Cost-Effective Health Care and Research: FAME Fits

In this issue of Cath Lab Digest, Dr. William Fearon from Stanford University talks about the FAME (Fractional flow reserve vs. Angiography in Multivessel Evaluation) study1 and how using fractional flow reserve (FFR) with a pressure wire was a highly successful approach to cost-effective stenting in patients with multivessel coronary artery disease (CAD) compared to using traditional angiography alone. FAME fits with cost-effective healthcare in a big way. How does FAME make percutaneous coronary intervention (PCI) cost effective? First, what does cost-effective health care mean? A medical procedure or treatment is cost effective when the expected clinical benefit is provided to the patient at a reasonable expense.2 For example, aspirin for primary heart attack prevention is cost effective at $0.05/pill for reduction of one heart attack in 1000 patients. On the other hand, a heart transplant is not very cost effective (>$100,000) but certainly is clinically beneficial in saving that one patient in need. Are coronary stents cost effective? Interventional cardiologists are trained to stent patients with coronary artery disease. We do it well, we do it often, but not always in a cost-effective manner. For example, is it cost effective to stent every lesion noted on the angiogram, even those that are remote from an area of ischemia? PCI has an American College of Cardiology/American Heart Association (ACC/AHA) class I indication for symptomatic angina patients with CAD who are not responding to anti-anginal medications (beta blockers, nitrates, etc.).3 It is true that stents relieve angina due to ischemia,4 but determining which of many coronary narrowings is causing the ischemia can be difficult. In theory and often in practice, the patient is screened for ischemia by stress testing before undergoing angiography. The angiogram and stress test together identify the lesion (or lesions) thought to be ischemia-producing, and the stents are placed, relieving chest pain.4 But what about those other lesions the angiographer sees? Some are only moderate (40-70% narrowed). “Well,” he says, “we’re already stenting. Let’s just treat that other lesion (or lesions) while we’re in here. No harm, right?” On the face of it, this approach may make sense at the time, but it is certainly not indicated or cost effective. Stenting lesions that are not ischemia-producing simply because they are there provides zero clinical benefit, but some risk (early procedure problems or late stent thrombosis) and substantial cost. “But,” says the interventionalist to justify the stenting, “at least that lesion won’t cause a heart attack.” This PCI is not only not cost-effective, but not clinically correct. While that specific lesion may not have plaque rupture, other very mild lesions nearby can activate and cause myocardial infarctions (MI) regardless of how many stents are placed. It is well known that stenting does not reduce the chances of MI or death in stable angina patients. (For ST-elevation MI, PCI does save lives, but that’s another discussion). The PCI teaching is “treat (stent) the lesions that need it (stenting), and continue medical therapy (statins, beta blockers, aspirin) for the others.” FAME focuses our attention to this end. Where does FAME fit into this scenario? The FAME study, a large, multicenter, prospective, international study (6 U.S. and 14 European centers), randomized patients with multivessel coronary artery disease to two different PCI strategies, either solely angiographically-guided using clinical, non-invasive stress testing data and stenting on that basis, or using a pressure wire to measure the fractional flow reserve (FFR) of the potentially treatable lesions and then stenting based on the FFR (cut point to stent Can FAME be applied widely to the large number of PCI patients encountered daily? Dr. Fearon clearly discusses how and in whom FAME was conducted. The patients in FAME had multivessel CAD with low SYNTAX5 angiographic scores, meaning relatively low-risk coronary anatomy. Nonetheless, and in a similar manner to daily practice, all lesions to be stented, whether moderate or mild, were identified by the operators in advance of randomization. The FFR showed that about one-third of the time, operators did not need to stent a particular lesion. In practice, many of these mild lesions that operators say they would not normally stent are found to have abnormal FFR and may go untreated, resulting in persistent symptoms or ischemia. FFR helps decide the best, most appropriate stenting, a finding in FAME which produced better clinical outcomes at the one-year follow up. Of course, not every lesion needs FFR nor is suitable for FFR. For example, minimal angiographic lesions in atypical anginal patients, total or critically narrowed (>90%) lesions in symptomatic patients, and mild lesions in patients with unequivocal stress test results do not benefit by FFR. When asked, “Do you do FFR in every one of your patients?” I say “Of course not, but I do FFR in every lesion in which I am uncertain as to whether it is ischemia-producing.” Every interventionalist should recall that FFR eliminates uncertainty about intermediate lesions. I also joke about the old dictum regarding interventionalists (myself included): “I may not be right, but I’m never uncertain.” (Blame me for this saying). Fortunately, I believe FAME can be applied to a very large number of our patients with multivessel disease undergoing stenting either at one sitting or in a staged approach. FFR can guide us as to which lesions may be treated at a subsequent setting, thus reducing uncertainty, delay and potential unneeded stenting. Multivessel FFR versus radionuclide perfusion scintigraphy: FAME helps In the case of patients with multivessel CAD, many operators are confused by the results of radionuclide perfusion stress imaging (e.g. SPECT scanning). Some patients only have one ischemic territory, while others with very severe three-vessel CAD have a near-normal perfusion imaging study.6 How can this happen? SPECT requires a significant perfusion mismatch across the heart to show up as a defect on the scan. If two areas are both ischemic, the more severe region may show a defect, but not the lesser. Similarly, in three-vessel CAD with all three territories ischemic to a similar degree, balanced ischemia may appear as a “negative ischemic study.” It is precisely in this circumstance that the FAME study and FFR help guide the operator as to which territory and lesion will benefit from stenting. FFR can be thought of as a “single-vessel in-lab stress test.” Its validation was derived in single-vessel disease with three stress tests performed, at least one of which was positive, and after PCI of that lesion, the stress test was negative. This method eliminated the false positive/negative problem of many stress tests and set a fairly narrow FFR threshold for ischemia. FFR can be used just as any stress test for appropriate lesion selection and treatment in the CAD patient. The Future and FAME We are in an economic healthcare crisis and obligated to consider ways to improve treating patients in a cost-conscious manner. FAME meets these criteria. The FFR procedural cost is more than offset by clinical benefit and the costs of unnecessary stenting. After many years of single-center, non-randomized outcome studies showing the benefits of appropriate lesion selection with FFR, the FAME study conclusively provides interventionalists with a rational, objective approach to treating difficult anatomic subsets (e.g. multivessel, or left main CAD) in a highly cost-effective manner. We should consider the FAME approach as we tighten our healthcare belts.

