Should We Treat Patients with Moderately Severe Stenosis of theLeft Main Coronary Artery and Negative FFR Results?

Since the description of left main coronary artery disease (LMCA),1 its prognostic importance has been shown in different scenarios.2 Observational3 and randomized studies4 have confirmed the benefits of surgical revascularization in these patients. The percutaneous approach5,6 may be an option in highly symptomatic inoperable patients. However, angiographic evaluation of LMCA segments is sometimes difficult to interpret.7 In some patients, intermediate lesions of the LMCA coexist with significant stenoses in other arteries; furthermore, some patients present equivocal symptons accompanying non-diagnostic results of different tests for ischemia in the presence of moderate obstructions of the LMCA, making it difficult to discern the true meaning of these obstructions and, thus, the ideal therapeutic approach. On the other hand, cardiac surgery represents a potential risk for the patient’s life, even in highly experienced hospitals.8 Consequently, a test that could assess the clinical significance of these intermediate obstructions of the LMCA and predict the probability of events would be extremely valuable. Fractional flow reserve (FFR), calculated as the ratio between maximum myocardial flow throughout the stenosis measured during maximum induced hyperemia and theoretical normal flow under basal circumstances,9 has been shown to be an accurate and lesion-specific index for determining the functional significance of intermediate lesions. Several studies investigated the correlation between FFR and noninvasive tests in determining myocardial ischemia.10 These studies identified values of FFR < 0.75 as indicative of functionally significant stenosis. Little information is available about this procedures in the subgroup of patients with LMCA lesions of unclear functional significance.11 We therefore conducted the present study to assess the negative predictive value of FFR measurements on patients with moderate left main coronary stenosis. The study was designed to investigate the occurrence of cardiac events in patients with equivocal left main coronary stenosis and negative FFR values in order to assess the usefulness of this technique in predicting coronary events during follow-up. Patients and Methods Patients. This was a prospective study including consecutive patients with LMCA stenosis of moderate severity (based on visual estimation from coronary angiographic images of 30–50% stenosis) and studied at our hemodynamics laboratory between September 1997 and February 2002. The study design and procedures complied with the Declaration of Helsinki. We excluded from this study all patients with LMCA moderately severe lesions and acute myocardial infarction (< 4 days since the onset of symptoms) or cardiogenic shock. We also excluded patients who presented three-vessel disease suitable for cardiac surgery. Clinical follow-up with face-to-face or telephone interviews lasted from 10 to 60 months. As clinical events of significance we recorded death (considered to result from heart disease unless a different cause was proved), acute myocardial infarction, unstable angina, cardiac by-pass surgery or coronary angioplasty. Each event is also classified as related or unrelated with the vessel analyzed in this study. Measurement of fractional flow reserve. A 6 French guide catheter was advanced to the ostium of the coronary arteries to be studied. During the procedure 5000 IU heparin IV and 200–300 µg nitroglycerine were infused in the coronary artery of interest. A 0.014-inch guidewire (Radi Medical, Uppsala, Sweden, or Cardiometrics EndoSonics, Rancho Cordova, Calif.) was calibrated, advanced posteriorly and positioned distal to the stenosis. Intravenous infusion of adenosine was then started at 140 µg/kg body weight per minute during 2 mins. to induce maximal coronary flow. Once hyperemia was achieved, flow was measured and FFR was calculated as the ratio of the mean pressure obtained with the guidewire divided by the mean pressure obtained with the guiding catheter. If FFR was negative (>= 0.75), the procedure was terminated, and neither angioplasty nor surgical revascularization was planned. All patients received optimal medical treatment for secondary prevention of coronary artery disease including aspirin, beta-blockers and statins, if neccesary. Quantitative coronary angiography. The reference diameter, stenosis length, and minimal luminal diameter were determined with the use of a validated edge-detection program (CAAS II for windows version 4.1, Pie Medical Imaging, Maastricht, The Netherlands). Statistical analysis. Quantitative variables were expressed as the mean ± standard deviation, and qualitative variables were expressed as percentages. Student's t-test was used to compare mean values for quantitative variables that showed a normal distribution, and the chi-squared test or Fisher's exact test was used to compare qualitative variables. Differences were considered statistically significant at p < 0.05. Overall survival and event-free survival curves were drawn according to the Kaplan-Meier method.12 All statistical analyses were done with the SPSS program (version 8, SPSS Inc, Chicago, Illinois). Results A total of 27 patients in whom FFR testing of the LMCA was performed in order to assess the hemodynamic severity of equivocal stenosis were studied. There were no complications during FFR measurements in any of the 27 patients. Twenty patients showed a negative FFR (>= 0.75) and 7 patients showed a positive FFR (< 0.75). Table 1 summarizes