This transcript has been edited for clarity.
Michelle L. O'Donoghue, MD, MPH: Hi. This is Dr Michelle O'Donoghue, reporting for Medscape. We're here in Philadelphia at the American Heart Association Scientific Sessions where one of the big stories has been ORBITA-2. The primary results were presented. Joining me here today are Rasha Al-Lamee and Chris Rajkumar, both from Imperial College in the UK. Before we talk about ORBITA-2, perhaps you could set the stage, Rasha; where were we at after ORBITA-1? What were the takeaways there?
ORBITA-1 Recap
Rasha Al-Lamee, MBBS, MA, PhD: Thank you very much, Michelle, for having us here. After ORBITA-1, you will remember well the fallout that came. Obviously, it was the first placebo-controlled trial of stable coronary artery disease and percutaneous coronary intervention (PCI), comparing PCI with a placebo procedure in patients who had guideline-directed medical therapy.
Importantly, the patients were on an average of three antianginal agents prior to being randomized. And what we found was that the benefit of angioplasty above placebo was far smaller than we expected, and in fact, not statistically significant on the primary endpoint of exercise time. Broadly, there was very little to talk to in terms of symptom relief; one in five more patients were free of angina. But otherwise, all of the symptoms and quality-of-life endpoints did not show a benefit for PCI, and so it left us in a weird space.
It was followed on by the ISCHEMIA trial, and people started to wonder about the role of angioplasty in stable coronary artery disease. For us, it was still important to think about symptoms and which patients might benefit from angioplasty, because we'd seen a signal that there was some benefit in those ORBITA patients, but just not in all of them. So that got us thinking about what factors in ORBITA-1 contributed to that surprising result. One of the factors was that they were on such high levels of antianginal medication, probably levels that are not what we're doing in the real world. Well, that's certainly what the data tell us, and our patients were telling us that it was too much for them and something that was difficult to sustain and adhere to over the long term. So the question became: What does angioplasty do in a more real-world setting, in a setting of patients without antianginal medication? Importantly, that question, and designing the trial that way, would allow us to work out the efficacy of angioplasty without any attenuating effects of medical therapy. That's what brought us to ORBITA-2.
O'Donoghue: ORBITA certainly got a lot of people talking, as you say. It's the first time that we really had — however you want to describe it — a sham procedure, in essence, depending on which treatment arm they were in. I think that after the COURAGE trial, there was some acceptance that perhaps for a stable angina patient, doing a PCI may not reduce the risk of death or myocardial infarction, but certainly we believed that it was going to offer symptomatic relief. I think after ORBITA-1, people paused and said, "Gee, if there's a sham procedure done, then people may derive as much benefit." But as you say, it was on a background of maximal antianginal therapy. But it's interesting, nonetheless, that people were still symptomatic despite the fact that they were on maximal antianginal therapies.
Al-Lamee: As you point to ORBITA-1, it is still a very important trial in my mind, and one that's very dear to my heart because it sets standards for how we do these trials. In performing ORBITA-1, we were able to understand that trials like this were feasible and ethical, and therefore it was easier to do a bigger trial that encompassed a broader set of patients that was more real-world to answer the question more clearly.
O'Donoghue: So that transitions us nicely to ORBITA-2. Chris, can you walk us through the design there and the topline results.?
ORBITA-2 Symptom Assessment and Sham Procedure
Christopher A. Rajkumar, MBBS, PhD: ORBITA-2 was a placebo-controlled trial of PCI for stable angina. As you mentioned, we took many of the aspects of ORBITA-1 in that these patients had undergone a coronary computed tomography angiography or a diagnostic coronary angiogram showing us evidence for an anatomical stenosis. We enrolled them into a symptom assessment period, which ran for 2 weeks prior to randomization. During this time, they documented their angina symptoms every single day using a dedicated smartphone app, which was something totally novel for this trial. They reported to us every day whether they'd had any angina and how many episodes occurred.
At enrollment, we did stop the antianginal medications, as we've discussed, but patients could restart them at any time in collaboration with the trial team. They had 24/7 access to the trial team, and if their symptoms required it, they would restart their antianginal medication, according to a protocol that we had prespecified.
The randomization visit worked in a similar way to the first ORBITA trial in that all patients underwent vascular access, a coronary angiogram, and pressure wire studies, and then they were sedated to a deep level of conscious sedation. At that point, they were then randomized either to the PCI or placebo. The PCI group got complete revascularization of all ischemic stenoses at that visit, and the placebo arm just remained on the cath lab table without any further intervention. Patients were all discharged with dual antiplatelet therapy and then entered a 12-week follow-up period where they continued to document their angina using a dedicated smartphone app.
In terms of the results, our primary endpoint was novel and it was patient centered; we call it the Angina Symptoms Score. This was a composite endpoint of how much angina the patients had, how much antianginal medication they'd had to be restarted on, and any adverse events, like acute coronary syndromes, unblinding for intolerable angina, or death. Our primary result of the ORBITA trial is that we found that PCI significantly improved the angina symptom score compared with placebo.
