Looks Aren’t Everything
FFR B4 U PTCA
The selection of patients for coronary revascularization procedures is one of the most important and widely studied decisions in cardiovascular medicine. The article by Bech et al1 in the current issue of Circulation is a landmark study that should guide clinicians in more precisely selecting which stenotic lesions should be dilated and which are better left alone.
Coronary angiography, once a complicated procedure, was developed to determine whether coronary arteries were narrowed enough to restrict blood flow to the myocardium. Now, coronary angiography is easy, but interpretation of the findings has become increasingly difficult as our knowledge of atherosclerosis has broadened. The problems have centered around 2 questions: how much stenosis is needed to cause a clinically significant reduction in blood flow, and does the severity of stenosis relate to its propensity to cause infarction?
The translation of angiographically determined arterial stenosis to physiologically relevant reductions in coronary blood flow dates to the seminal work of Gould et al in 1974.2 He demonstrated in animals that resting coronary blood flow remained normal until 85% to 90% of the coronary cross-sectional area was occluded. This is because blood flow in healthy coronary arteries is regulated by the microcirculation, which has substantial constrictive tone at rest. With progressive stenosis in the upstream coronary, the microcirculation dilates. This fall in microvascular resistance compensates for the stenotic resistance in the large coronary, preserving overall coronary resistance and blood flow at rest. This is one of the reasons that many patients with stenotic lesions have normal resting perfusion scans, normal distal myocardial function, and no resting symptoms. Hyperemic blood flow, however, is progressively limited when the artery is ≥75% obstructed (>50% diameter stenosis), leading to effort angina and distal myocardial dysfunction. Clinicians and third-party payers have subsequently used this degree of stenosis as the threshold for revascularization procedures.
There are 2 problems with this simplistic approach to assessing the impact of stenotic lesions on blood flow. The first is that atherosclerotic coronary lesions are different from artificial obstructions in normal animal vessels.3 Atherosclerosis is a diffuse process. Consequently, the concept of “percent stenosis” compares the most stenotic area to the adjacent artery, which is really the comparison of 2 abnormal segments. Furthermore, some atherosclerotic segments are actually dilated because of vascular remodeling, making stenoses appear more severe than they really are.4 These effects of diffuse atherosclerosis were found in pathology studies 40 years ago and repeatedly rediscovered recently with intravascular ultrasound (IVUS).
It is not difficult to infer the physiological significance of angiographically severe stenoses (>80% diameter stenosis) or minimal disease (<30% diameter stenosis). However, angiographic interpretation of intermediate stenosis has had a poor correlation with actual measurements of blood flow.5 Thus, decisions to revascularize patients with intermediate lesions based on angiographic appearance are potentially fraught with a high degree of inaccuracy. This inaccuracy also may have led to underestimation of the accuracy of noninvasive studies (in which angiographic percent stenosis was the “gold standard”).
IVUS allowed better definition of vascular dimensions. It demonstrated that angiography sometimes failed to show the most severe stenosis within a vessel. It also reconfirmed the pathology studies demonstrating that atherosclerosis is a diffuse process. Just as important, IVUS allowed measurement of the dimension of the “unobstructed” artery: the internal elastic lamina area. This showed us the caliber of the artery without the atherosclerotic lesion. Unfortunately, atherosclerotic remodeling can alter cross-sectional area of the entire artery. The problem with using IVUS measurements to determine blood flow obstruction is that like angiography, it uses a surrogate measurement (lumen cross-sectional area) to infer blood flow obstruction. Although there is a good relationship between IVUS assessments of arterial stenosis and physiological studies, the relationship in an individual patient can vary significantly owing to vascular remodeling and the size of the distal perfusion bed.6
To solve this problem, catheters and small wires were developed to measure coronary blood flow directly.7 Coronary flow reserve (the ratio of maximal hyperemic to resting blood flow) was first put forward as a method to assess the blood flow limitation imposed by a coronary stenosis. A flow-limiting lesion should reduce hyperemic blood flow and thereby reduce coronary flow reserve. This parameter works well in animal models, but it falls short in human atherosclerosis. Coronary flow reserve measures the ability of the entire vascular bed (distal to the probe) to conduct blood flow. Microcirculatory dysfunction is common in atherosclerotic vessels, and reductions in coronary flow reserve can occur without a contribution from the stenotic epicardial artery. Hence, a low flow reserve does not necessarily indicate that the stenotic lesion is limiting the flow; the problem might lie in the microcirculation.
Pijls and colleagues8 made a major contribution when they developed the concept of fractional flow reserve (FFR). FFR is beautiful because it is lesion specific and easy to measure. Despite its name, FFR does not measure blood flow; it is the transstenotic pressure gradient across a stenosis, measured at peak blood flow after administration of a microvascular vasodilator (eg, intracoronary adenosine) and indexed for the aortic driving pressure. It is based on the concept that a stenotic lesion obstructs flow only if a pressure gradient develops across the lesion when the microcirculation is maximally dilated. If there is no pressure gradient, the stenotic lesion is not the site of significant obstruction, and dilation cannot improve blood flow. This measurement is technically simple with the use of 0.014-in pressure wires that can be passed through diagnostic angiographic catheters (4F catheters in our laboratory). Moreover, it uses straightforward physics to detect obstruction, and it provides information that is lesion specific.
In extensive studies, Pijls et al9 demonstrated that an FFR <0.75 (that is, a mean pressure distal to the stenotic lesion <75% of the mean aortic pressure) correlated closely with inducible ischemia on stress testing. They also showed that angioplasty of lesions that reduced FFR to <0.75 caused remission of symptoms and normalization of stress tests.
