When to Stent in Stable CAD? That Is (Still) the Question

The ORBITA Sham PCI Trial

; David J. Maron, MD; Manesh R. Patel, MD


November 22, 2017

Robert A. Harrington, MD: Hi. I'm Bob Harrington from Stanford University. I'm here at the American Heart Association (AHA) Scientific Sessions in Anaheim with a couple of friends and colleagues to talk about angioplasty revascularization management in the patient with stable ischemic heart disease (SIHD) in light of the recent ORBITA trial[1] results.

Next to me is my good friend and colleague, David Maron. He is a professor of medicine at Stanford and the division chief of the Stanford Prevention Research Center. Welcome, David.

David J. Maron, MD: Thank you, Bob.

Dr Harrington: Next to him is my longtime friend and colleague from Duke University, Manesh Patel, who is the chief of the Division of Cardiovascular Medicine and also the director of the Duke Heart Center. Manesh, welcome.

Manesh R. Patel, MD: Thanks for having me.

Dr Harrington: David, you were in the New York Times when ORBITA was first reported on a few weeks ago. This has been big news. It was reported at Transcatheter Cardiovascular Therapeutics, but you cannot have a conversation at AHA without somebody bringing this up. Is that a fair assessment?

Dr Maron: A fair assessment. There is a lot of buzz about this trial.

Dr Harrington: There has been more buzz about these 200 patients than I have seen in quite some time. We are going to talk about ORBITA and put it in the broader context of SIHD. We have the steering committee chair of ISCHEMIA next to us, so we want to make sure we cover that. Manesh, kick us off.

ORBITA Trial Overview

Dr Patel: Part of the reason ORBITA has gotten so much buzz is because of the rigor with which it was carried out. That leads us to want to better understand these data and congratulate the investigators for carrying out something that had not been done for a long time. All the buzz sometimes forgets about the blood, sweat, and tears of the actual people who do these trials and take care of patients. I want to make sure people recognize that.

I think the most important point of this trial overall is that there is a powerful placebo effect to the procedure of PCI.

When you talk to the investigators, their intent was to prove the benefit of what happens in stable angina because it had not been carried out before. This is in the context of renal denervation[2] and other procedures being tested against a sham-controlled arm.

Their intention was to enroll patients with SIHD and one-vessel coronary artery disease (CAD) identified on the cath lab table. Patients were taken off the cath lab table and medically maximized. They had a treadmill test and a stress echo[cardiogram], and then they had symptom classification.

The study methods description is impressive. For 6 weeks, patients could call a cardiologist 24/7 who would titrate their medications and make sure they were understanding side effects, et cetera.

Medicines were adjusted a couple of times a week to get people onto maximally tolerated antianginal therapy. We write this in the appropriate use criteria (AUC) guidelines,[3] but we hardly ever do that. So again, kudos to the investigators. After 6 weeks, patient symptoms improve, and their tolerability to do other things and their anginal scores probably improve too. In fact, some patients came out of the study because they became asymptomatic.

About 230 patients went through an enrollment phase, and 200 patients were randomized to a sham versus actual percutaneous coronary intervention (PCI). Let me describe what that means. Patients wore headphones and blinders so that they did not understand what was going on. Investigators put a flow wire down the vessel. Physiology was not used to determine whether patients should undergo angioplasty. Angioplasty was or was not performed in that vessel. Patients were followed for about a month or so; functional tests were repeated and other evaluations were performed.

The primary endpoint was improvement in the patient's exercise function. The study was powered to see a 30-second improvement in exercise duration, but it did not show that. In fact, it looked like there was 28 seconds of improvement in the PCI arm versus 11 seconds of improvement in the sham PCI arm, which was not statistically different. There was no significant difference in the Seattle Angina Questionnaire (SAQ) score, although these patients did not have as many symptoms as in some other studies similar to COURAGE. One could argue that there is a ceiling effect there, but it did not change as much. There was also a reduction in ischemia on the stress test in the PCI arm. These are the general findings of the trial.

