The gold standard for assessing the hemodynamic significance of coronary lesions to determine if they should be revascularized or treated medically is fractional flow reserve (FFR). FFR is now written into percutaneous coronary intervention (PCI) treatment guidelines, and has been discussed as a possible future parameter if Medicare and other payors begin requiring documentation to show stent implantations are clinically necessary. Several new vendors have entered the FFR market in recent years (read the article “New Players, Technology Enter FFR Market”) and two new technology developments — instantaneous wave-free ratio (iFR) and FFR derived from computed tomography (FFR-CT) — will likely take FFR in new directions for both invasive and noninvasive FFR.
FFR offers quantifiable ratio measurement of the blood flow pressures before and after a lesion to determine physiological significance. In patients with multiple coronary lesions, FFR can be used to pinpoint which lesion is the main contributor to ischemia and may help reduce the number of stents implanted, leaving less severe lesions alone. The reduction of stents based on FFR measurements reduces the patient’s chances of developing stent-related complications, such as stent thrombosis or in-stent restenosis.
There have been three big recent technology advances in FFR. The first is technology that allows a visual overlay of the FFR readings to be registered on top of an angiographic imaging of the coronary artery. This allows interventional cardiologists to better identify lesions that are causing the most restriction in blood flow. The frozen overlay image also can act as a navigation reference for subsequent interventions. At the Transcatheter Cardiovascular Therapies (TCT) 2016 annual meeting, Philips Healthcare unveiled co-registration for its iFR system, which integrates the pullback data with the angiogram, which can remove the guesswork of which lesions correspond to which iFR readings.
The second big innovation is FFR-CT, which enables non-invasive FFR measurements to be taken for the entire coronary tree using a CT scan. This technology has been the biggest advancement discussed at the Society of Cardiovascular Computed Tomography (SCCT) conference for several years running. Many SCCT attendees view this technology as a future replacement for nuclear perfusion exams.
The third innovation is the development of iFR as a possible replacement for current FFR technology. FFR requires the injection of the pharmacological stress inducing agent adenosine to stimulate ischemic conditions in a patient with coronary lesions. The reaction in most patients is chest pain, discomfort and shortness of breath. iFR technology eliminates the need for adenosine, simplifies the procedure and eliminates patient discomfort. However, there has been debate in recent years since iFR’s introduction by Volcano (now owned by Philips Healthcare) that the algorithms used can match the accuracy of traditional FFR. Two key late-breaking trials presented at the 2017 American College of Cardiology (ACC) meeting in March showed iFR vs. FFR had the same incidence of major adverse events. Supporters of iFR said these trials show the technology can be used as an easier to use replacement for FFR.
iFR vs. FFR
The two iFR vs. FFR ACC late-breaking clinical trials, DEFINE-FLAIR and Instantaneous Wave-Free Ratio versus Fractional Flow Reserve guided intervention (IFR-SWEDEHEART), combined involved more than 4,500 patients. The studies showed iFR had comparable outcomes to FFR, but with better ease of use and eliminating patient chest pain and shortness of breath brought on by adenosine.
The data provided by these two trials added four times the amount of clinical data to date on iFR, noted Justin Davies, MBBS, of Imperial College London, who presented the DEFINE-FLAIR results. He said the landmark FAME and FAME II FFR studies that validated FFR only included patients who already were going to the cath lab, and most were known to have severe lesions. In the two recent studies, patients were enrolled when physicians were unsure of the physiological lesion severity or if the patient would benefit from stenting. Davies said these were more consistant with the real-world patient populations cardiologists tend to send to the cath lab for FFR evaluation.
The DEFINE-FLAIR study included 2,500 patients followed out to one year. “We confirmed the MACE rates were identical, regardless of whichever of these techniques you use,” Davies said. “iFR is also a kinder way to treat patients, with a 10-fold decrease in symptoms [due to adenosine] and in a shorter amount of time. It gives us a reliable and safe answer.”
Davies said adenosine in the FFR arm also caused serious side effects in a handful of patients, include seven cases of bronchial spasm and one patient who required cardioversion after onset of a ventricular tachycardia (VT).
Matthias Götberg, M.D, Ph.D., of Skane University Hospital, presented the iFR-SWEDEHEART study at ACC. “We found not only that iFR is non-inferior to FFR, but also found that patients had much less discomfort from the procedure,” Götberg explained. “We also found that operators investigated more lesions in the iFR group compared to the FFR group, meaning that they had a lower threshold to do physiological assessments in the iFR group.”
Davies and Götberg both agreed iFR was easier to use, so operators tended to use it more than FFR. “In our professional and nonprofessional lives, we all like things which are simple and easy to use,” Davies said. “When it comes to something that shortens procedure time, has a better quality patient experience and also has the same outcomes, that is a very attractive package.”
“We know from clinical experience the discomfort is tolerable, but we did not have any other options,” Götberg said. “But, now we have demonstrated in 4,500 patients that iFR is non-interior to FFR.
“These trials assessed more patients lesions and we treated less lesions, and we had the same outcomes,” Davies said. “When you look at the deferred patients in the DEFINE-FLAIR study, you actually see the MACE rate is actually considerably lower in the iFR arm, than in the FFR arm. What we found was if you are more selective in who you decide to implant stents, potentially there is a longer-term benefit. If we are putting in less stents and only putting them into patients who really need them, then the long-term problems associated with stent thrombosis or restenosis should be diminished.”
The measurement scales used in iFR compared to FFR are a little different. Some operators using both technologies say there is a gray area with iFR where they feel better converting over to FFR in order to make a final decision. However, Davies said this is a fundamental misunderstanding of iFR based on the available clinical data.
