More Ischemia on Stress Echo Equals Greater Angina Benefit With PCI: ORBITA

Myocardial ischemia documented by dobutamine stress echocardiography is associated with a significant reduction in the frequency of angina among stable CAD patients undergoing PCI, according to a new analysis from the ORBITA trial.

In fact, the greater degree of myocardial ischemia on stress echo, the greater the improvement in angina symptoms with PCI, report investigators.

“We always prespecified in ORBITA that once we’d done the primary analysis the secondary analyses were going to be based on stratifying [patients] by the prerandomization degree of ischemia,” principal investigator Rasha Al-Lamee, MBBS, PhD (Imperial College London, England), told TCTMD. The researchers, she said, wanted to gauge whether the severity of disease on various modalities—stress echo, fractional flow reserve (FFR), instantaneous wave-free ratio (iFR), and angiography—“would predict the placebo-controlled efficacy of PCI on any of the endpoints in ORBITA.”

In the new analysis, which was published this week in Circulation and is scheduled for presentation at the American Heart Association (AHA) 2019 Scientific Sessions, there were no significant interactions between the prerandomization stress echocardiography score and the effect of PCI on other patient-reported variables, such as freedom from angina, physical limitation, or quality of life, nor on the physician-measured Canadian Cardiovascular Society angina class or treadmill exercise time.

Al-Lamee stressed there are limitations to the secondary analysis, noting that they observed only one significant interaction among a number of clinical endpoints. Nonetheless, the interaction between ischemia on stress echo and the effect of PCI on angina frequency is “biologically plausible,” she said.

“It seems that by the time you see the effect of the angiographic stenosis by wall-motion abnormalities detected by stress echo, the disease is severe enough for PCI to have an impact,” said Al-Lamee. “We thought this important because the impact of stress echo ischemia on symptoms has never before been assessed in a placebo-controlled analysis like ORBITA. It is timely that these results are coming out at the same time as ISCHEMIA but a total coincidence. It will be interesting to see how they relate to the quality-of-life results we see from ISCHEMIA.”

The data examining the impact of baseline myocardial ischemia on patient symptoms with PCI are extremely timely, as Al-Lamee noted, given that the long-awaited National Heart, Lung, and Blood Institute (NHLBI)-sponsored ISCHEMIA trial is scheduled for presentation on Saturday, November 16, 2019, at the AHA meeting in Philadelphia, PA.

In ISCHEMIA, led by Judith Hochman, MD (NYU Langone Medical Center, New York, NY), and David Maron, MD (Stanford University School of Medicine, CA), investigators are testing whether patients with moderate-to-severe ischemia have fewer adverse cardiovascular events when managed using a strategy of invasive cath followed by revascularization with PCI or surgery, if feasible, over optimal medical therapy alone.

In an editorial accompanying Al-Lamee et al’s paper, Leslee Shaw, PhD (Weill Cornell Medicine, New York, NY), Harmony Reynolds, MD (NYU Langone Medical Center), and Michael Picard, MD (Massachusetts General Hospital, Boston), write that ISCHEMIA is also expected to shed light on the relationship between the severity of myocardial ischemia at baseline and the effects of revascularization on symptoms.

These latest ORBITA findings, according to the editorialists, are consistent with prior studies showing a greater improvement in angina symptoms with PCI over medical therapy in patients with stable CAD and show that “ischemia is an important mediator of improved patient symptoms following PCI.” The findings also “suggest that the severity of stress-induced myocardial ischemia plays a role in discerning a symptom benefit with PCI.”  

FFR and iFR Unable to Predict PCI Benefit  

For the uninitiated, ORBITA was the first sham-controlled trial to compare PCI and optimal medical therapy in patients with stable CAD and at least one stenosis of 70% or greater suitable for PCI. At 6 weeks, change in exercise time—the primary endpoint in ORBITA—improved significantly from baseline in patients in both trial arms, and while the change was greater in the PCI group, it was not significantly greater than that seen in the sham-treated patients.

Symptom improvement and quality-of-life scores were also no different between groups, although ischemia as assessed by dobutamine stress echocardiography was significantly reduced with PCI.

In 2018 at EuroPCR, Al-Lamee presented the first of their secondary analyses and showed that invasive functional testing with FFR and iFR was unable to identify stable CAD patients who would benefit from PCI in terms of symptoms and exercise time. The effect of PCI on the improvement in exercise time, after adjustment for prerandomization between-arm differences, showed no interaction with FFR or iFR. There was also no evidence of an interaction between FFR or iFR and the effect of PCI on angina measures. However, investigators did observe that the lower the FFR and iFR values, the larger the magnitude of ischemia benefit on stress echocardiography with PCI compared with placebo.

In ORBITA, prerandomization stress echocardiography scores were available for 98 patients treated with PCI and 85 patients in the sham-controlled arm. The mean prerandomization stress echocardiography score, which is a sum of wall-motion abnormalities within the 17 segments of the left ventricle, was 1.56 in the PCI arm and 1.61 in the placebo arm. Regarding the relationship between the stress echo score and the effect of PCI on the Seattle Angina Questionnaire (SAQ) angina frequency score (P = 0.031 for interaction), patients with a stress echo score ≥ 1 were more likely to have a lower angina frequency score at 6 weeks follow-up with PCI than with placebo (OR 3.18; 95% CI 1.38-7.34).

Interestingly, there was no interaction between stress echocardiography score and the effect of PCI on freedom from angina, which is a binary measurement as opposed to the continuous SAQ score, although there was a trend. “Given the small sample size, we were more likely to have the power to detect between-group differences for a continuous rather than a binary endpoint,” said Al-Lamee.

Explaining the difference between the FFR/iFR and stress echo findings, Al-Lamee said that invasive functional testing measures ischemia further upstream and is a more sensitive measure than stress echocardiography. “It might be that if you pick up ischemia at a very sensitive level, it may not necessarily have the same impact on the patients,” she said. While stress echo is less sensitive, it captures a stage in the disease where PCI can be beneficial.

In their editorial, Shaw, Reynolds, and Picard state that while the severity of baseline ischemia is important for identifying patients who will benefit from revascularization, it is likely not the only variable of importance.

What is currently unknown, write the editorialists, “is whether symptom improvement may only be realized above a threshold severity of ischemic myocardium,” noting that prior studies in stable CAD patients did not require a “given severity of stress-induced ischemia.” As such, low-risk patients with minimal ischemia were enrolled in these trials. ISCHEMIA, which is including patients with moderate-to-severe ischemia as assessed by stress imaging (nuclear, echocardiography, or MRI) or exercise ECG, may help fill in some of the current information gaps.