And because we had daily data, we were able to see the timing of that; we saw that very quickly following randomization, and it continued. That beneficial effect was seen all the way out to 12 weeks. We found that patients in the PCI arm were about three times more likely to be free from angina at the end of follow-up vs those in the placebo arm. The beneficial effect of PCI was seen across a range of different endpoints. Our Canadian Cardiovascular Society Angina class data were positive for PCI, as well as our exercise treadmill time, with about a 60-second advantage in the PCI group.
O'Donoghue: ORBITA-1 told us that if a patient is on antianginal therapy, then in that scenario, PCI may not have a marked improvement on symptoms. But in ORBITA-2, if they're not on antianginal therapy, perhaps it does offer symptomatic improvement. Do we think that the antianginal medication piece is the real effect modifier here, or is it something else to do with how you selected these patients, the duration of follow-up, or a key difference in terms of the study design?
Al-Lamee: Although ORBITA-2 was designed to recruit single- and multivessel disease patients, 80% of the patients had single-vessel disease once they were assessed for evidence of ischemia. In terms of their symptom burden, their invasive physiologic assessments, that burden of ischemia, they were relatively similar between the two trials. What I guess was different in ORBITA-2 is that we assessed symptoms in a symptom assessment phase on the smartphone app before enrollment. And if patients were asymptomatic, they were excluded from the trial; that could have had an impact.
The follow-up was longer at 12 weeks, but we saw that immediate improvement in the PCI patients that was sustained throughout, so I don't think that made the difference. And yes, there were 101 extra patients, but I think that's unlikely to have made the difference. One of the things that could have contributed is that the Angina Symptoms Score data gave us a daily score of their angina health status, which of course would increase the power to detect a benefit vs just having one follow-up data point, as we had in ORBITA-1. I still think that the impact of antianginal was probably quite important. And I think we're left now with two pathways for patients to consider as we talk them through their options.
Residual Angina
O'Donoghue: Chris, one of the interesting things to come from ORBITA-2 was the fact that even after PCI, the majority of patients were still describing ongoing angina symptoms. What explains that? What is causing those symptoms to continue, despite the fact that, in theory, you've now revascularized the patient? Is it microvascular disease? Is something else going on?
Rajkumar: That's correct. We found that 59% of our patients in the PCI arm still complained of some symptoms following PCI. Their symptoms may have improved, but they still had some residual symptoms. Our trial wasn't designed to detect microvascular status. However, what we can say is that we had excellent resolution of ischemia in our PCI arm, and therefore if the microvascular disease is detectable on standard ischemic testing, then we can rule out that form of microvascular disease.
There is always diagnostic difficulty when we're looking at symptoms, and, of course, there will be some patients with noncardiac chest pain in that cohort. The trial wasn't designed to look into that. But it's certainly the source of further research for our group, for sure.
O'Donoghue: Because then it does make an argument for perhaps doing the antianginal therapy in addition to PCI if it is something like a microvascular issue where being on, for instance, a nitrate or something may help to ameliorate the symptoms.
Al-Lamee: Some of the learning from that might come from ORBITA-1, because in ORBITA-1 they were on all of those antianginal therapies, yet a similar proportion of patients still remained symptomatic. I'm not sure that antianginal therapies treat microvascular disease; they clearly do to some extent, and perhaps we could think of other therapies in the future, but I don't think that's enough to explain it all. There's something about the link between symptoms and a stenosis that's not quite as linear as we expected, and that's part of the story as we do more research.
O'Donoghue: If you have a patient today with stable angina symptoms, do you feel that there is now an upfront conversation where you say, path A would be to consider antianginal medications, or you also have a path B that starts with PCI before even reaching for a medication option — is that the takeaway?
Rajkumar: I think a really important factor to remember is that every patient is an individual with different priorities and different likes and dislikes. Some patients will be willing to take that small upfront risk, albeit with perhaps long-term management concerns with PCI, and some patients will be much happier with medications. Everybody will have that individual choice and it's nice that we now have data to support both pathways.
O'Donoghue: I think it also reinforces the importance of doing these types of either sham or placebo-controlled procedures, because that does help to take an important element out of the question as to what is showing a benefit overall. It really ends up being the cleaner experiment.
Al-Lamee: What we learned from both studies is that the blinded effect is always much smaller than the unblinded effect size that we've seen before. That's really important to consider in clinical practice. We clearly deliver placebo as part of our medical care, and it's a good part of being a good physician. That will maximize the benefit of any symptomatic relief that you'd expect from any therapy.
O'Donoghue: Well, congratulations again, because I know that these studies are very hard to conduct, and I think it's an interesting one. Thank you very much. Signing off for Medscape, this is Dr Michelle O'Donoghue.
Michelle O'Donoghue is a cardiologist at Brigham and Women's Hospital and senior investigator with the TIMI Study Group. A strong believer in evidence-based medicine, she relishes discussions about the published literature. A native Canadian, Michelle loves spending time outdoors with her family but admits with shame that she's never strapped on hockey skates.
Cite this: PCI, the Antianginal 'Pill': ORBITA-2 in Detail - Medscape - Nov 15, 2023.
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