Trajectory Unknown: How ORBITA Lands in Clinical Practice Still Up for Debate

For a study with a mere 200 patients and relatively short follow-up, the ORBITA trial has punched well beyond its weight, sparking debate among interventional and general cardiologists alike about the benefits of PCI in stable CAD patients.

In the aftermath of its presentation at TCT 2017 and its publication in the prestigious Lancet, there has been no shortage of opinion about what clinical impact the study should have in real-world practice. On social media, #ORBITA has been vigorously debated, with physicians sharing angiographic images or details of “ORBITA-like” cases. Full details from ORBITA have been reported, uploaded, and dissected extensively on TCTMD, but the discussion shows no sign of winding down.

Even Darrel Francis, MD (Imperial College London, England), the study’s loquacious senior investigator, opened a Twitter account to join in on the conversation. ORBITA, he reminded TCTMD, is the first randomized, double-blind, placebo-controlled trial comparing PCI plus optimal medical therapy versus optimal medical therapy alone. As such, Francis said, it provides fresh insights as to what symptom benefit can truly be expected following PCI for single-vessel disease.

“When you have a patient in front of you, all you want is the best for them and you don’t care about anything else,” he said. “As a scientist, I’m curious about the true effect size of the various things we do. That’s why we do placebo-controlled studies. That information is for the ‘scientific hat’ only. It’s to inform the ‘clinical hat’ as to what is the right procedure to undergo.”

Francis, an interventional cardiologist, said he fully expected to see a benefit with coronary revascularization and was as surprised as anybody when they failed to find a between-group difference in their primary and secondary endpoints.

The placebo to a physician is like the sternum to the surgeon. You have to get it out of the way to do your work, but afterwards you must put it back. Darrel Francis

Francis pointed out, however, that the role of a physician and scientist differ considerably, and that the placebo effect is one of those things that absolutely separates them.

“The placebo to a physician is like the sternum to the surgeon,” he said. “You have to get it out of the way to do your work, but afterwards you must put it back.”  

Wide and Varied Reactions

Reactions to the ORBITA trial have varied widely, with one editorial saying it was time to downgrade the use of PCI in patients with angina and another physician calling it the “most influential interventional trial in cardiology since streptokinase.”

Others have received it with nothing more than a shrug, saying the study told them very little, or that it was flawed, too small, or too short in duration to be clinically meaningful.

“This study does not change, or should not change, our clinical practice,” Samir Kapadia, MD (Cleveland Clinic, OH), told TCTMD. He said it would be a “disaster” to conclude ORBITA showed no clinical benefit for PCI, arguing such a conclusion would be a “very aggressive interpretation of very flimsy data.”

Nonetheless, the results did take many cardiologists by surprise. 

“Frankly, I was stunned by the result,” said William Boden, MD (VA New England Healthcare System, Boston, MA). “I think the fact that it was a short-term follow-up should have played to the PCI arm, because if you’re not going to see a clear benefit of PCI during the first 6 weeks, there isn’t a whole lot of point following patients for a year or 2, or even 5 years. I’m not even sure having a sample size of 2,000 or 20,000 patients would have changed the outcome here.”

We have to accept the fact that with any intervention, whether it’s a drug intervention, an antianginal intervention, a PCI intervention, or surgery, there can be a procedural placebo or nocebo effect. I think that’s what we see here. William Boden

Boden was the lead investigator for the 2007 COURAGE trial showing that PCI did not reduce the risk of death or major cardiovascular events compared with medical therapy in patients with stable coronary disease. At the time, proponents of revascularization argued that PCI couldn’t have been expected to reduce hard events but rather that PCI’s important role in stable patients is to reduce intractable symptoms. For Boden, ORBITA is therefore an important clinical study, in that it suggests PCI is associated with a significant placebo effect when it comes to symptom improvement.   

