ORBITA: PCI Offers No Symptom Improvement Over Sham Procedure

DENVER, CO—Stable angina patients, even those with severe coronary stenosis, who undergo PCI for single-vessel disease fare no better than individuals who undergo a sham procedure when it comes to an improvement in exercise capacity and angina symptoms, according to the results of a new study presented here and published simultaneously in the Lancet.

On the last day of TCT 2017, the ORBITA study provided an intriguing twist to a meeting devoted to coronary revascularization, with investigators suggesting PCI is no better than a placebo when it comes to the improvement of symptoms in stable patients with single-vessel disease.

Lead investigator Rasha Al-Lamee, MBBS (Imperial College London, England), who presented the results during the late-breaking clinical trial session, cautioned against overinterpreting the findings. She pointed out that patients in ORBITA had good left ventricular function and single-vessel coronary artery disease easily treated by angioplasty.

To extrapolate those results to a higher-risk population would be a mistake, she said.

“I would say that this is the first placebo-controlled trial of angioplasty,” said Al-Lamee. “Of course, it’s something that’s interesting and will stimulate debate, and may even be used in guideline discussions, but the guidelines are based on thinking about the whole population.”

That interpretation is already finding some resistance. David Brown, MD, (Washington University School of Medicine, St. Louis, MO), and Rita Redberg, MD (University of California, San Francisco), who wrote an editorial accompanying the study, say the results of the trial are “profound and far-reaching.” For the editorialists, the results show that that there are “no benefits for PCI compared with medical therapy for stable angina, even when angina is refractory to medical therapy.”

Based on the findings, “all cardiology guidelines should be revised to downgrade the recommendation for PCI in patients with angina despite use of medical therapy,” state Brown and Redberg.

Al-Lamee disagreed. “To use [ORBITA] to downgrade angioplasty in the guidelines—and I say this as one of the investigators—would be an incredibly large overreach.”

Speaking with the media, Robert Yeh, MD (Beth Israel Deaconess Medical Center, Boston, MA), called ORBITA a “courageous and well-executed study.” He agreed with the conclusions of the researchers, stating that “in this particular population, with this particular intensity of medical care, in the first 6 weeks it is likely that medical therapy is quite effective for a large number of patients.”

And while the interventional community needs to do a better job in providing medical therapy to patients, Yeh also cautioned against reading too much into the findings. “I will say that to extrapolate this to mean elective PCI is not an indicated procedure is the furthest overreach that I can imagine,” said Yeh. “It’s a very small and hypothesis-generating trial with an interesting result.”  

To TCTMD, Redberg said she would be happy to see a bigger trial, but at this stage she doesn’t think one is needed.

“The data to support the current clinical recommendation is zero,” said Redberg. “There are no randomized controlled trials that show a benefit of PCI on symptoms that have been done blinded. There’s no benefit on MI and there’s no benefit on mortality and there’s no benefit on symptoms. I think the only reasonable conclusion is that we shouldn’t be offering PCI, certainly not routinely for patients with stable angina.” 

The ORBITA Trial

The ORBITA study investigators included 200 patients with angina or equivalent symptoms and at least one angiographically significant lesion in a single vessel appropriate for PCI. Patients were enrolled in a 6-week medical optimization phase that included guideline-directed antianginal therapy. As part of the blinded procedure, all patients underwent a research angiogram, including an assessment of fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR), before randomization to PCI or placebo.   

Regarding the primary endpoint, which was assessed at 6 weeks post-PCI or after the sham procedure, patients treated with PCI had a statistically significant 28.4-second improvement in exercise time while those treated with placebo had a nonsignificant 11.8-second improvement. The between-group difference, however, was not statistically significant. Angina symptoms, assessed with the Seattle Angina Questionnaire (SAQ), also improved in both treatment arms, so much so that there was no significant difference between the PCI- and placebo-treated patients. There was also no between-group difference in quality-of-life improvements.

Investigators did observe a greater improvement in the dobutamine stress echocardiography peak stress wall motion score index—a marker of ischemia—with PCI compared with placebo, however.

To TCTMD, Al-Lamee said there is an assumption that treating an epicardial stenosis observed on angiography will lessen ischemia and symptoms.

“Actually, the link is probably not as simple as that,” said Al-Lamee. “These patients might also have microvascular disease, might have noncardiac chest pain. We see that even in the COURAGE trial and in FAME 2—these patients don’t all become angina-free when you treat them. There’s a significant proportion who keep coming back.”     

