More Symptoms, Less Extensive Disease in Women With Stable CAD: ISCHEMIA

New findings from the ISCHEMIA trial reveal key differences between men and women when it comes to disease severity and symptoms, with women reporting a greater angina burden than men even though they had less extensive coronary artery disease and less ischemia.

The findings, selected for presentation at the now-virtual American College of Cardiology 2020 Scientific Session due to the continuing threat of COVID-19, suggest that factors other than epicardial obstructive CAD might be responsible for the severity of symptoms in women, according to the researchers.

“Why are women having more symptoms?” asked Harmony Reynolds, MD (NYU Langone Medical Center, New York, NY), the lead investigator of the new analysis. “A simplistic explanation would be that the women are just complaining more, but I don’t think that’s the whole story. I think it really fits nicely with an emerging body of literature that goes against the previous dogma [saying] that in order to have more symptoms, you need more plaque, you need to have a greater percent narrowing, or you need to have a greater number of arteries with plaque.”

Instead, Reynolds said the reasons for the differences in angina burden might be related to differences in how the nervous systems of men and women are “wired,” with women potentially more sensitive to myocardium at risk. It could also be the result of coexisting microvascular coronary disease and/or endothelial dysfunction in women. Other studies have suggested that mental stress is more likely to trigger ischemia in women than in men, and that this mental stress-induced ischemia in women is not related to disease severity in women. 

“It may be related to patient-specific pain sensitivity, different wiring, autonomic function input, or different susceptibility to mental stress,” she said. “It could be any or all of these things.”

Unique Opportunity to Study Obstructive CAD by Sex

To TCTMD, Reynolds said that women are well known to have less severe and extensive coronary artery disease than men and that epicardial obstructive CAD is more common in men. The ISCHEMIA study afforded researchers a unique opportunity to study differences in symptom burden, anatomic disease severity, and ischemia severity between men and women with documented obstructive CAD, which reduced any potential confounding effects that might result when studying a mixed population that could also include women without epicardial CAD.

In ISCHEMIA, 5,179 patients were randomized to a strategy of invasive coronary angiography followed by revascularization, if needed, on top of optical medical therapy (OMT) or to an initial conservative strategy of OMT alone. Randomization was done prior to angiography and blinded coronary CT angiography (CTA) was done in approximately two-thirds of the enrolled patient cohort to either exclude life-threatening left main disease (or disease deemed of comparable severity) or to confirm CAD was present.

Of the 2,262 women and 6,256 men enrolled in the trial—not all were randomized to invasive angiography or OMT—women were more likely to have nonobstructive CAD than men (34% vs 11%; P < 0.001), which was defined as less than 50% stenosis in all vessels on CTA. Similarly, the frequency of at least 50% stenosis was lower in women than in men in every vessel. As such, women were more likely to be excluded from randomization than men.

In the randomized cohort of 1,168 women and 4,011 men, women were more likely than men to have less severe ischemia as documented by stress imaging, a difference driven by the subset of patients who underwent nuclear stress imaging. Compared with men, women were less likely to exhibit severe ischemia, more likely to show evidence of moderate ischemia, and more likely to have mild to no ischemia. Ischemia severity determined by stress echocardiography or exercise tolerance test showed no differences in ischemia severity between the sexes.    

Despite having less extensive CAD on CTA than men, as well as less severe ischemia on stress imaging, women had significantly lower scores on the Seattle Angina Questionnaire’s angina frequency scale, a finding that suggests a greater burden of angina. Compared with 37% of men, only 27% of women reported being free of angina in the last month (P < 0.001). On multivariate analysis, female sex was associated with greater angina frequency (OR 1.41; 95% CI 1.13-1.76).

If women have a higher burden of symptoms, we need to be attentive to that and make sure that we’re giving them enough treatment to help them with their symptoms. Harmony Reynolds

“What makes this ISCHEMIA analysis unique is that we required so much disease,” said Reynolds. “The idea was that if we select for people with the worst disease, would there still be differences between the sexes? And there were. The women were more likely to have single-vessel disease, less likely to have triple-vessel disease, had a little less-extensive ischemia on average, and yet the women had more anginal symptoms. There’s a disconnect there that’s interesting.”     

In terms of the findings, Reynolds said one of the ISCHEMIA trial’s goals was to determine what made patients feel better. In ISCHEMIA, the invasive strategy on top of OMT did not prevent major cardiovascular events, but coronary revascularization with PCI or CABG did improve angina symptoms when compared with OMT alone.  

“When it comes to making people feel better, if women have a higher burden of symptoms, we need to be attentive to that and make sure that we’re giving them enough treatment to help them with their symptoms,” said Reynolds. “We have to be prepared for the idea that that might require perhaps more-intensive medical therapy and lifestyle changes than it might in a man because of a different starting point.”