Dr Harrington: It was well done and well reported. They were very transparent in their reporting. The methods of that paper are beautifully written.

Dr Patel: My favorite part is that they put every angiogram in the appendix, so if you wondered what the lesions looked like and you are an interventionalist like me, you could go look at them and know what they treated.

Dr Harrington: That was brilliant.

Dr Maron: It was. The blinding was maintained.

Dr Patel: Yes—another very rigorous thing about this study was formally testing the blinding. They asked the patients and the investigators which procedure they thought the patient got. It was a really well-conducted study. It may be the most rigorous PCI-alone study that we have seen. Of course, other rigorous trials have happened, certainly in revascularization, but for this segment, this is pretty good.

Dr Maron: It is the only sham-controlled trial in PCI.

Dr Harrington: That is right. If we go back to the ACME[4] days, there was not a sham control in PCI.

Dr Maron: You have to go back 30 years or more for a sham-surgery control with ligation of the internal mammary arteries.[5]

Practice Implications

Dr Harrington: David, give us your high-level thoughts on ORBITA and how you see ORBITA fitting into how you think about patients with SIHD.

Dr Maron: I think the most important point of this trial overall is that there is a powerful placebo effect to the procedure of PCI.

Dr Harrington: It would have been really nice to have an arm where you did absolutely nothing, would it not?

Dr Patel: Yes; I think that would have helped us quantify what the placebo effect was. Then some would argue for a little bit longer follow-up, because you might have some belief, but then it may dissipate. Those are small critiques for a well-done study.

Dr Maron: Those are fair comments. In COURAGE[6] at 1 month, there was a difference in the improvement in the SAQ score of 7. In this trial, it was 4.4. Whether that is the placebo effect because COURAGE was an open-label trial, we do not know.

These are people who had mild ischemia. It was adequately powered for the selected endpoint. We do not know the durability of the benefit from the placebo effect because it had to stop at 6 weeks. When you think about it in practical terms, it makes sense that it was only for mild ischemia and that it was a short-term trial because otherwise—you know better than anyone—how could you do such a trial?

Dr Harrington: That is a good comment. Manesh, you mentioned the fractional flow reserve (FFR). Again, they were fully transparent. They reported the median and the interquartile range. If I remember right, the upper part of the quartile range was 0.82. One quarter of the patients did not have physiologic ischemia as measured by FFR, but the people doing the procedure did not know that.

Dr Patel: They are probably going to give us those findings, which will be informative. There have been other critiques about diameter stenosis versus area stenosis. We are certainly moving toward more physiologically driven revascularization.

Having looked at the trial results, I am not sure how much it is going to change what we already know. If you are thinking about it from a Bayesian perspective rather than a P value perspective, what this trial really tells you is that if you maximally medically treat patients before they get to the cath lab with one-vessel CAD, this is the benefit range. Then you have to put that into the context of how many such patients exist and how you could do this.

Dr Harrington: Also, how willing are providers and patients to do that level of aggressive medical therapy? David, you think a lot about aggressive medical therapy. You are a preventive cardiologist and run a prevention center. In ISCHEMIA, guideline-directed medical therapy is a key component. What did you think of the medical therapy here?

'Stupendous' Medical Therapy

Dr Maron: It was unreal. In other words, within 6 weeks the average number of antianginal agents went from fewer than one to almost three. That is very unlike what we do in the real world. It was optimal. The access to a cardiologist up to three times a week is not what we ordinarily do. From an antianginal perspective, it was stupendous.

Dr Harrington: Do you think we could do it in practice? I remember when SPRINT[8] came out, people said, "We do not measure blood pressure to that level of rigor." Then the question was: Should we? Should we be this aggressive in medical therapy?

