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PARIS — After the first major prospective study to associate percutaneous intervention (PCI) with symptom relief in stable angina captured international attention, a new analysis of the sham-controlled trial is back in the news showing that it is not necessarily patients with ischemia who respond.

"Symptoms — not the severity of disease — is what powerfully predicts the clinical benefit from PCI," Florentina A. Simadar, MD, a cardiologist with the Imperial College London, United Kingdom, reported at the Congress of the European Association of Percutaneous Coronary Interventions (EuroPCR) 2024.

According to the new results, "the more typical the clinical angina symptoms, the greater the likelihood of angina reduction following PCI," she explained.

Although the anatomical severity of coronary disease has provided the rationale for revascularization even among patients with silent ischemia, this new analysis of data from the ORBITA-2 trial has revealed that lesions are not a useful way to predict symptom relief, she pointed out.

This secondary analysis, presented at EuroPCR and simultaneously published in the Journal of the American College of Cardiology, is the latest step toward understanding the relationship between revascularization and symptom control.

The First ORBITA

In ORBITA, the first of these studies by the same group, PCI was evaluated on top of anti-anginal therapy and was shown to have little effect on exercise time or angina symptom control. However, that study was not sham-controlled.

In the double-blind sham-controlled ORBITA-2 trial, patients with stable angina were evaluated when they were off antianginal therapy. At the end of 12 weeks, the mean daily angina score in the PCI group was half the score in the placebo group, a result associated with a more than twofold increase in the odds ratio (OR) of a reduction in angina (OR, 2.21; P < .001).

Despite the secondary analysis providing compelling evidence that PCI can reduce the burden of angina, nearly 60% of treated patients still reported symptoms. These symptoms persisted despite a revascularization that achieved nearly complete resolution of ischemia. 

The goal of the secondary analysis was to evaluate the source of the residual angina and the heterogeneity of response based on pre-PCI variables and symptom stratification. The "surprising" finding was that there was very little relationship between the nature and severity of symptoms and the physiological severity of ischemia, Simadar said.

Rather, the predictors were a positive response to the Rose angina questionnaire and typical guideline-based angina. The Rose questionnaire captures a classic angina presentation of pain on exertion, such as climbing stairs, that resolves after 10 minutes or so of rest. The pain must also be localized in the sternum, the left chest, the left arm, or any combination of the three.

Rose Questionnaire Predicts Benefits

Guideline-based angina is defined traditionally as chest discomfort induced by physical exertion that is rapidly relieved with nitroglycerin.

"There was little relationship" between angina defined by these criteria and anatomical disease severity measured with quantitative coronary angiography, or between angina and the severity of ischemia measured with stress echocardiography, fractional flow reserve, and instantaneous wave-free ratio, Simadar reported.

These findings fundamentally alter the goal of revascularization performed to relieve angina. It has been reasonably thought for decades that stenotic lesions were the source of symptoms and that relieving the obstruction would relieve the angina. This secondary analysis of ORBITA-2 data explains why this is not true.

If the symptoms are not consistent with Rose angina or guideline-defined angina, "they may not be cardiac in origin," Simadar said. This explains why the relief of stenosis does not always relieve symptoms.

These data have the potential to fundamentally revise how and when PCI will be performed to relieve symptoms in patients with stable angina. The data suggest that an individualized approach to PCI might be needed to screen for the nature and type of symptoms, rather than the extent or severity of the disease, she added.

Findings Not Wholly Unexpected

The findings are not a complete surprise, according to Robert Yeh, MD, professor of medicine at the Harvard Medical School and interventional cardiologist at Beth Israel Deaconess Medical Center, Boston. Clinicians have intuitively understood that baseline symptoms rather than extent of ischemia seem to be a better predictor of benefit from PCI, said Yeh, who is one of two co-authors of an accompanying editorial.

"The findings do suggest that greater focus on ascertaining the quality of the patient's symptoms, rather than anatomical or physiological measures, could improve shared decision-making" about whether PCI is an appropriate step, Yeh and his fellow editorialist, Christina Lalani, MD, cardiology fellow at Beth Israel Deaconess Medical Center, wrote.

Although ORBITA-2 was the first randomized placebo-controlled trial to demonstrate angina relief in patients with stable angina, the secondary analysis reveals that the story is more nuanced. It explains that the high rate of residual angina was confined to patients with atypical angina, and these patients do not respond to revascularization.

This secondary analysis of data from the ORBITA-2 study will require validation, as will the optimal methods of characterizing symptoms in patients with stable angina to identify PCI candidates.

Evidence-based strategies for personalized and targeted care are "critical" for turning these data into new standards for the selection of stable angina patients for PCI, Leh stated.