What Bech and colleagues1 have now demonstrated in a randomized trial is that a clinical decision not to dilate stable coronary lesions that do not limit blood flow (ie, FFR >0.75), despite angiographic appearance, is safe and provides an outcome equal to or better than angioplasty. These findings are reinforced by prior observational studies showing that the withholding of revascularization of angiographically severe but physiologically innocent lesions was associated with a benign outcome and spontaneous resolution of symptoms.10 11 For assessment of single lesions, we now have a body of outcome data that supports the decision not to revascularize lesions that do not cause flow obstruction.
Why are FFR measurements used so infrequently? One reason has been lack of convincing evidence that these measurements are reliable and can be used safely for patient care. Atherosclerotic lesions often constrict during exercise or during mental stress.12 13 In theory, stenosis hemodynamics measured at angiography might not reflect the degree of obstruction that occurs during stress, and angioplasty might reduce the impact of constriction in a stenotic lesion. That theory, however, has now been disproved by experiment. In most patients with chest pain, intermediate levels of stenosis, and an FFR >0.75, symptoms regressed spontaneously. Angioplasty did not reduce symptoms further.
A second reason for the infrequent use of FFR measurements is that such measurement has associated direct costs of up to $500 in the United States. It is possible, however, that FFR measurements might save resources because unnecessary revascularization is averted. Additional economic studies should address this issue.
A third reason is that a substantial number of invasive cardiologists regard this physiological approach as a “science project” rather than a clinical tool. Only a limited number of interventionists are comfortable with FFR measurements. Fewer still have a strong background in coronary physiology (despite working with in vivo coronary physiology on a daily basis). This is unfortunate but easily correctable. The technique of FFR measurement should be simple for any accomplished interventional cardiologist, and the required knowledge of coronary physiology is fairly straightforward.
We need more outcome information about the utility of FFR measurements in clinical decision making for patients with more complex lesions and those without symptoms. The dynamic nature of thrombotic lesions might render FFR measurements made at one point in time less predictive. Additional studies will be needed to ensure that these measurements can be counted on for standard clinical care. Serial lesions have more complex hemodynamics. De Bruyne and colleagues14 have also addressed this topic, but we do not have sufficient outcome data to use the measurements with certainty.
An additional, theoretical problem with the use of FFR to guide revascularization is that the presence or absence of flow limitation might not predict anything about the propensity of the stenotic plaque to rupture and cause an event (eg, infarction). The past 3 decades of clinical coronary research have demonstrated that patients with multiple severe, flow-limiting coronary lesions are marked as being at high risk for an event. Whether flow-limiting, stenotic lesions per se cause the increased risk or multiple, severe stenoses simply identify patients who are more likely to have very active atherosclerosis (with many fresh, minimally stenotic lesions) is unresolved. The difference is critical to interventional cardiologists, who fix stenotic lesions one at a time (as opposed to bypass surgery, which provides entirely new conduits that bypass long sections of coronary arteries).
At the present time, the use of FFR to decide which patients to revascularize based on a concern about risk rather than symptoms (eg, an asymptomatic patient with an abnormal stress test) awaits additional outcome data. However, the low incidence of events in patients with lesions with an FFR >0.75 (despite angiographic appearance) is promising. Similarly, selection of arteries for coronary bypass surgery (eg, bypass of an intermediate right coronary lesion in a patient with a severe proximal left anterior descending stenosis) based on the FFR of an intermediate lesion is attractive, but we need further outcome data.
The present study by Bech et al,1 however, provides strong clinical evidence that patients with nonthrombotic, stenotic lesions with an FFR >0.75 are not likely to benefit from angioplasty. Wider application of this measurement should improve patient selection for angioplasty and prevent staged procedures. The days of performing a stress test after angiography to decide whether a lesion should be dilated are over; an FFR measurement can be done on the spot. The challenge for the interventional community is to train ourselves in the method and apply it in clinical practice.
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
- Copyright © 2001 by American Heart Association
Bech GJW, De Bruyne B, Pijls NHJ, et al. Fractional flow reserve to determine the appropriateness of angioplasty in moderate coronary stenosis: a randomized trial. Circulation. 2001;103:2928–2934.
Takagi A, Tsurumi Y, Ishii Y, et al. Clinical potential of intravascular ultrasound for physiological assessment of coronary stenosis: relationship between quantitative ultrasound tomography and pressure-derived fractional flow reserve. Circulation. 1999;100:250–255.
Wilson RF, Marcus ML, White CW. Prediction of the physiologic significance of coronary arterial lesions by quantitative lesion geometry in patients with limited coronary artery disease. Circulation. 1987;75:723–732.
Pijls NH, van Son JA, Kirkeeide RL, et al. Experimental basis of determining maximum coronary, myocardial, and collateral blood flow by pressure measurements for assessing functional stenosis severity before and after percutaneous transluminal coronary angioplasty. Circulation. 1993;87:1354–1367.
Lesser JL, Wilson RF, White CW. Physiologic assessment of coronary stenoses of intermediate severity can facilitate patient selection for coronary angioplasty. J Coron Artery Dis. 1990;1:697–705.
Gage JE, Hess OM, Murakami T, et al. Vasoconstriction of stenotic coronary arteries during dynamic exercise in patients with classic angina pectoris: reversibility by nitroglycerin. Circulation. 1986;73:865–876.
De Bruyne B, Pijls NH, Heyndrickx GR, et al. Pressure-derived fractional flow reserve to assess serial epicardial stenoses: theoretical basis and animal validation. Circulation. 2000;101:1840–1847.