By Jeffrey Zimmet, MD, PhD
Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center
Dr. Zimmet reports no financial relationships relevant to this field of study.
SYNOPSIS: Two trials defined instantaneous wave-free ratio as the new standard for physiologic lesion assessment in the cardiac
cath lab.
SOURCES: Davies JE, Sen S, Dehbi HM, et al. Use of the instantaneous wave-free ratio or fractional flow reserve in PCI. N Engl J Med 2017. doi: 10.1056/NEJMoa1700445. [Epub ahead of print].
Götberg M, Christiansen EH, Gudmundsdottir IJ, et al. Instantaneous wave-free ratio versus fractional flow reserve to guide PCI. N Engl J Med 2017. doi: 10.1056/NEJMoa1616540. [Epub ahead of print].
What is the instantaneous wave-free ratio, also known as iFR, and why has one medical journal chosen to simultaneously publish two clinical trials using this technology?
Assessment of coronary lesion severity in the cath lab previously relied only on visual assessment of percent stenosis by angiography, which is recognized to be highly subjective. Thus, physiologic assessment by fractional flow reserve (FFR) has become the clinical standard for evaluation of intermediate coronary lesions. This technique involves the use of specialized coronary guidewires, with solid-state pressure transducers to measure translesional pressure gradients, and relies on the pharmacologic induction of hyperemia, most commonly through administration of adenosine. Randomized trials comparing FFR to angiographic assessment have demonstrated reduced adverse event rates for FFR-directed percutaneous coronary intervention (PCI), as well as lower cost. The practical use of a resting, as opposed to a hyperemic, pressure gradient was first demonstrated nearly a decade ago by Dr. Justin Davies from Imperial College in London. This alternate approach involves the capture of pressure data from what was called the wave-free period, a specific period during diastole during which myocardial resistance is relatively fixed. This measurement does not require the administration of adenosine to induce hyperemia, and is known as iFR.
Previous studies have compared values obtained by iFR with the FFR gold standard. Based on prior data, approximately one-third of iFR values fell into a gray zone, where conventional FFR with administration of adenosine was still required. However, the just-published DEFINE-FLAIR and iFR-SWEDEHEART trials used a single binary iFR cutoff value of 0.89 and relied on this binary value alone to determine the need for revascularization. DEFINE-FLAIR was a multinational, blinded comparison of clinical outcomes of iFR-guided vs. FFR-guided coronary revascularization among 2,492 patients from 49 centers. IFR-SWEDEHEART was a multicenter, randomized, controlled, open-label, clinical trial involving 2,037 patients enrolled at centers in Sweden, Denmark, and Iceland. Both trials used the same primary endpoint: a one-year composite of death, nonfatal myocardial infarction, and unplanned revascularization. Both studies showed no significant difference between iFR and FFR for this primary endpoint, and event rates were remarkably similar between trials (all groups showed event rates between 6% and 7% at 12 months).
However, the effect of skipping adenosine infusion led to predictable differences in secondary outcomes in favor of iFR. In both trials, the iFR groups experienced shorter procedure times than the FFR groups, and this difference was statistically significant in DEFINE-FLAIR. In that trial, the percentage of patients with adverse procedural symptoms and clinical signs was significantly lower in the iFR group compared to FFR (3.1% vs. 30.8%; P < 0.001). Similarly, iFR-SWEDEHEART reported that the rate of chest discomfort during the procedure was markedly lower in the iFR group (3.0% of the patients in the iFR group vs. 68.3% of the patients in the FFR group; P < 0.001).
Both trials concluded that the use of iFR to guide coronary revascularization was noninferior to an FFR-based strategy, with respect to the occurrence of major adverse cardiac events at 12 months.
COMMENTARY
Most clinicians recognize that for stable coronary artery disease, a physiologic evaluation for ischemia has significant advantages over a visual assessment by angiography. Despite this, multiple studies have shown that FFR is substantially underused in the community. The added time, cost, and patient discomfort involved in administering adenosine for FFR are clearly at least part of the equation here. The outcomes-based validation of adenosine-free iFR represented by these two trials should go a long way toward lowering the barriers to more evidence-based care.
Several important points are worth noting. In each trial, fewer patients in the iFR groups were identified as ischemic, resulting in fewer PCI procedures and lower rates of coronary artery bypass grafting with iFR compared to FFR. In this relatively low-risk group, this did not lead to a difference in hard outcomes at 12 months. However, the question remains whether the numerical setpoints used in the trial result in relative under-diagnosis of ischemic lesions by iFR or in over-diagnosis by FFR.
The pre-specified noninferiority margins used in these trials were large (3.4% for DEFINE-FLAIR, 3.2% for iFR-SWEDEHEART) compared with other contemporary trials. Since iFR and FFR are only about 80% concordant, it will be interesting to see what becomes of the discordant patients (approximately 500 patients from the DEFINE-FLAIR population). Additionally, when compared to earlier trials such as FAME, the patients in the two recent trials were relatively low risk, with a substantially lower proportion of highly symptomatic patients (as defined by Canadian Cardiovascular Society class) and higher average FFR values. Whether the same results would have been achieved under different conditions is at least debatable.
Finally, it is worth noting that iFR is a proprietary product only available through Philips Volcano, and even then it is an add-on product with additional cost compared with the FFR console alone. Even with the boost provided by these trial results, it will be some time before this modality is available in most cath labs.
Two trials defined instantaneous wave-free ratio as the new standard for physiologic lesion assessment in the cardiac cath lab.
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