ORBITA was the first sham-controlled PCI trial and was appropriately considered a better type of study than the PCI studies that had come before. With the physiologic data being released, we are able to gain further insight.

When the original ORBITA data were released, it was reported that that the degree of ischemia measured with dobutamine stress echocardiography was improved in patients with PCI more than with medications alone. This was noteworthy because dobutamine stress echo is a relatively reliable measure of ischemia. In a statement from the Society for Cardiovascular Angiography and Interventions, I noted that this measure may have greater relevance to patient care than exercise time, since it may be less influenced by factors that could impact a patient’s tolerance to exercise. There are many reasons why one would not exercise to one’s true maximum tolerance, that is, the degree that is determined by ischemic burden, when on an exercise treadmill. A dobutamine stress echo test eliminates all those factors and is in many ways a better measure of ischemic burden. So, we knew before the physiology data were released that this measure of ischemic limitation was improved more with PCI than medications alone.

The release of the physiology data now confirms that impression. We can now see how patients fared with angioplasty as a function of their iFR or FFR values. Happily, the improvement on dobutamine stress echo was greatest among those who had the lowest FFR values. This tells us that patients who have the most ischemia are likely to get the most ischemic relief from PCI. This makes sense.

What is interesting and as yet unexplained is why patients did not also seem to have the same degree of benefit in relief of anginal symptoms. We now know that even among patients with very abnormal FFR or iFR values, the relationship between PCI and angina relief is not very good, except when you consider the dichotomous variable of presence or absence of angina. PCI was much more effective than medications alone in rendering patients angina-free. However, among patients who continued to have angina, the degree of benefit after PCI didn’t correlate well with the magnitude of FFR or iFR abnormality.  

What we can say is that we can be highly confident that angioplasty, when done correctly and successfully in appropriate patients, relieves ischemia, and that ischemia relief can improve function and render patients angina-free. There are still patients who will be limited by angina despite having a successful PCI experience. Perhaps microvascular disease or other problems may limit them.  We still do not understand all the variables that may be at play in those patients.

The new ORBITA data confirm the value of FFR and iFR. We use those tools to identify patients who are suitable for PCI. Nothing in the ORBITA dataset convinces me that I should change my approach with respect to using those invasive tools to help identify patients who are likely to benefit.

Right now, clinical practice should remain the same. Nothing in the new analysis seems to run counter to our current clinical guidelines, which say that patients must have limiting symptoms or objective findings of ischemia and must have a reasonable trial of medical therapies without evidence of adequate improvement before they go to the cath lab. For patients who go to the cath lab, lesions of indeterminate severity should be assessed further with FFR, iFR or a similar tool to confirm that the lesions are sufficiently severe to induce ischemia. Nothing in the ORBITA study should change any of that.

A larger trial with hard endpoints such as objective measures of ischemia would be welcome. Criticisms have been levelled against the ORBITA study about its relatively small sample size and the use of exercise time as a primary endpoint. Conducting an ORBITA-like study in a larger population of patients with unimpeachable endpoints would increase confidence in findings, and that would certainly be welcome.

These findings are similar to the old saying that “beauty is in the eye of the beholder.” The finding that the worse the FFR/iFR values, the more severe the ischemia, and thus one would predict significantly improved regional wall stress by echo (shown also in the original Lancet paper) is reinforced in this new presentation and paper. However, one would predict improved angina and exercise tolerance in these patients compared with those with less severe ischemia (based on iFR/FFR criteria), and yet there was no relationship with the FFR/iFR results predicting a symptomatic improvement — so there is an apparent disconnect between the physiologic improvement in regional wall motion score and exercise capacity. This tells me that the PCI was technically successful in improving regional echo wall motion but not exercise treadmill time, nor most of the Seattle Angina Questionnaire quality of life domains — except for the “freedom from angina” domain. That is, the angina frequency, physical limitation, and overall quality of life Seattle Angina Questionnaire domains were no different for the PCI group compared with the sham group. Overall, I would conclude that these are somewhat discordant results and “mixed signals.” Nor do these findings really change the overall ORBITA findings.  

However, I predict that many interventional cardiologists will seize upon the “freedom from angina” domain with PCI and will now argue that ORBITA is actually a “positive trial for PCI,” and many may simply choose to ignore the other quality of life domains, including no change in exercise increment, and will attempt to argue that these findings negate the original Lancet findings — though I do not agree with this interpretation.