“We have to accept the fact that with any intervention, whether it’s a drug intervention, an antianginal intervention, a PCI intervention, or surgery, there can be a procedural placebo or nocebo effect. I think that’s what we see here,” he told TCTMD.

The other key trial still enrolling in this space is ISCHEMIA, a large trial comparing an invasive strategy versus optimal medical therapy alone in patients with moderate ischemia on stress testing. Speaking with TCTMD, ISCHEMIA study chair Judith Hochman, MD (NYU Langone Medical Center, New York, NY), applauded the ORBITA investigators for conducting such a difficult trial. Like Boden and others, she too was taken aback by the results.

“I was not surprised there was some placebo effect—there is always a placebo effect—but I was surprised they were not able, despite the small sample size and the fairly conservative change in exercise the study was powered to look at, to show a difference,” Hochman told TCTMD.

Does FFR Explain ORBITA?

Everybody has a theory as to why the trial was negative, ranging from the types of patients selected to the fact that antianginal therapy was intensively managed with multiple weekly cardiology consults.

Daniel Simon, MD (UH Cleveland Medical Center, OH), said that while the angiographic evidence suggests these were high-grade lesions, the hemodynamic data likely explain the result. For example, while the mean baseline fractional flow reserve (FFR) was 0.69 in both treatment arms, meaning the lesions were hemodynamically significant, patients were not randomized to treatment based on the FFR results. In total, approximately one-third of patients with an FFR of greater than 0.80—the usual cut point for identifying a nonfunctionally significant lesion—were randomized to PCI.

“The explanation for ORBITA is right in the FAME-2 trial,” said Simon. Long-term outcomes from FAME-2 were presented at TCT 2017 immediately following those of ORBITA. “It teaches us that [when looking at] optimal medical therapy compared with optimal medical therapy plus PCI in patients who have ischemia as determined by FFR, medical therapy is not as good,” he explained.

While PCI reduces the need for urgent revascularization and “basically keeps you out of trouble if you actually have ischemia,” FAME-2 showed that if the FFR was negative and the patient did not have ischemia, “they did just fine with medical therapy,” said Simon.

Kapadia agreed, noting that the FAME-2 trial was a larger study with clinical endpoints, the only difference being that patients were not blinded to treatment and there was no “sham” PCI.

“How do you reconcile this?” Kapadia asked. “Even if you’re a skeptic, saying angioplasty doesn’t work, even then I can’t conclude that based on these data. In my practice, I do angioplasty and I have grateful patients. It’s not rocket science for me to figure out if [PCI] works or not. This is a real tragic study in the sense that, scientifically, ORBITA is a novelty with a sham-controlled arm.”

In my practice, I do angioplasty and I have grateful patients. It’s not rocket science for me to figure out if [PCI] works or not. Samir Kapadia

For those patients without FFR-documented ischemia who underwent PCI, Boden accepts this as a limitation of ORBITA, “but I would submit to you that there are probably a lot of people out there in the real world who are getting PCI for normal-FFR lesions as well.”

Overall, Boden said the focus should be on the totality of the data, pointing out that nearly all patients had class II or III angina symptoms for 9 months, on average, and the mean area stenosis by quantitative coronary angiography (QCA) was 84%, which was similar to that in COURAGE. The highly stenotic coronary artery was corroborated by the abnormal FFR or instantaneous wave-free ratio (iFR) data.

“You can slice that seven ways until Sunday, but that’s a significant flow-limiting stenosis,” said Boden. “It wasn’t like it was 0.75 or 0.78. It was 0.69.”

Although 27% of patients with an FFR-negative lesion underwent PCI, Francis doesn’t see this as a downside of ORBITA, arguing that there’s no evidence to show that angina only occurs in lesions with an FFR of less than 0.80. When ORBITA was designed, the purpose was to cover the full spectrum of lesions physicians treat based on angina symptoms in normal clinical practice, which includes those with FFR-negative lesions, said Francis.

