The Use of Pressure Gradient in the Diagnosis of Restenosis
Volker Klauss, MD
and Nico H. J. Pijls, MD , P h D
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INTRODUCTION
The limitation of coronary angiography to assess the functional significance of coro- nary stenosis as well as coronary restenosis has been recognized for years (1,2). It is well known that the angiographic assessment of an epicardial lesion correlates poorly with its physiological relevance (3,4). Coronary angiography with its inherent limita- tions may not reliably predict whether a stenosis produces ischemia (5). In addition, the determination of the severity of stenoses varies significantly among observers. In one study, experienced operators disagreed 30% of the time when deciding on the number of coronary arteries with a 70% stenosis (6). Despite these limitations the decision for performing an intervention is often based on the angiographic appearance of a coronary lesion. It is known from many angiographic studies that revascularization rate increases after scheduled control angiography meaning that repeat intervention is more often based on morphological criteria, i.e., quantitative coronary angiography or solely “eye balling” than on physiological considerations (7). Furthermore, as restenosis, which means in most of the cases in-stent restenosis may occur as a diffuse, proliferative process, the assessment of the hemodynamic significance is even more complex by angiography alone.
From: Contemporary Cardiology: Essentials of Restenosis: For the Interventional Cardiologist Edited by: H. J. Duckers, E. G. Nabel, and P. W. Serruys © Humana Press Inc., Totowa, NJ
247
Given this limited accuracy of morphological methods to assess true stenosis sever- ity, diagnosis of restenosis by angiography is even more disputable. In the view of the risk of a second restenosis, the higher costs of a reintervention (i.e., brachy therapy or drug eluting stents), potential procedural complications, and the lower long-term bene- fit, it is imperative that the decision of performing an intervention in a restenotic lesion is combined with objective evidences of myocardial ischemia.
In the present chapters, the potential of intracoronary pressure measurements for the diagnosis of restenosis will be discussed. As the vast majority of clinical studies dealing with intracoronary pressure measurements have been performed in de novo lesions the results and observations to restenotic lesions are extended where it seems possible. For conceptual reasons as illustrated later the focus will be on more details of the principle of fractional flow reserve than on the determination of coronary pressure gradient alone.
DEFINITION OF FRACTIONAL FLOW RESERVE
The concept of fractional flow reserve has been developed as an invasively deter- mined index of the functional severity of coronary stenosis (8). Fractional flow reserve is defined as the ratio of maximum blood flow to the myocardium in the presence of a stenosis in the supplying coronary artery to the theoretical maximum flow in the absence of the stenosis (9). This ratio represents the fraction of maximum flow that can be maintained in spite of the presence of this stenosis. In the clinical context the index of fractional flow reserve indicates to what extent maximum blood flow in a stenosed coronary vessel can be improved by a coronary intervention.
The determination of fractional flow reserve by pressure measurements requires the induction of maximal hyperemia. Only at maximum vasodilation, corresponding to maximum coronary and myocardial hyperemia, myocardial resistance is minimal and constant and blood flow is proportional to driving pressure. In the presence of a coro- nary stenosis, perfusion pressure over the myocardium and thus maximum attainable blood flow to the myocardium will be affected to the same proportion under hyperemic conditions. Thus, fractional flow reserve can be calculated by comparing the mean coronary pressure distal to a stenosis, as measured with pressure wire, with the proxi- mal coronary pressure, as measured with the guide wire (10).
Fractional flow reserve has several and unique features compared with other phys-
iological indices. First, this index is independent of changes in systemic blood pres-
sure, heart rate, or myocardial contractility (11). Second, the normal value of
fractional flow reserve is one in all patients and in all coronary arteries (12). Third,
it considers the contribution of collateral circulation (13). Fourth, it can be applied
in single and multivessel disease. Furthermore, a fractional flow reserve of less than
0.75 accurately identifies lesions associated with inducible myocardial ischemia
(14). Fianally, fractional flow reserve accounts for the extension of the perfusion
territory of the stenotic artery: two identical stenoses with a different perfusion ter-
ritory yield different values of fractional flow reserve, thus correctly matching the
supplying artery to the area to be perfused. In a practical setting, fractional flow
reserve can be derived easily from the ratio of mean distal coronary artery pressure to
mean aortic pressure under maximal vasodilation by means of a 0.014-in. pressure
guide wire (Fig. 1).
