coronary artery bypass grafting, and PCI), stent implantation in other lesions, number of vessel disease, current smoking, cerebral vascular disease, peripheral vascular disease, infusion method of adenosine. Events rate of non-DM&FFR >0.85 group was as the reference and the other five groups had higher hazard ratio for cardiovascular events. FFR, fractional flow reserve; DM, diabetes mellitus; MI, myocardial infarction.

Figure 5A. Unadjusted Kaplan-Meier curves for death or MI in the three non-diabetic subgroups according FFR.

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The event rate of death or MI in patients with FFR≤ 0.8 was significantly higher than the other two groups.

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Figure 5B. Unadjusted Kaplan-Meier curves for death or MI in the three diabetic subgroups

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according FFR.

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The rates of death and MI were not significantly different between the three groups

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Figure 5C. Unadjusted Kaplan-Meier curves for coronary revascularization in the three non-

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diabetic subgroups according FFR.

The event rate of coronary revascularization in patients with FFR≤ 0.8 was significantly higher

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subgroups according FFR.

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Figure 5D. Unadjusted Kaplan-Meier curves for coronary revascularization in the three diabetic

The event rate of coronary revascularization in patients with FFR≤ 0.8 was significantly higher than the other two groups.

FFR, fractional flow reserve; DM, diabetes mellitus; PCI, percutaneous coronary intervention; MI, myocardial infarction.

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