ORBITA Reactions

Martin Leon, MD (NewYork-Presbyterian/Columbia University Medical Center, New York, NY), who was not involved in the study, congratulated the investigators on the difficult-to-perform sham-controlled trial. He noted that all patients had very good exercise capacity at the time of their interventions, which would have made it difficult to show an incremental benefit with PCI. The heart-failure trials, for example, exclude such patients with high exercise thresholds given how difficult it is to show a treatment benefit.

Also, at the start of the trial, 97-98% of patients had CCS class II or III angina, but after the 6-week run in during which all patients underwent “medical optimization,” angina symptoms had improved (76%-77% CCS class II or III). Moreover, at the time randomization, the anginal frequency scores suggested individuals had “monthly” angina, noted Leon, meaning it would be very difficult for an intervention to shown an improvement over such a short follow-up period.

“I wouldn’t want people to say PCI doesn’t improve symptoms, that’s really not the message here,” he said. “Given all the caveats of the trial, it allows thoughtful physicians to make decisions about how to treat patients with single-vessel coronary disease.”

Indeed, Ajay Kirtane, MD (Columbia University Medical Center, New York, NY), who chaired the morning press conference, pointed out that prior to randomization, average VO2max of patients in the trial was 25 ml/kg/min,  roughly the same as what you'd find in individuals the same age, with no coronary artery disease.

In ORBITA, "we're basically talking about patients that are not that symptomatic, not that limited," Kirtane said.

For many, the lesson of ORBITA may be the importance of maxing out medical treatment, in patients who can tolerate it,  before proceeding to PCI. To TCTMD, Redberg stressed that most patients who go to the cath lab for PCI have not been optimized on medical therapy, noting there was not even an increase in the use of medical therapy following the publication of COURAGE.

“We have institutions built on it,” she said, referring to PCI. “It’s very hard for people to look at data objectively.”

Moreover, in their editorial, Brown and Redberg argue that PCI is not benign, citing an MI risk following MI of 5%, and the risk of acute kidney injury of 13%.

Kirtane, however, called those numbers “factually incorrect,” telling TCTMD that those estimates are off “by a factor of 10.”

The key, Kirtane continued, is that these results "should not be overextrapolated, and that's my fear," he said. "To me, the editorial does a disservice to the trial, the trial investigators, and to patients."

Two Good Options for Selected Patients

B. Hadley Wilson, MD (Sanger Heart and Vascular Institute, Charlotte, NC), chair of the American College of Cardiology board of governors, told TCTMD that in the nuclear substudy of COURAGE, treatment with PCI was more effective at reducing the total burden of ischemia as measured by SPECT myocardial perfusion imaging.

Like others, Wilson was intrigued by the findings, noting there was a trend toward improved symptoms in the PCI group. “I agree with the investigators, that the relief patients have with PCI is likely a combination of the relief of the blockage but also there can be some residual chest pain that may or may be angina,” he said.

And like everybody else, he was cautious against extrapolating too much from a small clinical trial, noting the results don’t speak to PCI for patients with multivessel disease. He also noted that medical therapy frequently includes ranolazine, an agent that is often expensive given that it’s not always covered by insurance companies.

For Al-Lamee, the results will not necessarily change how she treats patients in clinical practice, but they will certainly alter the discussion.

“In the single-vessel disease patient with good LV function, I’ll tell them there are two options,” she said. “One, an angioplasty procedure, with a small upfront risk, that may reduce the need to have high doses of antianginal medications, or medical therapy.”

Some patients, though, especially the elderly who might not want to take a risk, might be content with medical therapy knowing they’ll gain some relief of angina symptoms. For others, especially given the intensity of drug therapy, the preference may be PCI.

Indeed, in ORBITA, patient-physician interaction was frequent in order to keep prescriptions optimized and to monitor heart rate and blood pressure—a degree of contact that is difficult to maintain in the real world.

Speaking with the media, Yeh said there is a need to avoid analogies that pit interventionalists against general cardiologists or internists in the treatment of patients with stable disease.

“The best interventional cardiologists that I know would be absolutely pleased to send a patient down to buy a pair of shoes even though we sell hats,” said Yeh. “At the end of the day, what we don’t do is sell PCI to patients. What we’re trying to do is offer good care. That includes PCI for some patients, and for others it includes medical therapy.”

In the hours since ORBITA’s presentation, Twitter has exploded with wide-ranging reactions using the hashtag #ORBITA.

 

 

Imp message of #ORBITA might be the power of optimal medical therapy. Patients treated well before randomization. https://t.co/4jpmJUZe3W pic.twitter.com/TFQGRMDmRX

— Harlan Krumholz (@hmkyale) November 2, 2017

 

And if anyone claims “mild disease”, please take a look at the online angios... there is nothing mild about them. Great work from @rallamee

— Ricardo Petraco (@RicardoPetraco) November 2, 2017