CLINICAL VALIDATION OF FRACTIONAL FLOW RESERVE Although not all theoretical concerns regarding the limitation of direct physiological measurements can be completely satisfied, the clinical validation strongly supports the value of intracoronary pressure measurement. In patients, the validation of physiological criteria has been established by population correlations with clinically accepted norms of several types of ischemic stress provocation (15–18). In a landmark study, Pijls and colleagues (14) compared fractional flow reserve in 45 patients with intermediate lesions with bicycle exercise testing, nuclear perfusion imaging, and stress echocardiography. In all 21 patients in whom the fractional flow reserve was less than 0.75, at least one non- invasive test demonstrated inducible ischemia and reversed to normal after treatment. In 21 of the 24 patients in whom the fractional flow reserve was 0.75 or higher, there was no inducible ischemia on any of the noninvasive tests. The sensitivity, specificity, and concordance of fractional flow reserve were 88%, 100%, and 93%, respectively.
Although the first validation studies were performed in selected patients more recent studies confirmed consistently good correlations between fractional flow reserve cut-off values and noninvasive stress tests also in patients with multivessel disease and previous myocardial infarction (Table 1). Thus, sensitivity and specificity of fractional flow reserve vary between 69 and 100%, respectively. The cut-off value of fractional flow reserve for identifying reversible ischemia in these studies was consistently between 0.72 and 0.75, underlining the diagnostic accuracy of this index.
Fig. 1. Fractional flow reserve can be derived easily by means of a 0.014-in. pressure guide wire, which is placed distally to a stenosis of questionable hemodynamic relevance. By inducing maximal vasodilation with intravenous adenosine in this example, fractional flow reserve can be calculated by the ratio of mean distal coronary artery pressure (Pd) to mean aortic pressure (Pa). (Please see insert for color version.)
To summarize there is enough evidence based on multiple validation studies that frac- tional flow reserve is a reliable index for indicating or excluding reversible ischemia at least equivalent or even superior to noninvasive stress test, such as exercise-electrocardiogram, myocardial scintigraphy, and dobutamine stress-echocardiography. Thus, in patients presenting with restenosis of intermediate narrowing, no or not typical angina, and missing or not conclusive stress tests, the decision whether to perform a revascularization can be based on the result of intracoronary pressure measurement immediately. Especially, in patients with debortable in-stent restenosis—many stents show some intimal hyperpla- sia without meaning that this is associated with any ischemia—demonstration of reversible ischemia is paramount before embarking in questionable brachytherapy or placing a drug eluting stent within the other stent.
PRACTICAL SET-UP OF PRESSURE MEASUREMENTS IN THE CATHETERIZATION LABORATORY
No major adaptations are necessary in a catheterization laboratory to perform intracoro- nary pressure measurements on a routine basis. Currently, two microsensor-tipmanometer wires with a diameter of a standard guide wire are available. Each is connected through a cable to its specific interface, which indicates the pressure values (distal coronary and aortic) and—depending on the system—the corresponding pressure curves. Both inter- faces are normally connected to the registration system of the cath lab. The quality of these pressure guide wires is nowadays similar to standard guide wires with respect to torquability and access to the lesion. Thus, for an experienced angiographer a pressure guide wire can be used as a first line wire and all manipulations and exchange proce- dures can be performed in a regular way.
Although the use of a regular guiding catheter is recommended because the inner coat- ing allows for better torque control there is growing experience with the use of regular 4°F and 6°F diagnostic catheters (19). A crucial point as alluded to before is the induction a maximum hyperemia. Once the wire with sensor is distal to the lesion or segment of inter- est, a maximum hyperemic stimulus should be administered for a complete physiological evaluation. Multiple studies reported on the effect of different stimuli given either intra- coronarily or intravenously (20–22). Generally, long acting drugs, such as papaverine,
Table 1
Validation Studies Comparing FFR With Noninvasive Stress-Testing
Study Patients Noninvasive tests FFR Sensitivity (%) Specificity (%)
De Bruyne B 60, SVD, Exercise ECG 0.72 100 69
et al. (9) no MI
Pijls NH 45, SVD, Exercise ECG, 0.75 88 100
et al. (25) no MI DSE, SPECT
Chamuleau 127,2VD, SPECT 0.74 69 79
et al. (17) no MI
De Bruyne 57, SVD, SPECT 0.75 82 87
et al. (18) MI
Usui et al. 167, MVD, SPECT 0.75 79 79
(26) MI
MI, myocardial infarction; SVD, single vessel disease; 2VD, Two-vessel-disease; MVD, multivessel disease; DSE, dobutamine stress echocardiography; SPECT, single photon computed tomography; ECG, electrocardiography.