“FFR is the gold standard today, but it is based on two trials that by today’s standards are fairly small that are 10 years old. We have now shown equipoise in much larger clinical trials,” Götberg explained. “We also need to look back at the ischemia validation trials, which always showed iFR is equally as good or better than FFR when it comes to detection of ischemia, so we don’t have any worrying trends. I think we have a very good sense of validation now from both the ischemia trials and now with the outcomes trials. So yes, we do have some classification differences, but just saying the older index, which is the gold standard, is the right one, is not correct anymore.”
For more information on implementing these technologies, read the article “FFR and iFR in the Diagnosis and Treatment of Heart Disease,” by Juan A. Pastor-Cervantes, M.D., is medical director, cardiac catheterization lab at Memorial Regional Hospital in Hollywood, Fla.
CT-FFR vs. FFR
FFR-CT offers a way a new to non-invasively evaluate patients presenting with chest pain using a CT scan. Traditionally CT angiography (CTA) scans have been great at showing anatomical detail, including the percentage obstruction a lesion presents. But often in the cath lab, significant blockages seen on CT do not greatly impact blood flow according to FFR measurements. FFR-CT can now determine the virtual hemodynamic significance of lesions and may offer the true ability for CT in the emergency department to be the gate-keeper to the cath lab. The CT technology offers the promise of faster discharge of patients who do not have serious blockages and only sending those with flow-limiting lesions to the cath lab. Experts say this will help reduce the number of patients sent to the cath lab for diagnostic caths to only those who truly need PCI.
The technology uses a super-computing computational fluid dynamics algorithm to calculate data points throughout the coronary arteries. The software is similar to that used for weather prediction modeling and in the aerospace industry to design aircraft and high performance race cars. Multiple trials comparing FFR-CT to invasive FFR in the same patients show an 80 percent correlation.
However, FFR-CT currently has two drawbacks that have hindered its wider adoption since gaining U.S. Food and Drug Administration (FDA) clearance in November 2014. These include the lack of reimbursement and slow turnaround times (TAT). HeartFlow, which developed FFR-CT, requires CT datasets to be sent to its supercomputer facility in California for processing and it takes up to 24 hours to return results. The company said its TAT has come down significantly in the past couple years and it will be reduced further with upgrades using some of the newest computing technologies. Some centers using the HeartFlow technology report TATs have come down to just a couple of hours. For patients who come in late in the day or at night, this can often eliminate the need to admit the patient over overnight or sending them for a nuclear perfusion scan in the morning.
Another barrier to FFR-CT adoption is the lack of reimbursement. However, SCCT was proud of the fact that it helped push through a new CPT reimbursement code for FFR-CT, which was among the big news at this year’s meeting. Watch the SCCT 2017 VIDEO “New CPT Reimbursement Codes for Cardiology,” an interview with Randall Thompson, M.D., professor of medicine at the University of Missouri, Kansas City, attending cardiologist, Mid-America Heart Institute, St. Luke’s Health.
Hospitals using FFR-CT in Denmark and the United States reported reductions in the number of patients sent to the cath lab and earlier discharge of patients without flow limiting disease. Beaumont Health System in Michigan has been using FFR-CT for nearly two years. The system performs about 4,000 cardiac CTs annually and FFR-CT is used to decide which patients with coronary lesions in the 50-70 percent range should be sent to the cath lab.
“FFR-CT really acts as a gatekeeper to avoid bringing those patients to the cath lab and needing additional non-invasive studies to determine the hemodynamic significance,” said Simon Dixon, M.D., MBChB, chairman of the Department of Cardiovascular Medicine at Beaumont Health System and a professor of medicine at the Oakland University William Beaumont School of Medicine. “We get the anatomical information and the physiological information in one study, which is great for patients, it is great for doctors and it is great for our program because it can expedite the triage and clinical care of those patients.”
Dixon said Beaumont now gets FFR-CT results back within two to three hours, which has impacted earlier discharge of non-ischemic chest-pain patients. “We have one of the busiest emergency rooms (ER) in the country, with more than 140,000 ER visits per year, so the quicker the ER physicians can get out the low- and intermediate-risk patients who don’t need to be in the hospital, the better. We have seen a drop off in the number of diagnostic caths sent to the cath lab,” Dixon explained.
In patients with a 50-70 percent blockage seen on CTA, he said FFR-CT has reduced the number of these patients sent to the cath lab by about 25 percent. Dixon explained Beaumont has not yet conducted a cost effectiveness analysis of CT-FFR, but he expects the healthcare cost savings to be very high for these deferred patients.
Watch the VIDEO “Early U.S. Experience With FFR-CT in Evaluating ED Chest Pain Presentation,” an interview with Dixon at the 2016 TCT annual meeting.
Several vendors are working to develop FFR-CT technology. In sessions at SCCT 2017, examples of Toshiba's prototype software were shown by physicians who are testing it.
HeartFlow was the first company, and currently the only, to offer FFR technology that is FDA cleared. Its development program is way ahead of potential competitors, which has led to some CT vendors forming partnerships with Heartflow. Siemens Healthineers announced a partnership in March 2017, and GE Healthcare announced a partnership with HeartFlow just before the 2017 SCCT meeting. Philips announced a partnership with HeartFlow in August 2017, which includes using HeartFlow's FFR-CT technology applied to rotational angiography in the cath lab to possibly eliminate the need for catheter based FFR.
How Does FFR-CT Work?
James Min, M.D., professor of radiology and medicine and director of the Dalio Institute of Cardiovascular Medicine, Weill Cornell, New York Presbyterian Hospital, was instrumental in the development of FFR-CT and served as a principal investigator or was involved in all the key FFR-CT trials. He explained how the technology works in the VIDEO “Implementation and the Science Behind FFR-CT.”