Correspondence

Fractional Flow Reserve for Guiding PCI

N Engl J Med 2009; 360:2024-2027May 7, 2009

Article

To the Editor:

Tonino et al. (Jan. 15 issue)1 report on the Fractional Flow Reserve versus Angiography for Multivessel Evaluation (FAME) study (ClinicalTrials.gov number, NCT00267774), which compared an angiography-only strategy with routine measurement of fractional flow reserve (FFR) in addition to angiography in patients with multivessel disease who were undergoing percutaneous coronary intervention (PCI). The authors report a lower 1-year rate of adverse events with angiography guided by FFR measurement. Although their findings provide an encouraging perspective on the relative safety of selective stenting with the use of FFR measurement, some aspects of the trial design may have led to a bias in favor of the FFR group. Forty-one percent of the lesions in the angiography group and 44% of those in the FFR group were of intermediate severity, as defined by 50 to 70% occlusion on visual estimation. On the basis of quantitative coronary analysis, the mean extent of stenosis was 61% or less (intermediate severity). If the FFR evaluation was negative in a sizable proportion of lesions of intermediate severity, the protocol-mandated stenting of these stenoses in the angiography group probably accounted for the higher use of stents and increased costs and therefore the differences in clinical outcomes, primarily driven by early, periprocedural infarctions. Thus, the results of this trial may not have elucidated the role of FFR measurement in multivessel disease but instead may have reaffirmed that mandated stenting of stenoses of intermediate severity is neither cost-effective nor associated with improved outcomes.

Somjot S. Brar, M.D.
William A. Gray, M.D.
Columbia University Medical Center, New York, NY 10032
sbrar@cvri.org

Dr. Brar reports receiving research support from Boston Scientific. No other potential conflict of interest relevant to this letter was reported.

1 References

1. 1

   Tonino PAL, De Bruyne B, Pijls NHJ, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360:213-224
   Full Text | Web of Science | Medline

To the Editor:

In the FAME study, 40.7% of lesions in the angiography group and 44.1% in the FFR group had stenosis of 50 to 70%. Moreover, more than 55% of patients had class I or II angina. In this study, noninvasive evidence of inducible ischemia was not a prerequisite for coronary angiography.1 In the absence of demonstrable ischemia or a large area of at-risk myocardium, PCI is not recommended for these lesions.2-4 It is likely that most of the 513 lesions in the FFR group that did not warrant PCI (37.0%) were from the 44.1% of lesions with stenosis of 50 to 70% (624 lesions). Routine use of PCI for these lesions in the angiography group could have contributed to the worse outcomes in that group. A larger study specifically evaluating the FFR strategy in lesions of more than 70% stenosis or at least an analysis of this subgroup in the FAME study is needed before one concludes that routine use of FFR measurement in all lesions is beneficial. The angiographic details of the lesions in the FFR group that did not warrant PCI would also be useful information.

Nagapradeep Nagajothi, M.D.
Rohit Arora, M.D.
Sandeep Khosla, M.D.
Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064
nagapradeepnagajothi@yahoo.com

4 References

1. 1

   Fearon WF, Tonino PA, De Bruyne B, Siebert U, Pijls NH. Rationale and design of the Fractional Flow Reserve versus Angiography for Multivessel Evaluation (FAME) study. Am Heart J 2007;154:632-636[Erratum, Am Heart J 2007;154:1243.]
   CrossRef | Web of Science | Medline

2. 2

   Smith SC Jr, Feldman TE, Hirshfeld JW Jr, et al. 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 (ACC/AHA/SCAI Writing Committee to Update 2001 Guidelines for Percutaneous Coronary Intervention). Circulation 2006;113:e166-e286
   CrossRef | Medline

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   Patel MR, Dehmer GJ, Hirshfeld JW, Smith PK, Spertus JA. ACCF/SCAI/STS/AATS/AHA/ASNC 2009 appropriateness criteria for coronary revascularization: a report of the American College of Cardiology Foundation Appropriateness Criteria Task Force, Society for Cardiovascular Angiography and Interventions, Society of Thoracic Surgeons, American Association for Thoracic Surgery, American Heart Association, and the American Society of Nuclear Cardiology. Circulation 2009;119:1330-1352
   CrossRef | Web of Science | Medline

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   Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction -- summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol 2002;40:1366-1374
   CrossRef | Web of Science | Medline

To the Editor:

Tonino et al. show the importance of FFR in patients with multivessel coronary disease, continuing the long-standing debate regarding the question of whether all coronary-artery lesions require immediate angioplasty. Previously, we were encouraged by the results of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) study (NCT00007657), which showed that it is safe to defer coronary angioplasty until symptoms cannot be controlled with optimal medical therapy.1