the basal characteristics in these patients. Eighteen patients had additional coronary artery disease and were treated with either an interventional approach or optimal medical treatment depending on the lesion charateristics and the patient’s clinical situation. Four patients in the negative FFR group had a stent implanted in an affected coronary artery other than the LMCA (3 in the right coronary artery and 1 in the proximal descending anterior artery). Patients with positive FFR of the LMCA were treated with coronary revascularization of that vessel: one received a stent (she refused surgery) and six with bypass surgery. Two patients in the negative FFR group were initially operated on due to aortic prothesis dysfunction and severe mitral insufficiency. Angiographic findings. The angiographic features of the stenoses are also described in Table 1. Quantitative angiographic studies yielded mean values of 3.57 and 3.22 mm for the reference diameter in negative and positive FFR groups (p = 0.6). Minimum lumen diameters were respectively 2.21 versus 1.8 mm (p = 0.1). There was no significant difference between both groups in relation to the percentage of stenosis (34.2 versus 43.8%; p = 0.1). The mean FFR value was 0.68 in the positive FFR group and 0.88 in the negative FFR group. Follow-up. Follow-up was analyzed in all patients (Figure 1). Mean follow-up was 26.2 ± 12.1 months. In the positive FFR group, 7 patients were treated with coronary revascularization, 1 with stent implantation and 6 with coronary surgery. One patient died during cardiac surgery and another patient died 4 years later due to pneumonia. The remaining 5 patients are alive and have experienced no further cardiovascular events. In the negative FFR group, two cardiovascular events occurred in follow-up. One patient experienced unstable angina 42 months after the FFR measurement and surgical revascularization was required due to the progression of atherosclerotic disease on the LMCA. Another patient without changes in his clinical symptoms underwent surgical revascularization 3 months later in another country. Finally, 2 patients died due to non-cardiovascular reasons: 1 patient died 1 year after, due to lung cancer, and another died 4 years later due to gastrointestinal hemorrhage. Coronary angiography was repeated in 2 patients 8 and 26 months after FFR was determined because of equivocal symptons with an inconclusive exercise test; no changes in their coronary anatomy were found. Discussion Our findings show that the decision to defer angioplasty on the basis of negative FFR results in equivocal left main coronary stenosis is reasonably safe: only 2 of 19 patients studied required revascularization during follow-up, and in 1 patient, this was clearly due to progression of the severity of the stenosis 4 years after FFR measurement. This percentage is similar to that found in other recently published studies on the follow-up of patients with moderate coronary stenosis and negative FFR findings11,13–15 in different clinical scenarios, including those with chest pain of uncertain origin and negative ischemia test results of coronary syndromes. These studies confirm the hypothesis of a good prognosis after negative FFR results in different clinical situations. We found only 1 study focusing on the value of FFR to assess equivocal LMCA stenosis.11 Bech et al. studied 54 patients, 30 with positive FFR results (56%) and 24 with negative FFR tests (44%). Five of 24 patients in the negative FFR group had complications at follow-up: 20% with chest pain and a positive exercise test, which required a new revascularization procedure for all of them. Only 2 of these 5 patients showed progression of the LMCA stenosis and required bypass surgery. In our series, only 2 of 19 patients required surgical revascularization in the follow-up: 1 patient underwent revascularization 4 years later due to progression of his stenosis, and 1 patient did so 3 months later in another hospital following a second opinion evaluation; this patient had no change in his symptoms. Patients described in our study had smaller reference diameters and minimum lumen diameters of the LMCA which can modify FFR results. They also had a greater incidence of previous myocardial infarction. No incidence of death or myocardial infarction occurred after a mean follow-up of 2.5 years in the Bech et al. study, as well as in the present study. It is important to point out that in our study, of the 19 patients with negative FFR results in LMCA stenosis, 4 underwent percutaneous revascularization of a different artery after FFR had been measured for a lesion of intermediate severity. These patients were followed clinically and were not candidates for surgical treatment despite an initial suspicion of multivessel disease. Bypass surgery of LMCA disease presents a risk even in the best hospitals.8 Intermediate left main coronary stenoses are occasionally found in diagnostic procedures with significant stenosis in other arteries or equivocal symptons on diagnostic tests. Physiological assesment of these stenoses could avert surgical procedures in some of these patients. Moreover, coronary angioplasty of a functionally nonsignificant stenosis, rather than reducing the risk of coronary events, may actually produce conditions favorable to plaque degeneration due to scaling, acceleration of arteriosclerosis and subsequent restenosis.16 Therefore a premature surgery may be harmful arterial graft patency.17 Stenting culprit lesions in other arteries and aggressive medical treatment, seems to be justified. On the other hand, it is well-known that angiographic