should be used if the intracoronary line is preferred; for intravenous application, adenosine or ATP are recommended. The most convincing mode to demonstrate the location of a lesion is a so-called pullback curve, also named as “physiological road map” of a coronary artery (Fig. 2). During maximum hyperemia the sensor is slowly pulled back from the dis- tal position in the vessel to the ostium. The pullback curve also allows the detection of mul- tiple lesions within one vessel or the presence of diffuse disease. It is therefore strongly recommended to perform pressure measurements in a standardized way by means of pres- sure pullback curves. Having the interface permanently installed in the cath lab, a diagnos- tic procedure can simply be extended by a physiological evaluation within a few minutes and thus applied on a routine basis by every operator.
APPLICATION OF PRESSURE MEASUREMENTS IN THE DIAGNOSIS OF RESTENOSIS
In the present chapter, several cases will be shown in whom the application of pressure measurements was used for assessing the hemodynamic relevance of in-stent restenosis.
In the first case, a 50-yr-old man was scheduled for 6-mo control angiogram.
Initially, a proximal left anterior descending coronary artery (LAD) lesion was treated with stent. The follow-up angiography revealed a moderate in-stent restenosis (Fig. 3), the patient was asymptomatic at that time. Many operators would probably have treated this restenosis with another percutaneous coronary intervention (PCI) including expensive procedures, such as brachytherapy or drug eluting stents. In this case, a pressure wire was used in combination with intravenous adenosine and showed a only mildly impaired frac- tional flow reserve clearly indicating no need for any revascularization procedure. The next case was a 64-yr-old male with former bypass surgery. Eight months ago the ostium of the venous graft to a small obtuse marginal branch was treated with stent implanta- tion (bare metal stent). He presented with diffuse symptoms interpretated as angina by the referring physician. A myocardial scintigraphy was not conclusive so finally a diagnostic angiography was performed revealing a in-stent restenosis of the ostial stent of the graft (Fig. 4). By pressure measurements fractional flow reserve was 0.91 indicating no need for another PCI procedure in this graft.
A 58-yr-old male was scheduled for PCI of the LAD. Nine months ago the right coro- nary artery has been treated with a stent, 3 mo ago an in-stent restenosis was dilated with angioplasty alone. Before targeting the LAD a control angiogram of the RCA showed a mild-to-moderate restenosis again. Pressure measurement indicated a reduced but not clearly pathological fractional flow reserve (FFR) (Fig. 5). Pressure measurements of the lesions of the left coronary artery showed functionally diffused disease with clearly patho- logical FFR values in the LAD and first diagonal branch. The treatment of this patient was finally switched to bypass surgery, based on the results of the pressure measurement.
As demonstrated in these cases, coronary pressure measurement is a helpful tool to eval- uate the hemodynamic relevance of an instent restenosis, which is most often impossible to assess alone by angiographic means. Pressure measurements help to confirm the appro- priateness of an intervention or to avoid on the other side additional interventions.
COST-EFFECTIVENESS OF FRACTIONAL FLOW RESERVE
In a recent study, the cost-effectiveness of measuring fractional flow reserve in patients with intermediate lesions was assessed by use of decision analysis model (23).
Although the model assumptions were made for patients with single coronary vessel
disease and de novo lesions, the differences in costs of each of the strategies compared with fractional flow reserve measurements illustrates the potential impact of the use of pressure measurements in restenotic lesions. On-line pressure measurements in case of intermediate lesions and no previous functional study was compared with a nuclear stress testing strategy and a strategy of stenting of all lesions. As the result of this study, immediate pressure measurements saved $1795 per patient compared with delayed noninvasive stress testing and $3830 compared with the stent strategy. Quality-adjusted life expectancy was similar among the 3 strategies, but the cost per quality adjusted life year for the nuclear stress testing strategy was substantial (>$800,000/quality adjusted life year). Keeping in mind that this model was applied in a patient subset not includ- ing patients with restenosis, the differences between the strategies are so pronounced that essential changes in a model with restenotic lesions might not be expected. This analysis war performed from a societal perspective. From a hospital perspective, each strategy might be attractive, depending on the reimbursement system.
