Physiology-stratified analysis of ORBITA
Invasive physiology data from 196 patients from the Objective Randomised Blinded Investigation with optimal medical Therapy of Angioplasty in stable angina (ORBITA) trial were used to assess the fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) predictors of placebo-controlled efficacy of percutaneous coronary intervention (PCI) in stable coronary artery disease. Patients enrolled had stable angina and single vessel coronary artery disease. At pre-randomisation the majority had Canadian Cardiovascular Society class II or III symptoms (150/196, 76.5 percent). Mean FFR and iFR were 0.69±0.16 and 0.76±0.22, respectively. 97 percent of patients had one or more positive non-invasive or invasive tests for ischaemia.
"In particular, from this study, we've seen that the degree of ischaemia on iFR and FFR entirely predicts the degree of improvement in ischaemia that's seen on dobutamine stress echo. What this means for physicians is that we will be able to use the iFR and FFR data before an intervention to predict exactly how much improvement in ischaemia we can expect for our patients following successful stenting. This is the first placebo-controlled evidence we have had of this kind," says Rasha Al-Lamee, Interventional Cardiology Consultant and Principal Investigator, ORBITA.
FFR and iFR was performed solely for this research question, and so the Interventionalist in the catheterisation laboratory was blinded to the results. Assessment of response variables, treadmill exercise time, stress echo score, symptom frequency, and angina severity were performed at pre-randomisation and blinded follow-up. Effects were calculated by analysis of covariance. The ability of FFR and iFR to predict placebo-controlled changes in response variables was tested using regression modelling.
The placebo-controlled effect of PCI was more clearly seen by stress echo score and freedom from angina than change in treadmill exercise time. The estimated effect of PCI on between-arm pre-randomisation-adjusted total exercise time was 20.7s (95 percent CI: -4.0 to 45.5; p=0.100) with no dependence on FFR (pinteraction=0.318) and iFR (pinteraction=0.523). PCI improved stress echo score more than placebo (1.07 segment units, 95 percent CI: 0.70 to 1.44, p less than than 0.00001). The placebo-controlled effect of PCI on stress echo score increased progressively with decreasing FFR (pinteraction<0.00001) and decreasing iFR (pinteraction less than 0.00001). PCI resulted in more patient-reported freedom from angina than placebo (49.5 percent versus 31.5 percent; OR 2.47, 95 percent CI: 1.30 to 4.72; p=0.006) but neither FFR (pinteraction=0.693) nor iFR (pinteraction=0.761) modified this effect.
This report of ORBITA stratified by invasive haemodynamic measures of stenosis severity provides the first placebo-controlled evidence of the association between FFR and iFR and the magnitude of benefit attributable to PCI.
Dr. Al-Lamee went on to say that "this is the first placebo-controlled trial looking at how invasive physiology predicts the efficacy of PCI. In this publication and in the primary publication in The Lancet we saw that angioplasty improved ischaemia as assessed by dobutamine stress echo. However, in this analysis we were also able to assess an additional secondary endpoint of freedom from angina. What is most interesting is that we found that angioplasty increased the number of patients who were free of angina by 20 absolute percentage points. For physicians, this means that one in 5 patients that we treat with angioplasty vs. placebo will be more likely to be free from angina. For our patients, this is one of the most important things we can tell them, that they are more likely to become symptom free."
"The next step for ORBITA is to look at the degree to which stress echo itself predicts the placebo-controlled impact of PCI", Rasha Al-Lamee concluded. "In order to build on some of the questions answered in ORBITA as well as being able to apply ORBITA to a wider patient base, we are also preparing for ORBITA 2 which will be a larger trial, with wider inclusion criteria for patients with stable angina".
The study's main findings are:
- PCI improves ischaemia as assessed by dobutamine stress echocardiography.
- Per 100 patients treated, PCI delivers freedom from angina in ~20 more patients than placebo (Number Needed to Treat = 5).
- FFR and iFR predict the placebo-controlled PCI effect on stress echocardiography.
- FFR and iFR did not predict the placebo-controlled PCI effect on symptoms or treadmill exercise time.
The main clinical implications are:
- PCI renders more patients free of angina than does placebo.
- FFR and iFR do predict the strength of the PCI effect on ischaemia, but this is only clearly seen on blinded stress echo evaluation. It is not visible in the symptom scores or exercise times.