Physiological Analysis of ORBITA Trial Yields New Lessons for Stable Angina Management in Patients with CAD

Dr Rasha Al-Lamee; Prof Bernard Prendergast

Disclosures

June 08, 2018

Prof Bernard Prendergast: Hello, I’m Bernard Prendergast, an interventional cardiologist based at St. Thomas' Hospital in London. I am very pleased to be broadcasting to you from Paris from the European Association of Percutaneous Cardiovascular Interventions (EuroPCR) 2018.

I'm here with Dr Rasha Al-Lamee from the Hammersmith Hospital in London. We are here on behalf of Medscape UK having a conversation about the role of angioplasty in the management of stable angina, and the ongoing controversy and most recent results from the ORBITA trial.[1]

The role of revascularisation by means of angioplasty for stable angina has been under scrutiny for a number of years now, since the publication of the COURAGE trial[2] suggested that medical therapy is perhaps as good as percutaneous coronary intervention (PCI) procedures. That's generated a lot of controversy, with interventionists believing that they do effect important change in patients’ symptoms and quality of life, whereas on the other hand, there is an argument that there is a high risk of complications related to intervention.

Looking For Clarity on Clinical Benefits

This controversy was addressed by the ORBITA trial, which was published a number of months ago, and since then has been the subject of ongoing discussion both in the medical and mainstream press. It is a great privilege therefore to be here with Rasha, who led the study, to talk about the experiences that have arisen as a consequence and perhaps some of the more sophisticated insights into the data which have emerged during this EuroPCR 2018 meeting.

Rasha, could you explain the thinking behind the study, the headline results that generated such controversy, and maybe a little bit more about how today has begun to set the record straight?

Dr Rasha Al-Lamee: Thank you very much. ORBITA was a trial we designed to test what is currently our primary goal in those patients with stable angina, which is whether those patients gain any symptomatic or quality of life benefit from angioplasty. In the absence of a reduction in the rate of myocardial infarction or mortality, we're left with the hope that we can improve our patient’s quality of life. We felt that the only way to do this adequately and scientifically was to test this question in a placebo-controlled trial. This was novel and hadn't been done before.

In our clinical experience, we all see patients get better. We also see patients who we expect to have symptomatic relief, but who come back telling us they still have pain.

The clinical trial data has been mixed. In some trials, we've seen quite significant angina relief such as FAME 2[3] and COURAGE[2], and in other trials such as RITA-2[4] and BARI 2D[5] we've seen more modest angina benefit.

The question was, is some of this benefit due to placebo? That was really what we wanted to test. What was the true therapeutic efficacy? Perhaps even more importantly, and pertinent to being here at EuroPCR, was whether we could tease out exactly which patients gain the most benefit.

Designing ORBITA

Prof Prendergast: Give us a thumbnail sketch of the study design, and what the headline results were a few months back?

Dr Al-Lamee: This was a very specific cohort of patients. They all had stable angina. They had all come to cath labs by normal clinical care pathways, and the vast majority of patients had had a positive ischaemic test. They all had single-vessel coronary artery disease, which was defined as severe by angiography.

The trial was designed so that at the point of enrolment, having had a series of questionnaires and assessment of their angina and life status, patients went on to have intensive medical therapy. That was deliberate, because we wanted to test angioplasty as it is within the guidelines, as an adjunct to pharmacotherapy.

Prof Prendergast: And that medical therapy optimisation phase, on average, consisted of one to three telephone consultations per week with a consultant cardiologist.

Dr Al-Lamee: Yes, more than we would actually achieve in reality. In fact, many of those patients probably would've had an angioplasty on 0 or 1 anti-anginal that they started with; I think most of us are used to that.

After the medical optimisation phase, we then brought them back. They all had a treadmill, a stress echo, and had their symptoms and quality of life questionnaires repeated.

Then, the crux of ORBITA was the randomised procedure. They came in for an angiogram. They all had an invasive procedure. They were wearing headphones and listening to music.

Prof Prendergast: So it was a true sham randomisation?

Dr Al-Lamee: It really was, absolutely. They chose which music they wanted to listen to.

They then had instantaneous wave-free ratio (IFR) and fractional flow reserve (FFR) measurements, but most importantly, the operator was entirely blinded to those results. They were then sedated until they reached the level of conscious sedation, so not requiring airway or ventilation management. They were randomised 1:1 to PCI or placebo. If they have placebo, they waited on that cath lab table for 15 minutes, still asleep, before coming outside. Angioplasty was done with standard techniques, and FFR and iFR were repeated still with the interventionists blinded to those results.

Then, those patients came out blinded, with the ward team blinded to what they had done and, then had a 6-week blinded follow-up period before they came back and had their baseline tests repeated.

Trial Results

Prof Prendergast: What were the bottom-line results for that study without physiological guidance?

Dr Al-Lamee: The primary endpoint for ORBITA was a change in treadmill exercise time. We had chosen that because previous drug trials, and the US Food and Drug Administration and European Medicines Agency, had recommended treadmill exercise time as the primary endpoint for placebo-controlled drug trials. We thought we would mimic that and also the ACME trial,[6] which is the older angioplasty trial published in the early 1990s.