evaluation of LMCA segments is difficult to assess angiographically.7 Intravascular ultrasound (IVUS) allows detailed, cross-sectional imaging of coronary arteries. Abizaid et al reported18 the one-year prognosis of 122 patients with intermediate LMCA who presented a similar rate of complications to that descibed in our report (14%). Using logistic regression analysis, diabetes mellitus or untreated vessel disease were the only independent predictors of cardiac events. Reference diameter and minimum lumen diameter show a trend toward signifciance difference. Diameter of the stenosis was not a predictor of cardiac events. However, Bech et al.11 described smaller reference diameter and smaller minimum lumen diameter by quantitative coronary angiography in patients with positive FFR. The diameter of the stenosis was not different in both groups, as happens in our study. In the present study minimum lumen diameter show a trend toward significance difference to be smaller in positive FFR group. We could assume that the percentage of stenosis in patients with moderately severe stenosis of the LMCA is a poor index of severity but diameters could play a role as indepedendent predictors of severity. Recently a very interesting study has shown the prognostic significance of angiographically silent left main disease detected by intravascular ultrasound.19 Study limitations. The main limitation of this study is that it is observational and not based on random assignation of the patients to different interventions or control groups and the limited number of patients. The correlation between values of FFR below 0.75 and ischemia is well documented9 and we considered that randomizing patients with these findings to no intervention is not acceptable. Conclusion Our results suggest the safety of deferring coronary revascularization in patients with LMCA moderately severe stenosis and FFR >= 0.75. These patients presented a low complication rate without any death or myocardial infarction in the mean follow-up of 23 months. A non-significant stenosis might be safely deferred if it is not hemodynamically significant. Finally our study emphasizes the inability of the percentage of luminal stenosis to differenciate physiologically between significant and no significant stenosis. Acknowledgements. We thank Juan Méndez Rubio, Rocío Gil Pérez, Ramón Dávila Berrocal and Gabriela de Prada, of the Hemodynamics Unit staff, and Francisca Díaz Fernández, of the Hemodynamics Laboratory, Virgen de la Victoria University Hospital, for their expert assistance with this study.

1. Herrick J. Clinical features of sudden obstruction of the coronary arteries. J Am Med Assoc 1912;59:2015–2020. 2. Bergelson BA and Tommaso CL. Left main coronary artery disease: assessment, diagnosis and therapy. Am Heart J 1995;129:350–359. 3. Oberman A, Kouchoukos NT, HarRell HR, et al. Surgical versus medical treatment in disease of the left main coronary artery. Lancet 1976;2:591–594. 4. Caracciolo EA, Davis KB, Sopko G, for the CASS Investigators. Comparison of surgical and medical group survival in patients with left main coronary Aartery disease. Circulation 1995;91:2325–2334. 5. Tan WA and Tamai H, Park S, for the ULTIMA Investigators. Long-term clinical outcomes after unprotected left main trunk percutaneous revascularization in 279 patients. Circulation 2001;104:1609–1614. 6. Ellis SG, Hill CM, Lytle BW. Spectrum of surgical risk for left main coronary stenoses: benchmark for potentially competing percutaneous therapies. Am Heart J 1998;135:335–338. 7. Cameron A, Kemp HG, Fischer LD, et al. Left main coronary artery stenosis: Angiographic determination. Circulation 1983;68:484–489. 8. Dewey TM, Magee MJ, Edgerton JR, et al. Off-pump bypass grafting is safe in patients with left main coronary disease. Ann Thorac Surg 2001;72:788–791. 9. Pijls NH, van Son AM, 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. 10. Pijls NH, De Bruyne B, Peels K, et al. Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenosis. N Engl J Med 1996;334: 1703–1708. 11. Bech GJW, Droste H, Pijls NHJ, et al. Value of fractional flow reserve in making decisions about bypass surgery for equivocal left main coronary disease. Heart 2001;86: 547–552. 12. Kaplan EL, Meier P. Nonparametric estimation of incomplete observations. J Am Stat Assoc 1958;53:457–481. 13. Bech GJW, De Bruyne B, Bonnier HJ, et al. Long-term follow-up after deferral of percutaneous transluminal coronary angioplasty of intermediate stenosis on the basis of coronary pressure measurements. J Am Coll Cardiol 1998;31:841–847. 14. 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. 15. Hernández-García JM, Alonso-Briales JA, Jiménez-Navarro MF, et al. Clinical management of patients with coronary syndromes and negative fractional flow reserve findings. J Interven Cardiol 2001;14:505–510. 16. Ischinger T, Gruentzig AR, Hollman J, et al. Should coronary arteries with less than 60% diameter stenosis be treated by angioplasty ? Circulation 1983;68:148–154. 17. Hashimoto H, Isshiki T, Ikari Y, et al. Effects of competitive blood flow on arterial graft patency and diameter. Medium-term postoperative follow-up. J Thorac Cardiovasc Surg 1996;1112:399–407. 18. Abizaid A, Mintz G, Abizaid A, et al. One-year follow-up after intravascular ultrasound assessment of moderate left main coronary artery disease in patients with ambiguous angiograms. J Am Coll Cardiol 1999;34:707–715. 19. Ricciardi MJ, Meyers S, Choi K, et al. Angiographically silent left main disease detected by intravascular ultrasound: A marker for future adverse cardiac events. Am Heart J 2003;1463:507–512.