DEFINE-FLAIR and IFR-SWEDEHEART Evaluate Instantaneous Wave-Free Ratio
March 18, 2017— The American College of Cardiology (ACC) that the DEFINE-FLAIR and IFR-SWEDEHEART studies found instantaneous wave-free ratio (iFR) was equivalent to fractional flow reserve (FFR), in terms of incidence of major adverse events, and that showed iFR resulted in less patient discomfort and reduced procedure-related adverse events compared to FFR.
The two studies were presented in a late-breaking trial session at ACC's 66th annual scientific session in Washington DC. Simultaneous with the presentations, DEFINE-FLAIR was published by Justin E. Davies, MBBS, PhD, et al online in The New England Journal of Medicine. Matthias Götberg, MD, PhD, et al published IFR-SWEDEHEART in The New England Journal of Medicine.
At ACC, Dr. Davies, a consultant cardiologist at Imperial College London in London, United Kingdom, presented the primary results from DEFINE-FLAIR. The trial is a multicenter, prospective, international, randomized, blinded comparison of clinical outcomes and cost efficiencies of iFR and FFR decision making for physiological guided coronary revascularization. DEFINE-FLAIR involves sites in the United States, Europe, Africa, the Middle East, Asia, and Australia.
Dr. Götberg, a cardiologist at Skane University Hospital in Lund, Sweden, presented IFR-SWEDEHEART, which compares IFR-guided versus FFR-Guided interventions in a multicenter, prospective, registry-based randomized clinical trial.
The ACC announcement noted that iFR has been validated in several smaller studies, but the two new trials are the largest to date and the first to assess how using the method affects patient outcomes.
The investigators stated that despite being a recommended diagnostic tool for assessing the condition of the coronary arteries, FFR has been underutilized in practice, in part because it causes discomfort, chest pain, and shortness of breath for many patients.
According to the ACC, the results suggest that iFR could offer the same benefits as FFR while avoiding its downsides. Both studies showed no significant difference between iFR and FFR for the same primary endpoint, which was a composite of all-cause mortality, nonfatal heart attack and unplanned revascularization, at 12 months.
Dr. Davies commented in the ACC press release, “Our study shows that it is safe to use either the iFR or FFR technique. I think iFR lowers the barriers to physiological measurement, which I believe is key to getting more people to use coronary physiology to guide coronary revascularization decision-making. iFR technology really enables ease of use; it’s very friendly for the physician and patients alike.”
Dr. Götberg stated, “In FFR we have a good diagnostic method, but people are not using it enough because of the side effects. Our study shows that for cardiologists who currently use FFR, iFR provides a similar clinical benefit but without patient discomfort. For cardiologists who are hesitant to use FFR, iFR might provide an opportunity to increase adoption rates of coronary physiology and benefit more patients.”
Like FFR, iFR is based on coronary blood pressure measurements using a thin pressure sensor wire. Unlike FFR, it uses a mathematical algorithm to measure the pressure in the coronary artery only when the heart is relaxed and the coronary blood flow is high, so a vasodilator drug is not needed.
Both studies enrolled patients who had stable angina or acute coronary syndrome and needed coronary physiology to inform treatment. Participants were randomly assigned to receive either iFR or FFR. For patients enrolling in the study after a heart attack, the studies only included data related to blockages other than the one that caused the heart attack. Patient outcomes were tracked for 12 months.
For DEFINE-FLAIR, investigators enrolled 2,492 patients at 49 centers in 17 countries. Half of the patients received iFR and half received FFR. For IFR-SWEDEHEART, researchers enrolled 2,037 patients at 15 centers in Sweden, Denmark and Iceland. A total of 2,019 patients in this study were treated according to protocol, with 1,012 patients receiving iFR and 1,007 patients receiving FFR.
In addition to showing no significant differences between iFR and FFR in terms of the composite primary endpoint, both studies revealed no significant differences in separate analyses of all-cause mortality, subsequent heart attack, or revascularization.
The IFR-SWEDEHEART data showed a substantial reduction in patient discomfort, with just 3% of iFR patients reporting discomfort in a postprocedure questionnaire compared to 68% of FFR patients. Dr. Götberg commented, “If patients could choose between the two methods, given that there is no difference in outcomes, patients would probably appreciate not having to experience the side effects of the vasodilator.”
According to the ACC announcement, DEFINE-FLAIR showed a substantial reduction in symptoms of both patient-reported and physician-reported procedure-related adverse events, which occurred in 3% of iFR patients and 30.8% of FFR patients overall.
In DEFINE-FLAIR, FFR was associated with a significantly higher rate of shortness of breath (reported in 1% of iFR patients and 20% of FFR patients); chest pain (1.5% in iFR and 7.2% in FFR); heart rhythm disturbances (0.2% in iFR and 4.8% in FFR); abnormally low blood pressure (0.3% in iFR and 1% in FFR); and serious adverse events, which included severe shortness of breath or requiring cardioversion to restore normal heart rhythm (0.1% in iFR and 0.6% in FFR).
Both studies also demonstrated a substantial difference in the number of significant atherosclerotic lesions found using iFR versus FFR, likely a result of subtle differences in the physiological basis of how the two approaches work and their slightly different thresholds for determining when stenting is required, according to the researchers.
In IFR-SWEDEHEART, significant lesions were found in 29.2% of patients undergoing iFR and 36.8% undergoing FFR. A similar pattern was reflected in DEFINE-FLAIR, in which stents were used in 46% of patients receiving iFR and 50% of patients receiving FFR.
The use of iFR in DEFINE-FLAIR significantly reduced the overall length of the procedure, from an average of 45 minutes for FFR to 40.5 minutes for iFR. The combination of a reduced procedure length, the use of fewer stents, and the elimination of the need for a vasodilator drug could translate into significant cost savings with iFR, stated Dr. Davies in the ACC announcement.
Dr. Davis concluded, “The study provided a very good, real-world snapshot of the time it takes to actually get a patient in, do the physiological assessment, do the stenting if necessary, and finish." He added, "iFR is quicker and results in fewer stents, which is likely to lead to significant reduction of cost.”
The DEFINE-FLAIR investigators will conduct a follow-up analysis to formally compare the cost-effectiveness of iFR and FFR. In addition, Dr. Davies and Dr. Götberg are working together to conduct a follow-up analysis combining the data from the two studies in a meta-analysis of primary outcomes that will include approximately 4,500 patients.
DEFINE-FLAIR and IFR-SWEDEHEART were funded by unrestricted grants from Philips Volcano. In a press release from Philips Volcano, the company noted that it first released the iFR pressure-derived index in 2013. Manesh Patel, MD, Chief of the Division of Cardiology and Co-Director of the Duke Heart Center at Duke University School of Medicine in Durham, North Carolina, stated in the company’s press release, "Findings from these two major clinical outcome studies have the potential to significantly improve the use of coronary physiological assessment. One of the barriers to iFR adoption has been the lack of outcome data, however now we have evidence that an iFR-guided treatment strategy is as reliable as an FFR-guided strategy with regard to future cardiovascular events. Additionally, I believe iFR will reduce patient discomfort. Together the results of these studies demonstrate large simple trials in clinical practice can be done, and should remove any barriers to the use of coronary physiology in interventional procedures."