Fractional flow reserve to guide percutaneous coronary intervention in multivessel coronary artery disease

Coronary heart disease is a leading cause of death, morbidity, and substantial economic costs in the United States and Europe. The pathological process responsible for coronary heart disease is atherosclerosis. It can cause diffuse disease or local narrowings in the coronary arteries, which impair blood flow and therefore oxygen supply to the myocardium. In case oxygen demand by the heart, for instance during exercise, exceeds oxygen supply through the narrowed coronary arteries, myocardial ischemia is induced, resulting in chest discomfort known as angina pectoris. In patients with coronary artery disease, the presence of inducible myocardial ischemia not only causes symptoms, but it also has significant prognostic implications i.e. increased chance for myocardial infarction or sudden death. Restoring blood flow and therefore oxygen supply to the myocardium reliefs myocardial ischemia, improves symptoms, and reduces the risk of death and myocardial infarction. Revascularization by percutaneous coronary intervention (PCI) with stent placement or by coronary bypass surgery, should therefore be targeted at relieving myocardial ischemia. In chapter 1, the introduction of this thesis, it is explained that non-invasive stress testing and coronary angiography will not always provide adequate or complete information about the functional importance of coronary artery narrowings. Particularly in patients with multivessel disease, it can therefore be difficult to determine which out of several lesions cause myocardial ischemia and therefore warrant revascularization. Because of the low restenosis rate, some investigators have proposed stenting of all intermediate lesions with drug-eluting stents, irrespective of their physiological significance. However, drug-eluting stents are expensive and are associated with potential late serious complications, occurring in 2 to 3% of stents per year. Therefore, a more judicious use of stents is paramount. The index of fractional flow reserve (FFR) is considered as the gold standard for the detection of myocardial ischemia, related to a particular stenosis. The concept and practical application of this diagnostic tool in the catheterization laboratory are described in chapter 2. By using FFR in patients with multivessel disease, the interventional cardiologist is able to accurately distinguish between coronary stenoses that induce myocardial ischemia and stenoses that do not induce myocardial ischemia. Consequently, it is possible to selectively treat those functionally significant stenoses (those responsible for reversible ischemia, also called ‘ischemic stenoses’) by stent placement and leave the non-ischemic stenoses for medical treatment in such patients. This led to the hypothesis that, compared to commonly practiced angiography-guided stenting, a strategy of FFR-guided stenting would decrease the number of stents deployed and typically stent-related complications, but still result in complete relief of myocardial ischemia, thereby improving clinical outcome and decreasing health care expenditure. The ‘windtunnel’ for testing a novel strategy or treatment is a randomized trial, in which the new treatment can be tested against the treatment that is commonly used in daily practice. That was the rationale to perform the Fractional Flow Reserve versus Angiography in Multivessel Evaluation (FAME) study. Chapter 3 describes the design of the FAME study. This international, multicenter study compares angiography-guided PCI with FFR-guided PCI in patients with multivessel coronary disease. In both treatment arms the coronary intervention is performed with drug-eluting stents. In little more than a year, 1005 patients were randomized in 20 centers in Europe and in the USA. Only a limited number of in- and exclusion criteria were applied and an exceptionally high percentage of 53% of all screened patients entered into the study Amongst others, these two factors paved the way for an unselected patient population with complex and severe multivessel coronary artery disease, truly reflecting daily practice as much as possible. The results after 1 year of follow-up are discussed in chapter 4, and showed a significant reduction in the primary, combined endpoint of death, myocardial infarction, and repeat revascularization for the FFR-guided strategy. In fact not only the primary endpoint, but also the rates of all its individual components were decreased consistently by roughly 30% with this strategy. Moreover, while using less stents per patient, the FFR-guided approach results in a similar relief of myocardial ischemia and subsequent anginal symptoms, as with the common angiography-guided approach. It is important to stress that the use of FFR in these patients does not prolong procedure time and even reduces the amount of contrast agent used. In chapter 5, an in-depth analysis of the patients in the FFR-guided treatment arm of the FAME study confirms the poor performance of coronary angiography in predicting the presence of inducible myocardial ischemia, related to a coronary stenosis. Generally, coronary narrowings with a stenosis percentage of 50% or more of the vessel diameter on the angiogram are defined as clinically significant and are therefore revascularized. However, this analysis shows that of all coronary stenoses with an angiographic severity of 50-70%, two-thirds are functionally non-significant and only one-third is functionally significant. Even in more severe stenoses between 71 and 90% angiographic stenosis severity, 20% of all lesions are not functionally significant. Therefore, in patients with multivessel CAD, one cannot rely on the angiogram to identify ischemia-producing