1. Tonino PAL, DeBruyne B, Pijls NHJ, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. New Engl J Med 2009;360:3:213-224.

2. Samsa GP, Reutter RA, Parmigiani G, et al. Performing cost-effectiveness analysis by integrating randomized trial data with a comprehensive decision model: application to treatment of acute ischemic stroke. J Clin Epidemiol 1999; 52(3): 259-271.

3. King SB, Smith SC, Hirshfeld JW, et al. 2007 focused update of the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: (2007 Writing Group to Review New Evidence and Update the 2005 ACC/AHA/SCAI Guideline Update for Percutaneous Coronary Intervention). Circulation 2007; DOI: 10.1161/CIRCULATIONAHA.107.188208.

4. Shaw LJ, Berman DS, Maron DJ, et al; COURAGE Investigators. Optimal medical therapy with or without percutaneous coronary intervention to reduce ischemic burden: results from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial nuclear substudy. Circulation 2008;117:1283-1291.

5. Serruys PW, Morice MC, Kappetein AP, et al. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med 2009 Mar 5;360(10):961-972.

6. Ragosta M, Bishop AH, Lipson LC, et al. Comparison between angiography and fractional flow reserve versus single-photon emission computed tomographic myocardial perfusion imaging for determining lesion significance in patients with multivessel coronary disease. Am J Cardiol 2007;99(7):896-902.