PCI Benefits Stable Patients More in Focal vs Diffuse Disease: ORBITA-2

Patients with stable angina and a focal disease pattern, as opposed to more diffuse coronary disease, stand to gain the most from coronary revascularization, according to a new analysis of ORBITA-2.

The largest placebo-controlled benefits of PCI, specifically angina relief, were observed in patients with the most focal disease, with investigators led by Kayla Chiew, MBBS (Imperial College London, England), reporting in JACC that disease pattern was a strong modifier of the response to PCI.

“We saw that if people have focal disease, they were much more likely to have symptom improvement with PCI than if they have diffuse disease,” senior investigator Rasha Al-Lamee, MBBS, PhD (Imperial College London), told TCTMD. “Also, if they have focal disease, they’re more likely to have typical Rose angina symptoms. We’ve seen from previous ORBITA-2 analyses that [the presence of Rose angina] predicts symptom improvement.

“So, it kind of tells a story that once you are in the cath lab, you can take a physiological assessment and that’s obviously an important part of your decision-making,” Al-Lamee explained. “But, if you assess a focal pattern of disease, it’s much more likely you can improve that patient’s angina with a stent.”

Diffuse disease, on the other hand, may be “better left alone and treated with medical therapy,” she said.

ORBITA-2, which was published in 2023, showed that PCI significantly reduced angina symptoms when compared with a placebo procedure. That trial followed ORBITA, a 2017 study in stable angina patients that had previously found no difference between PCI and a sham procedure when it came to treadmill exercise time or angina. Unlike ORBITA, though, ORBITA-2 was better able to isolate the treatment effect of PCI by eliminating background antianginal medications during the prerandomization phase.

While PCI for patients with stable coronary artery disease can improve symptoms, it isn’t as effective in every patient, said Al-Lamee. “In some it’s very effective, and in some it’s less, and we need to get to the place where we can target PCI to the right patients.”

Pinpointing Focal vs Diffuse Disease

A prior analysis of ORBITA, the earlier trial, found that PCI of focal lesions resulted in a greater reduction in ischemia on stress echocardiography compared with diffuse disease, but there was no impact on angina relief.

“Of course, the symptom endpoint [in ORBITA] was largely neutral between the two study arms, but this time, in ORBITA-2, where the symptom data was very positive for PCI, albeit in a proportion of patients on no antianginal therapy, we wanted to do the same analysis again to see whether a pattern of physiological disease predicted PCI efficacy,” Al-Lamee said.

The ORBITA-2 study, conducted at 14 sites in the United Kingdom, included 301 patients (mean age 64 years; 79% male) randomized to PCI or a placebo procedure. Of these, 118 patients in the PCI arm and 127 in the placebo group had prerandomization instantaneous wave-free ratio (iFR) or resting full-cycle ratio pullback assessments from 300 target vessels. The pressure-wire pullbacks allow operators to measure physiology along the vessel length and to better discriminate between focal and diffuse disease.

Seven interventional cardiologists assessed each pullback trace to categorize the disease as focal, diffuse, or mixed. The disease patterns were quantified as continuous variables, with the mean score determined by the assessor’s evaluation (0 = diffuse, 1 = focal, and 0.5 = mixed disease). In the PCI arm, 79 had focal disease and 39 had diffuse disease. In the placebo group, 79 and 48 had focal and diffuse disease, respectively.  

The angina symptom score and number of daily angina episodes were reduced with PCI compared with placebo. With both endpoints, there was “strong evidence of an interaction between disease pattern,” say investigators, with focal disease associated with a greater treatment response to PCI with respect to symptom score (OR 1.80; 95% CI 1.48-2.18; probability of benefit > 99.9%) and daily angina episodes (OR 1.55; 95% CI 1.26-1.81; probability interaction > 99.9%).

There was also a strong interaction between disease pattern and the placebo-controlled effect of PCI on several measures of the Seattle Angina Questionnaire (angina frequency, physical limitation, quality of life, and treatment satisfaction) as well as quality-of-life metrics, such that focal disease was associated with a larger treatment effect. Focal disease was also associated with an increase in treadmill exercise time and physician-assessed symptoms.

Overall, the probability of Rose angina was strongly linked to focal disease. When stratified by angina phenotype, the interactions between disease pattern were largely seen in those with Rose angina.

Angiogram Not as Informative

One aspect of the analysis highlighted by Al-Lamee is that all ORBITA-2 patients had been indicated for PCI based on the coronary angiogram.

“Then, when you actually do the pressure wire, you find there’s more diffuse disease than you imagine. What we found with those patients is that PCI has almost the same efficacy as a placebo procedure,” she said. “You often end up finding diffuse disease that you didn’t expect, and where you find that, you should probably just treat that patient with conservative therapy.”

Angiography, she added, can be used to visually gauge disease patterns, but it has poor sensitivity for teasing out whether a patient has diffuse or focal disease. Physiology, on the other hand, can provide more information than a binary cutoff to guide PCI and can be used to evaluate disease patterns that might not have been expected from the angiogram. The pressure-wire pullback is very intuitive, and “you can understand what’s very focal,” said Al-Lamee. “I would encourage people to really look at that.”  

Past randomized trials in stable patients, such as COURAGE and ISCHEMIA, have not demonstrated any benefit on hard clinical outcomes, but those studies also never considered coronary disease patterns, said Al-Lamee.

“It’s possible that PCI was less effective than you might expect because patients have been recruited who wouldn’t get a benefit from PCI,” she said. “They might have a pattern of disease that can’t be fixed by a stent.”