Dr Maron: I am not sure that accelerating therapy that quickly, within 6 weeks, is really necessary. In the context of how long they were going to be able to retain patients in this trial, I think they had to get there as quickly as possible.

Dr Harrington: To really test their hypothesis.

Dr Patel: I think the paradigm is going to be moving a little bit, Bob. If you asked me how I would put it into practice, first I would have to know anatomy. Five years from now, I can see us having many more patients with coronary computed tomography angiography (CTA) and a variety of tests within the CTA, so that we will know the anatomy and do medical therapy run-in before making revascularization decisions. If you know the patient has two-vessel or three-vessel disease, you are going to act very differently from with one-vessel disease. Just like the sham PCI trial, we are going to need a variety of studies to be able to understand how to get these patients there.

Dr Harrington: David will remember how we argued about whether or not we should do the CTA during the planning of ISCHEMIA. We are finding that you identify a lot of people who have nonobstructive disease, and you find a lot of people who have left main disease. I argued vigorously against doing the CTA because I thought we should just take them to the cath lab and see how it plays out, cath or no cath. It may be that having that piece of CTA information is usually helpful clinically.

Dr Maron: Almost 10% of the patients whom we screen in ISCHEMIA who have at least moderate ischemia have left main disease.

Dr Harrington: A big percentage have nothing.

Dr Maron: Twenty percent have no obstructive disease, defined as 50% [diameter stenosis].

Dr Harrington: And this is after having had an exercise test with moderate to severe ischemia.

Dr Patel: This certainly tells us that microvascular disease is present. It tells us that there are other things going on in the myocardium that we do not fully understand.

The Last Bastion for PCI in SIHD?

Dr Patel: There has been such a firestorm about ORBITA. What often happens is, good science like this allows people who have biases to get into those positions. I would say we already knew that we wanted to medically manage our patients before we get to the cath lab in one- or two-vessel disease if we can. This is going to put an impetus on us to ask: How can we do it well, and how will we know? I certainly do not think stable angina in one-vessel disease is a large portion of the population.

There is nothing wrong with attacking a guideline class I recommendation.

Dr Harrington: Let us talk about that. You tweeted something out this week, Manesh, that was interesting. You had access to the National Cardiovascular Data Registry (NCDR) data.[8] We know the percentage of people undergoing PCI with SIHD, and we know whether they have one-, two-, or three-vessel disease. What did NCDR show us?

Dr Patel: We recognize, of course, that coding and things are occurring, so people might say [that more people are unstable (ie, overreported)], but I also believe over the past 5-7 years that we are doing more appropriate PCI. We are getting more patients who have worse symptoms, ischemia, and acute coronary syndrome (ACS).

The data would say that 80% or so of patients have ACS—acute symptoms and syndromes. Twenty percent are stable, and about one half of these have one-vessel disease. That's about 10% or so undergoing single-vessel PCI for stable angina in the United States.

Dr Harrington: Hallway chatter here is that NCDR does not represent American angioplasty practice. You want to dispel that?

Dr Patel: I would counter that NCDR is in 1300 hospitals.

Dr Harrington: A pretty good sample.

Dr Patel: This is a pretty good sample. There are more hospitals for sure, but I do not know how many more hospitals are doing angioplasty.

Dr Maron: The class I indication for elective PCI is for the relief of angina. ORBITA is attacking what the interventionalist would perceive to be the last protective reserve. I think that is why there has been so much buzz.

Dr Patel: It is okay to make people feel better, no matter how you do it (PCI or optimizing medical therapy [OMT] only), as long as it can be done in a safe and cost-effective way. We would certainly say that it is okay to do a procedure to make people feel better if you have tried other things and they still do not feel well.

I agree with you that the ORBITA findings attack how people might think. Relief of angina is extraordinary, and many of our patients will get it with medicine, and some will get it with medicine and angioplasty. We are just learning how to quantify that better.