Although the current study adds compelling arguments to the ongoing discussion, we are surprised by the absence of any reference to the patient outcomes in the Arterial Revascularization Therapies Study Part II (ARTS II) (NCT00235170).2 Table 1Table 1Patient and Procedural Characteristics in the ARTS II and FAME Studies. shows that a population with a similar, if not higher, risk was enrolled in ARTS II, as compared with the population in the FAME study; however, the rates of death, repeat revascularization, and myocardial infarction were all higher in the FAME angiography group than in ARTS II (3.0% vs. 1.0%, 9.5% vs. 8.5%, and 8.7% vs. 3.3%, respectively). This group of patients receiving the standard intervention in the FAME study may just have been unfortunate; however, the authors' conclusions might have been significantly different had the outcomes in this group been similar to these published results.

Scot Garg, M.B., Ch.B.
Erasmus Medical Center, 3015 CE Rotterdam, the Netherlands

Tessa Rademaker, M.Sc.
Cardialysis, 3000 CC Rotterdam, the Netherlands

Patrick Serruys, M.D., Ph.D.
Erasmus Medical Center, 3015 CE Rotterdam, the Netherlands
p.w.j.c.serruys@erasmusmc.nl

2 References

1. 1

   Boden WE, O'Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356:1503-1516
   Full Text | Web of Science | Medline

2. 2

   Serruys PW, Ong ATL, Morice MC, et al. Arterial Revascularisation Therapies Study part II -- sirolimus-eluting stents for the treatment of patients with multivessel de novo coronary artery lesions. Eurointervention 2005;1:147-156
   

Author/Editor Response

In response to the comments by Brar and Gray and by Nagajothi et al.: we do not believe that inclusion of lesions involving stenosis of 50 to 70% created a bias in favor of the FFR group. The FAME protocol directed the investigator to stent a lesion if it involved stenosis of at least 50% and if the investigator thought that stenting was warranted on the basis of the available clinical data, including the results of noninvasive testing, if performed. The protocol did not mandate treatment of all stenoses of 50% or more. Lesions to be stented had to be indicated before randomization, in order to avoid any possible bias.

Currently, some interventionalists do not stent stenoses of 50 to 70% routinely, but many others do. The FAME study showed that without measuring FFR, the first group of operators neglects to revascularize 40% of ischemia-producing lesions in patients with multivessel coronary disease, and the second group unnecessarily stents 60% of such lesions. The FAME study provides strong evidence that coronary angiography and clinical data alone are not sufficient for decision making about appropriate revascularization in patients with multivessel disease.

The difference in clinical outcome between the FAME study groups was not driven by small periprocedural infarctions (creatine kinase MB fraction, 3 to 5 times the normal value). The rates of periprocedural infarction were 3.2% and 2.4% in the angiography and FFR groups, respectively, and did not significantly affect the statistical difference in outcome between the two groups.

In response to the question posed by Garg et al.: we believe that it makes little sense to compare the randomized FAME study with the ARTS II registry, which excluded vessels smaller than 2.5 mm and patients with previous PCI.1 It seems more appropriate to compare FAME with the only other large, randomized, controlled trial of drug-eluting stents for the treatment of multivessel disease — that is, the recently published Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) study.2 In the SYNTAX study, PCI was guided by angiography alone. Not surprisingly, the clinical outcome was similar to that in the angiography group in the FAME study. In contrast, the clinical outcome in the FFR group in the FAME study was similar to that in the group of patients in SYNTAX who underwent coronary-artery bypass grafting (Table 1Table 1Characteristics of Patients and Outcomes in the SYNTAX and FAME Trials.).

Taken together, the results of the FAME study show how to perform PCI in patients with multivessel disease with a better clinical outcome and at lower cost.

Nico H.J. Pijls, M.D., Ph.D.
Pim A.L. Tonino, M.D.
William F. Fearon, M.D.
Catharina Hospital, 5623 EJ Eindhoven, the Netherlands
nico.pijls@inter.nl.net

for the FAME Investigators

This letter (10.1056/NEJMc090286) was updated on October 6, 2010, at NEJM.org.

2 References

1. 1

   Serruys PW, Ong ATL, Morice MC, et al. Arterial Revascularisation Therapies Study part II -- sirolimus-eluting stents for the treatment of patients with multivessel de novo coronary artery lesions. Eurointervention 2005;1:147-156
   

2. 2

   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;360:961-972
   Full Text | Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

   Martijn Meuwissen, Maria Siebes, Steven AJ Chamuleau, Bart-Jan Verhoeff, Jose PS Henriques, Jos AE Spaan, Jan J Piek. (2009) Role of fractional and coronary flow reserve in clinical decision making in intermediate coronary lesions. Interventional Cardiology 1:2, 237-255
   CrossRef