Here is another issue: If PCI was technically successful in normalizing the post-PCI FFR and iFR values and also improved regional echo wall stress scores, why were so many patients (47%) still assessed by their blinded physicians as having persistent Canadian Cardiovascular Society Class 2-3 angina post-PCI, and why did 50% of the PCI-treated patients not have complete “freedom from angina,” as noted in Figure 4 of the Circulation publication, post-PCI at 6 weeks? There seems to be a disconnect between symptom relief and physiologic parameters (incremental improvement in exercise duration) and all but one Seattle Angina Questionnaire domain. So, there are still more questions than answers.

It is also notable that the FFR/iFR values post-stenting were good to very good (0.9 and 0.95 respectively, although not perfect), and the majority of patients (95% to 98%) had values that were in the normal range after PCI. This argues against significant residual ischemia due to poor technical result or diffuse untreated epicardial CAD.

The only way I could try to rationalize these findings (aside from statistical concerns or small sample size) is by citing the “ischemic cascade.” But, the first changes with ischemia are regional wall motion and the last change temporally is chest pain/angina, which is the last parameter temporally that manifests physiologic improvement. FFR/iFR parameters are based on coronary flow, and thus are most sensitive at detecting the early signs of ischemia based on reduced perfusion. Other factors such as collateral recruitment or microvascular augmentation might be able to compensate for the decrease in flow to maintain enough myocardial supply to prevent the last stage of ischemia (chest pain). Changes in regional wall motion abnormalities are more sensitive and occur at an earlier stage of ischemia compared with angina.

Another plausible explanation for the disconnect between improved regional wall stress and freedom from angina without any notable change in exercise parameters is that the patients’ angina and exercise limitation was not predominantly due to the epicardial coronary stenotic lesions to begin with, and could potentially be explained by other mechanisms for angina that are separate from severe epicardial disease, such as microvascular angina and ischemia — which can co-exist in the same patient. Therefore, by stenting a high-grade 90%+ segmental coronary stenosis, they “fixed the ischemia” as manifested by both the FFR/iFR and the echo improvement, but not the symptoms. In these patients, it is plausible that the predominant driver of angina is microvascular disease in the culprit coronary artery or the other coronaries that were not evaluated; one would typically use an adenosine infusion to assess coronary flow reserve. In that situation, iFR/FFR is not going to be valuable tool to help predict those that will have improvement in angina or exercise. One could suggest that any future study that is going to analyze the effect of medical therapy or PCI on angina as the primary outcome should also involve parameters that carefully assess the microvasculature at baseline and follow up, such as global coronary flow reserve, hyperemic microvascular resistance or index of microcirculatory resistance.

The takeaway is that not all angina is due to obstructions or stenosis of the epicardial coronary arteries and that angina and ischemia can also be caused by microvascular disease and endothelial dysfunction. Many critics bashed the ORBITA trial because they disbelieved that stenting a flow-limiting coronary stenosis would not be associated with improvements in angina and improved exercise duration, but these new findings do show some evidence for the “freedom from angina” Seattle Angina Questionnaire domain — yet angina frequency, physical limitation, Seattle Angina Questionnaire quality of life and the EQ-5D measures were unrevealing of a clear PCI benefit. And, why do only 50% of successfully stented patients not have complete angina relief post-PCI at 6 weeks when one would expect the maximal benefit to be discernible?

Obviously, we await the outcomes of the large ISCHEMIA trial, where we will have an opportunity to examine clinical outcomes and detailed quality of life in over 5,170 patients with stable CAD and moderate-to-severe baseline ischemia where half the patients will get revascularization, mostly with PCI, plus optimal medical therapy and the other half will get optimal medical therapy alone, though this is an unblinded trial. But, if ischemia is the major driver of events, we will likely be able to test this hypothesis fully during long-term follow-up

But, when the dust settles, I do believe the present analysis tells us that PCI, as it would be expected to, improves regional wall motion and at least the one Seattle Angina Questionnaire domain of "freedom from angina" — which it also should if you relieve a 90%+ segmental stenosis. However, not all angina domains were improved nor was exercise, so at the present time, there are still more questions than answers. That said, hopefully, the discourse and dialogue post-ORBITA will now proceed in a more civil and less contentious fashion.