Moreover, even the 2017 appropriate use criteria (AUC) for coronary revascularization in patients with stable ischemic heart disease consider PCI “appropriate” if patients have single-vessel disease and ischemic symptoms while taking two or more antianginal medications, which is exactly the type of patient included in ORBITA, said Francis.

Was Medical Therapy Too Good?

Another criticism of ORBITA is that the medical therapy, as practiced in the trial, was simply too good; in real-world clinical practice, ORBITA-type patients are not particularly common and those who mirror the trial’s enrollment criteria don’t typically get this level of attention, with weekly cardiologist contact to help manage their meds. Inevitably, some argue, compliance would drop off over the long term.

Cindy Grines, MD (North Shore University Hospital, Manhasset, NY), told TCTMD that stable patients with single-vessel disease are rare in her practice, making up about 10% of the patients she sees. Moreover, she says that in the real world, 30% of patients are not compliant with medication at 1 month. By 1 year, almost 80% are not taking the drug or are not taking it at its recommended dose.

Boden, for his part, remains puzzled by physicians lamenting how hard it is to maintain patients on optimal medical therapy.

It doesn’t matter if you’re a general cardiologist or an interventional cardiologist, we have to really explain to patients the procedures we’re doing and that they’re being done simply for symptom benefit. Adnan Chhatriwalla

“Yes, it’s hard, but that’s our responsibility as physicians,” he said. “We should be trying to give our patients the best advice and best care we can. All I hear right now is what I heard 8 or 9 years ago [with COURAGE]. ‘Medical therapy is too tough, it’s too hard.’ I want to say, ‘Get over it. It works.’”

Adnan Chhatriwalla, MD (Saint Luke’s Mid America Heart Institute, Kansas City, MO), told TCTMD that ORBITA reinforces how good medical therapy can be for improving patients’ symptoms and that patients should be given the option of medication first.

“It doesn’t matter if you’re a general cardiologist or an interventional cardiologist, we have to really explain to patients the procedures we’re doing and that they’re being done simply for symptom benefit,” said Chhatriwalla. Additionally, patients need to hear that medication can also help with symptoms, with physicians stressing the facts: “It might be more of a hassle—we’ll have to titrate those medications, and you’ll have to be compliant—but it’s probably just about as good as PCI.”

Any discussion around the relative strengths and drawbacks of PCI versus medical therapy is complicated by time constraints, Chhatriwalla added. In the current climate, that conversation may be truncated or skipped when physicians have another 20 patients in clinic to see that day, he added.  

Medical Therapy: Does It Get Short Shrift?

Nearly everyone who spoke with TCTMD said that ORBITA will leave a lasting impression, not the least for being the first placebo-controlled trial in PCI. Many see its legacy in getting physicians to think critically about medical therapy in stable patients, specifically those with disease in a single vessel.

Hochman argued that the reasons patients aren’t optimized on medical therapy prior to undergoing PCI are complex. While it might come down to the patient not wanting to take multiple drugs, some physicians still believe “in their heart of hearts” that they’re preventing important clinical events when stenting a lesion in symptomatic patients with stable coronary disease, she said.

“If you put two and two together—the patient is having angina and I really believe [PCI] is going to improve their clinical outcomes—I think it’s one of the reasons people are not optimizing medications,” said Hochman.

Ajay Kirtane, MD (NewYork-Presbyterian/Columbia University Medical Center, New York, NY), told TCTMD that in his practice, discussions about the role of medical therapy do occur. In the weeks since ORBITA was presented, he’s had conversations about the trial’s findings with several patients, but he had also discussed the COURAGE findings with them previously.

“I think ORBITA is a good trial,” said Kirtane, “and for patients with single-vessel disease, you can give them the choice. I even have patients in my practice who have FFR-positive lesions that I am managing medically and I’m very comfortable doing that.”

On the flip side of that equation, Kirtane said he is frequently referred stable patients who are undertreated. These are patients taking multiple medications who are still symptomatic, and the only thing they can do to feel better is not exert themselves.