There were 200 patients in ORBITA. It was powered to detect a 30-second difference in the exercise time between the two groups. We expected to see a greater increment in treadmill exercise time on the angioplasty arm, but we didn't find that. We actually found a much smaller-than-expected effect size, which was not statistically significant between the two arms.

Prof Prendergast: I imagine there were other secondary endpoints, reported symptoms, wellbeing on medical therapy, and so on.

Dr Al-Lamee: Of the secondary endpoints, I guess the one to highlight that was positive in the primary analysis was ischaemia reduction by stress echo. We found that angioplasty significantly improved the level to which you had ischaemia detectable via stress echo. It certainly seemed to work in terms of improving the blood supply.

Prof Prendergast: The heart was behaving better on the stress echo, but the patient was not necessarily walking further as a benefit.

Dr Al-Lamee: Exactly. Nor were they telling us they felt much better in that initial analysis.

Physiology-Stratified Analysis: Following Up On ORBITA

Prof Prendergast: We know that that caused a lot of upset in the community. You've endured a difficult period in the press and so forth.

Dr Al-Lamee: I have a lot of white hair these days, yes.

Prof Prendergast: Importantly, you have got a paper out in Circulation today,[7] which looks at the physiological measures of those procedures and the findings at the time of randomisation. Tell us about that study and the findings.

Dr Al-Lamee: Believe it or not, we entirely expected that the primary endpoint and the majority of the secondary endpoints would demonstrate a very large effect size for PCI. What we then expected was that if that effect size was large enough, we'd be able to stratify patients based on their baseline level of ischaemia, as assessed by an iFR and FFR, to work out which patients may get the greatest benefit, and perhaps even give us a cut-point for angina relief in a blinded trial for the first time.

We took the ORBITA patients—196 of them managed to have invasive physiology—and we stratified the endpoints of ORBITA based on the pre-randomisation FFR and iFR. We found the FFR and iFR at baseline very strongly correlated with a placebo-controlled efficacy of PCI on stress echo; the lower your FFR and iFR value, the more angioplasty stood to show ischaemia reduction. At the higher FFR and iFR values, there seemed to be less impact of PCI versus placebo.

Prof Prendergast: Which would intuitively be what you would expect?

Dr Al-Lamee: It absolutely was. It was very strongly significant, both for FFR and iFR.

We then looked at whether we could tease out the same for symptoms or exercise time, and actually did not find that baseline FFR and iFR predicted improvements there. However, of course at this point, we're taking a small effect size and trying to stratify that.

I’d like to just add that we also did an additional secondary analysis, which showed actually that we improved freedom from angina. Our results show that 20% more patients in the angioplasty arm did say that they were free of angina.

Lessons Learned

Prof Prendergast: This shows, number one, a strong vote in favour of physiological assessment of coronary disease, and also demonstrates that reversal of ischaemia has a benefit on function as assessed by means of stress echocardiography.

Dr Al-Lamee: Exactly. That may have an impact on long-term outcomes, and of course, that is not what ORBITA was designed to test. But perhaps we’ll see that in upcoming trials.  

Prof Prendergast: The ISCHEMIA trial is going to investigate this further. When is that going to be reporting?

Dr Al-Lamee: I suspect the primary results to come out in 2 years or late next year. Now, if we see mortality and myocardial infarction reduction with the angioplasty group that have high ischaemia burden in ISCHEMIA, then these results tally up.

Prof Prendergast: We need to remember also that having angina is not a pleasant phenomenon for the patients. They are also taking a lot of medication. It’s not easy for them.

Dr Al-Lamee: Interestingly, I've been asked this a lot. How many of those ORBITA patients having had placebo chose to have angioplasty at the end when they were unblinded? In fact, when you give them the option to carry only on with those tablets or potentially stop some of those tablets and have stenting, the vast majority (85%) chose the latter. Of course, at this point, we did not have the results, but that was what they opted for.

Prof Prendergast: What are your messages for the interventional community and the general cardiological community based upon your results?

Dr Al-Lamee: For the interventional cardiologists, I’d say that we can certainly be pretty pleased of/with the fact that angioplasty in this cohort of single-vessel coronary artery disease patients improves ischaemia, as assessed by invasive measures of physiology and by stress echo. We can also see that a proportion of our patients will become free of angina with angioplasty; not all of them, but a significant proportion.

For those general cardiologists, I think it's important to remember that angioplasty certainly does work. It doesn't work for everyone in terms of symptom relief and exercise time improvement. However, that's probably because the link between seeing the stenosis, fixing the stenosis, getting ischaemia benefit, and then expecting all of our patients to come back, exercising more, and telling us they feel better, is perhaps too simplistic. There's a lot more going on than just fixing the epicardial stenosis.

Prof Prendergast: And it should be coupled with clinical assessment that the symptoms are ischaemic in the first instance.

Dr Al-Lamee: I agree. Many of those patients that get to our cath lab table may not have anginal symptoms, and perhaps the proportion that become free of angina are the patients with true cardiac pain.

Prof Prendergast: So there we are, some very positive messages from ORBITA, some demystification of the trial and the results, and some very supportive physiological evidence published today. Thank you for watching.

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