ORBITA: FFR/iFR Predict Ischemia but Not Symptoms After PCI

Patrice Wendling

May 22, 2018

PARIS — New findings from the controversial ORBITA trial provide a lift for percutaneous coronary intervention (PCI) in stable angina but also mixed results for the predictive power of fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR).

Analyses of 196 patients with invasive physiology data show that baseline FFR and iFR values strongly predict reduction in ischemia on stress echocardiography after PCI.

Surprisingly, however, FFR and iFR did not predict the effect of PCI on angina symptoms or the primary endpoint of change in exercise time, lead investigator, Rasha Al-Lamee, MBBS, Imperial College London, United Kingdom, reported in a hotline session here at the Congress of the European Association of Percutaneous Cardiovascular Interventions (EuroPCR) 2018. The results were also published online in Circulation.

"The tighter your iFR/FFR or the lower your iFR/FFR, the more ischemia reduction you will have with stenting, but symptoms and exercise are multifactorial," she told theheart.org | Medscape Cardiology. "So the link between how tight or low your IFR and FFR is and improvement in symptoms or exercise time is not as simplistic or as easy to link as a reduction in ischemia."

Another possible explanation is that the small effect size observed for the outcome in the main ORBITA analysis reduced the ability to further stratify the results.

The first sham-controlled trial of PCI caused a firestorm last fall after findings showed that PCI did not improve exercise time or angina symptoms at 6 weeks beyond the effect of placebo in symptomatic patients with stable, single-vessel angina.

The results prompted an editorial calling to downgrade guideline recommendations for PCI in patients with angina despite medical therapy, but also instant criticism that the study was too small, too short, and  conducted in the wrong population with the wrong endpoint.

Al-Lamee noted that all 200 ORBITA patients had a clinical indication for PCI;  the trial was trying to identify the FFR/iFR cutpoint for angina relief and thus had to enroll patients with a range of FFR/iFR values. Still, 25% of patients had a negative FFR according to the standard cutpoint of 0.80. Mean baseline FFR and iFR were 0.69 and 0.76, respectively.

"I absolutely agree that exercise time, if I was to do this again, is probably not the primary endpoint I would choose," she said during a discussion of the results. "We chose that because of FDA [US Food and Drug Administration] and European Medicines Agency regulations recommending exercise time as a primary endpoint for drug trials."

Prespecified Endpoints

To address criticism of the primary analyses and strengthen statistical power, the investigators adjusted the invasive physiology analyses for baseline differences between treatment groups.

Notably, the difference between arms in total exercise time changed from 38 seconds to 20.7 seconds but was still not statistically significant (P = .100), Al-Lamee said. Neither FFR (P for interaction = .318) nor iFR (P for interaction = .523) predicted exercise time.

The analyses showed that PCI improved stress echo score more than did placebo (1.07 segment units; 95% CI, 0.70 - 1.44; P < .00001). The effect increased with decreasing FFR (P for interaction < .00001) and decreasing iFR (P for interaction < .00001) but without a clear threshold or cutpoint for benefit.

"It makes sense to have a threshold if we're designing a clinical trial or to give to healthcare providers or insurers but it doesn't make biological sense that there would be a black or white threshold," Al-Lamee said in an interview. "It makes much more sense this would be a continuous variable."

Overall the results by iFR vs FFR were similar, although a head-to-head comparison has not been conducted, she said.

A "Win for PCI"

A separate ordinal regression analysis that was not prespecified showed that PCI more than doubled the odds of Seattle Angina Questionnaire freedom from angina compared with maximal medical therapy (odds ratio [OR], 2.47; 95% CI, 1.30 - 4.72; P = .006).

In all, 49.5% of patients in the PCI group were free from angina vs 31.5% in the sham group. The 20 absolute percentage-point improvement translates into a number needed to treat for PCI of 5. Neither baseline FFR (P for interaction = .693) nor iFR (P for interaction = .761) predicted benefit.

"You are sharing a new secondary endpoint, which is a binary one and this is a win for PCI. So interventionalists will be happy to see that but of course it is a secondary outcome," panelist Davide Capodanno, MD, PhD, University of Catania, Italy, said.

Co-chair of the ongoing ISCHEMIA trial, David J. Maron, MD, Stanford University, California, told theheart.org | Medscape Cardiology via email, "The ORBITA investigators have now presented a 'responder' analysis that shows the proportion in each group that is angina free, and PCI is clearly superior. This provides a more clinically useful interpretation of the trial."

He added, "The fact that FFR/iFR did not predict freedom from angina is disappointing, but a larger blinded trial might resolve this unexpected discordance between physiology and symptoms."

ISCHEMIA is comparing angiography and revascularization plus optimal medical therapy vs optimal medical therapy alone in stable angina, with a primary endpoint of time to cardiovascular death, myocardial infarction, or hospitalization for unstable angina, resuscitated cardiac arrest, or heart failure.

"If ISCHEMIA shows us that angioplasty improves mortality and myocardial infarction rates in the long-term and that is related to patients with higher ischemic burden at their recruitment in the trial, then the results of this analysis are very nicely in line with that," Al Lamee said.

ORBITA was funded by grants from National Institute for Health Research Imperial Biomedical Research Centre, Foundation for Circulatory Health, and Imperial College Healthcare Charity. Al-Lamee has received honoraria or consultation fees from Philips Volcano, which supplied the coronary pressure wires for the trial.

Congress of the European Association of Percutaneous Cardiovascular Interventions (EuroPCR) 2018. Presented May 22, 2018.

Circulation. Published online May 22, 2018. Abstract, Editorial

Follow Patrice Wendling on Twitter: @pwendl. For more from theheart.org | Medscape Cardiology, follow us on Twitter and Facebook.

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