“We treat them successfully with PCI and take them off [their] antianginal medication,” he said. “So, I think we need to focus collectively on the patients who are most likely to benefit from an invasive procedure. That involves curtailing PCI when patients could do well with medicines, but it also involves correctly identifying folks in whom medicine is not a great option or in whom medication has failed.” 

“I think we need to focus collectively on the patients who are most likely to benefit from an invasive procedure. That involves curtailing PCI when patients could do well with medicines, but it also involves correctly identifying folks in whom medicine is not a great option or in whom medication has failed.” Ajay Kirtane

To TCTMD, Simon said that optimal medical therapy is the first approach, followed by revascularization if the patient is refractory to treatment. Patients with mild coronary disease, he stressed, are not sent directly to the cath lab. If they have pronounced ischemic burden, they might undergo PCI without a prolonged attempt with antianginal medications, but “generally, people who go to the cath lab are people who have failed medical therapy,” he said.

“The question is, is it optimal?” asked Simon, referring to their medication use. “It then becomes a discussion with the patient. Part of the problem with this is that for a lot of people who don’t have angina, they’ll say, ‘Well, angina doesn’t kill you.’ You can be on three antianginals and take a nitroglycerin if you have angina, and you’re fine. That’s true, but the problem is that a lot of patients say they don’t want to have chest pain playing tennis or running on the treadmill.”

Kapadia agreed, adding that the definition of “responding” to medical therapy depends on the patient’s goals. For example, an 85-year-old patient might be content to move from room to room without chest pain, but younger patients with stable coronary disease have higher expectations. Adding multiple medications, including beta-blockers, which can cause fatigue, to a 50-year-old who wants to exercise can be challenging.

“The reason why we are doctors is that we have to use judgement,” said Kapadia. “There’s expectations when we treat human beings. It’s not a mathematical protocol.”     

The Role of (Social) Media

Before many of those doctor-patient discussions could even have taken place, ORBITA was already erupting on Twitter. In the past, a study would be presented, and it may or may not have been accompanied by an editorial. Subanalyses would then follow, as might letters to the editor. The study would be hashed over in journal clubs, or within a group of physicians, or at the next big meeting.

In ORBITA’s case, Kirtane pointed out, the entire process is accelerated on social media, in real time, not only by doctors but also by journalists and patients.

“I almost view the most important story about this trial to be less about the trial itself and more about the process of how you can get such rapid outbursts of knowledge, analyses, critiques, and even acrimony,” said Kirtane.

Some of the explosive reaction and criticism, said Kirtane, was likely the result of how the study was picked up in the mainstream media. Some major outlets covering the study did not lead with the most nuanced of headlines, he observed, adding that there was also some overextrapolation of the data.

“You can argue with that opinion and it’s worthy of debate, certainly in an academic forum,” he said. “Unfortunately, when we see patients being told [by newspaper articles] that their stents are useless, that’s a tough situation to deal with and that prompted a response to refute some of those claims.”

To TCTMD, Simon stressed that ORBITA looked solely at patients with stable coronary disease, but many patients who read the newspapers or the see the results on the evening news fail to make that distinction. In the days following the presentation of ORBITA and its widespread launch into the public sphere, a number of confused patients were calling their doctors to ask whether their stents were necessary.  

“It’s important for people to definitively understand that opening blocked arteries in the setting of heart attacks is lifesaving,” he said. “And we know that balloons are better than clot-busting drugs and stents are better than balloons. The last thing we want people to think is they don’t need a stent in the setting of a heart attack.”

Kirtane said ORBITA was selected by the Cardiovascular Research Foundation as a late-breaking clinical trial before the results were known. At the time, TCT’s planners had actually expected the results to be positive and slated it to be presented on Thursday, to group it with the 3-year FAME-2 data.