lesions when assessing stenoses between 50 and 90%. In fact, this is probably one of the key explanations for the superior clinical outcome of FFR-guided stenting in the FAME study; by selectively stenting ischemic stenoses, ‘collateral damage’ from unnecessary stenting of non-ischemic coronary stenoses is prevented, with similar relief of myocardial ischemia as with angiography-guided stenting. Coronary heart disease not only effects clinical outcome, but it also consumes large parts of health care budgets. An extensive economic evaluation of the FAME study is described in chapter 6. This evaluation shows that a FFR-guided strategy also saves health care resources and improves health outcomes at 1 year. The cost savings occurs at the index procedure due to a decrease in drug-eluting stent use, and it occurs during follow-up as a result of a decrease in events and re-hospitalization. Combining the economic and clinical outcome results of the FAME study reveals that FFR-guided placement of drug-eluting stents in patients with multivessel coronary disease is one of those rare situations in which a new technology not only improves outcomes, but also saves resources. After 2 years of follow-up in the FAME study, the favorable results of an FFR-guided strategy were maintained, as discussed in chapter 7. The combination of death and myocardial infarction, but also the rate of myocardial infarction alone, both very important endpoints from a clinical and patient’s perspective, were significantly reduced at 2 years when compared to the common angiography-guided approach. The high percentage of patients free from anginal symptoms was maintained after 2 years for both treatment strategies. This chapter also describes the outcome of the 513 stenoses in the FFR-guided treatment arm, that were deferred from stenting, because they were functionally non-significant at the index procedure. After 2 years, only 0.2% of the deferred stenoses led to a myocardial infarction and only 3.2% of these stenoses needed revascularization because of progression of atherosclerosis. These findings confirm the excellent long-term safety of deferral of non-ischemic stenoses from stenting. The 2-year results of the FAME study show durability of the improved outcomes noted at 1 year. Thereby they continue to support the evolving paradigm of functionally complete revascularization, or in other words revascularization of ischemic stenoses and medical treatment of non-ischemic stenoses. It is intended to collect data up to a follow-up of 5 years for the FAME study In chapter 8, the findings in this thesis are presented in a general discussion and the following conclusions are drawn: 1. In patients with multivessel coronary artery disease undergoing PCI with drug-eluting stents, routine measurement of FFR in addition to angiographic guidance, as compared with PCI guided by angiography alone, results in a significant reduction of all major adverse events at 1 year by 30-35%. 2. This is achieved without prolonging the procedure time and with less contrast agent. 3. Performing PCI guided by FFR in patients with multivessel coronary artery disease also saves health care resources and improves health outcomes at 1 year compared to a traditional strategy of angiographic guidance. Thus, PCI guided by FFR in patients with multivessel disease is one of those rare situations in medicine in which a new technology not only improves outcomes, but also saves resources. 4. This advantage of an FFR-guided strategy is maintained at 2 years. Although there is a mild catch up for repeat revascularization, the difference between both strategies in the combined rate of death and myocardial infarction, and also in the rate of myocardial infarction alone, further increases in favour of the FFR-guided strategy. 5. In patients with multivessel coronary artery disease one cannot rely on the angiogram to identify ischemia-producing lesions when assessing stenoses between 50 and 90%. 6. The findings in this thesis support the evolving paradigm of ‘functionally complete revascularization’; stenting of ischemic lesions and medical treatment of non-ischemic lesions. Finally, the FAME study and its implications for the treatment of multivessel coronary disease are discussed within a wide scope in chapter 8 and appendix I, and reflected to other recent landmark studies in the field of treatment of patients with multivessel coronary artery disease: the COURAGE and the SYNTAX trial. These recent, large trials compared PCI with medical therapy and coronary bypass surgery, respectively. In the COURAGE trial PCI did not show better results than medical therapy, and in the SYNTAX trial PCI was inferior to coronary bypass surgery. However, PCI in those trials was performed with the standard angiography-guided strategy and not with an FFR-guided strategy. Although great caution should be taken when comparing different studies, due to the many similarities in patient populations and characteristics, it might be speculated that the results and even conclusions of these studies might have significantly changed in favour of PCI if performed with the guidance of FFR, like in the FAME study (figure 4 in chapter 8). To prove this standpoint definitely, this theme has resulted in starting two new prospective, large, multicenter trials to show the superiority of FFR-guided PCI over medical treatment (FAME II study) and equality to coronary bypass surgery in patients with multivessel coronary disease (FAME III study). With the unequalled support of the excellent group of investigators and institutions who perform the FAME study, an extensive but exciting future task is waiting for us. In appendix II of this thesis, all authors and members of the FAME Study Group, and their affiliations are listed