LIMITATIONS
Fractional flow reserve is limited by its reliance on achieving maximal hyperemia. If
maximal hyperemia does not occur, the pressure gradient across a stenosis will be
Fig. 2. Pressure-pullback curve, also named as “physiological road map” of a coronary artery. During maximum hyperemia the sensor is slowly pulled back from the distal position in the vessel to the ostium. The pullback curve allows the detection of multiple lesions within one vessel or the presence of diffuse disease as in the present example. This patient had typical angina and a positive single photon computed tomography on the anterior wall. The LAD is occluded and the pressure measurements of the diagonal branch showed a pathological FFR, which is owing to diffuse disease but not circum- script lesions. That means that an intervention at the angiographic lesion sites marked by the arrows will not really lead to a better functional result.underestimated and the fractional flow reserve overestimated. For these reasons, careful and adequate administration of the vasodilating agent, particularly when using the intracoronary route, is critical. Intravenous adenosine is considered the reference standard for inducing hyeremia, but the added expense for the medication might be prohibitive. However, in hospitals with own pharmacies adenosine for the intravenous application can be provided at very low costs. Fractional flow reserve is furthermore affected by significant microvascular disease. Because achieving maximal hyperemia when measuring the pressure distal to stenosis is critical to accurately assess fractional flow reserve, a dysfunctional microcirculation secondary to, for example, diabetes can impair the microvascular vasodilator capacity. This can result in what one initially might consider an overestimation of the fractional flow reserve. However, the fractional flow reserve measurement continues to provide useful information about the epicardial lesion in this setting: a fractional flow reserve higher than 0.75 implies the absence of myocardial ischemia and the lack of need for revascularization.
Although the decision on the interventional treatment of a restenosis can be based on the result of pressure measurements currently there is a lack of the data on the safety of deferring an intervention. But whether the interventional treatment of a restenosis is decided by use of fractional flow reserve or by means of a noninvasive test by none of these tests the natural course of an individual restenosis can be determined.
Fig. 3. A 50-yr-old man was scheduled for control angiography. Six months before, a proximal LAD lesion was treated with stent. The present angiogram revealed an in-stent restenosis, the angiographic severity was similar to that of the index procedure. Many operators would probably have treated this restenosis with another PCI, including expensive procedures, such as brachyther- apy or drug eluting stents. In this case, a pressure wire was used in combination with intravenous adenosine and showed a only mildly impaired fractional flow reserve clearly indicating no need for any revascularization procedure. (Please see insert for color version.)
Thus, the decision to perform a PCI should primarily be based on the result of either stress test and not on the nature of the lesion itself. Having convincing data on the prognostic impact of postinterventional fractional flow reserve measurements after coronary stenting such data are missing for treating a restenotic lesion (24). Although the importance of the functional result of any intervention might be assessed, cur- rently the contribution to the long-term outcomes in restenotic lesions is not known.
Furthermore, the widespread use of fractional flow reserve measurements in most European countries is limited by the price of the pressure guide wire combined with the lack of reimbursement as a specific procedure. Additional studies are necessary to con- vince health insurances and hospital administrations that the use of fractional flow reserve is cost-effective and might even lower the costs when the method is adequately integrated in the diagnostic algorithm.
CONCLUSIONS
Recognizing the above limitations fractional flow reserve can be performed easily,
rapidly, and safely in patients with coronary artery disease. By its diagnostic accuracy
this index can be used for on-line clinical decision making in patients with de-novo and
restenotic lesions to decide on repeat intervention on one hand and to avoid unnecessary
Fig. 4. Angiogram of a venous graft to a small obtuse marginal branch, which was treated with stent implantation (bare metal stent) 8 mo ago. The patient presented with diffuse symptoms inter- pretated as angina by the referring physician. A myocardial scintigraphy was not conclusive so finally a diagnostic angiography was performed revealing a in-stent restenosis of the ostial stent of the graft. By pressure measurements fractional flow reserve was 0.91 indicating no need for another PCI procedure in this graft. (Please see insert for color version.)revascularization on the other side. This applies especially when the hemodynamic sig- nificance of the lesion is questionable and no noninvasive functional evaluation has been performed or a test has been performed with a nonconclusive result.
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