“Social media can be really tough,” said Kirtane. “On the one hand, there were people who had sent direct messages or tweeted, asking why this study was accepted as a late-breaking trial, let alone presented in a featured session. And then there were others saying the only reason it was presented on Thursday [the last day at TCT] was to bury the results.”

Gregg Stone, MD (NewYork-Presbyterian/Columbia University Medical Center), a TCT course director, said the late-breaking trial submissions are peer-reviewed by a large committee for their “relevance, quality, and likely impact.” Whether ORBITA was positive or negative had no bearing on its acceptance as a late-breaking trial or the day it was presented, he said.

“All of the TCT late-breaking trials receive a great deal of attention, regardless of the day of presentation, as is obvious from the amount of press and social media that ORBITA has generated,” Stone told TCTMD. “We do try to group similar randomized trials together, and in this regard, we did feel that its pairing with the long-term results from FAME-2 was logical.”

Will It Change Practice?

While many congratulated the ORBITA investigators for completing a difficult trial, they were split on its impact in clinical care.

“In terms of changing practice, I don’t think it will,” Mamas Mamas, BMBCh (Keele University, Stoke-on-Trent, England), told TCTMD. “Why? Mainly [since] the sorts of patients in ORBITA are a small minority of our case mix. The results don’t apply to patients with more extensive disease, such as patients with much more ischemia who are likely to be much older.” 

Indeed, recent data from the National Cardiovascular Data Registry (NCDR) CathPCI Registry showed that the volume of PCIs for nonacute indications declined from 2010 to 2014. In total, just 14.8% of all PCIs performed in the United States were for nonacute indications and roughly half of those were performed in patients with single-vessel disease. 

Robert Byrne, MBBCh (Deutsches Herzzentrum München, Germany), told TCTMD that ORBITA-like patients—those with single-vessel disease and symptoms—do turn up in the cath lab. He praised the ORBITA investigators for providing angiographic images of the lesions in the Lancet, and said that based on those images, as well as the corroborative FFR data, they appeared to be high-grade stenoses.

That said, Byrne isn’t sure the results will change clinical practice given the study’s limitations. Like others, he questioned whether such aggressive medical therapy could be maintained in the real world and cited the short-term duration of the trial. He also wondered whether the trial might have been underpowered. For him, ORBITA is a small, provocative study that will inform conversations with patients. 

“Do I think this study will form the basis of a study that could perhaps influence guidelines, something larger with clinical endpoints? Perhaps, but I’m not sure if such a study will take place,” said Byrne. “I don’t know if it would be funded. Also, once you’re looking at patients over a much longer time period, say 12 months, you might have difficulty getting approval to leave these types of lesions alone.”

Asked if ORBITA changes her approach, or if she has taken a patient off the table since the trial was presented, Grines said “absolutely not.”

“Anyone who would change their practice based on a 200-patient study does not understand the substantial limitations of clinical trials and the need to enroll much greater numbers,” she said.

Anyone who would change their practice based on a 200-patient study does not understand the substantial limitations of clinical trials and the need to enroll much greater numbers. Cindy Grines

Boden, however, isn’t buying it.

“Should [ORBITA] have an impact on clinical practice?” he asked. “Yes. Will it? No. I say that only based on my experience with COURAGE and BARI-2D, which were both very similar and well-conducted large trials that have continued to show, evidence be damned, we’re not going to use medical therapy. I think it’s sad. It’s a sad indictment of our medical profession that we can’t get over trials that have shown the benefit of medical therapy.”

Francis, meanwhile, understands the shock at the ORBITA results. Yet he was unprepared for criticisms, most of which surfaced online following the study’s presentation, slamming the trial or arguing that such a placebo-controlled trial shouldn’t have been performed.

“When the data don’t match with one’s prejudices,” he told TCTMD, “it is the prejudices that need to be corrected, not the data.”

 

Editor's Note: An earlier version of this story incorrectly attributed a statement by Samir Kapadia to Dan Simon.