Dr Harrington: There is nothing wrong with attacking a guideline class I recommendation. In fact, techniques change, technology changes, medicines get better. Good for them that they went after a long-held belief. That is an important step forward.


Dr Harrington: David, we have a couple of minutes left. Let's talk about ISCHEMIA. You are the co-principal investigator, along with Judy Hochman. The trial is going along well. It has been a slog to get it done.

Another commentary might be that for things that we do so commonly, why can't we get the community to participate more regularly in research? That has been one of the things I have been beating the drum about. This procedure is done a million times a year in the United States, and we are struggling to get the trial done. We are going to get it done. Give people an update on the status.

Dr Maron: We have randomized over 4850 participants and have 150 to go. We will probably complete that within the next couple of months. We have a lot of ischemia and a lot of coronary disease. We have an incredible database. We have coronary CTA on the majority.

Dr Harrington: This is going to take the story way beyond single-vessel disease, is it not?

Dr Maron: Absolutely. There is a great preponderance of multivessel disease, and of course, unlike ORBITA, we are looking at long-term outcome.

Dr Harrington: Including the hard outcomes of death, myocardial infarction, and repeat revascularization.

Dr Maron: And heart failure.

Dr Harrington: No matter what it shows, it will definitely shed some insight into how we manage patients with SIHD.

On Questioning Current Strategies

Dr Patel: I absolutely think so. We need more upfront studies where we randomize patients to no test on the basis of symptoms and have them come back a few weeks later, test them, and then see what we do. One would learn from PROMISE[9] and other studies (as you are learning in ISCHEMIA) that probably 10%-20% of the patients whom we test noninvasively do not need a test, but need to come back later after some reassurance and maybe an antianginal.

Dr Harrington: Manesh, in your role leading AUC, you have been talking for years about all of these strategies that we just accept but that have not been well tested.

Dr Patel: The most cost-effective and potentially patient-centric view upfront is to say: How can we reassure patients who do not need anything more?

Dr Harrington: Embarking on a trial of aggressive lifestyle management and aggressive medical therapy is not only perfectly acceptable, but it can be the right choice.

Dr Patel: It can be. You just need to make sure that the patient has CAD or has the angina that you think you are relieving. It certainly can be medically treated—just figure out how to get to that point.

More Sham Controls

Dr Harrington: David, what else have you been thinking and learning about regarding SIHD? What do you want to leave the audience with?

Dr Maron: Going back to ORBITA, does it set the standard? Should we be doing more sham studies with placebo PCI?

Dr Harrington: When appropriate, we absolutely should be thinking about sham procedures for a variety of procedures. We have had such studies with knee arthroscopy and with back evaluation. There are a lot of powerful effects.

Dr Patel: Where is the study in atrial fibrillation (AF) ablation?

Dr Harrington: Yes, AF ablation is a great one.

Dr Patel: Where are sham studies in noninvasive testing? It should be easy to randomize patients to a sham stress test. I would argue that there are a variety of places we could be doing this to find out what makes people feel better.

Dr Maron: Of course, we need to give medical therapy a chance. Whether or not PCI is performed, we need to optimize medical therapy, and we know from study after study that this is just not done.

Dr Harrington: Rob Califf, whom all of us are good friends with, has returned from the US Food and Drug Administration and is spending time in Silicon Valley. He is always bringing up A/B testing. Tech companies do it constantly; it is just part of the culture. We do not do that, yet there are many common things we do where A/B testing and randomization would be hugely valuable. But the system is not set up to do that.

Final word, Manesh?

Dr Patel: I think you are right. I look forward to finding ways in which we can get patients engaged to help us do that.

Dr Harrington: Final word from you, David?

Dr Maron: Please help us with the recruitment for these last 150 patients for ISCHEMIA.

Dr Harrington: I will see you around campus, and you will be smiling more if that happens.

Thank you, Manesh Patel and Dave Maron. Thank you, the viewers, for joining us. This has been a terrific discussion on SIHD.


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