This transcript has been edited for clarity.
Michelle L. O’Donoghue, MD, MPH: Hi. This is Dr Michelle O'Donoghue, reporting for Medscape. I'm here at the 2025 American College of Cardiology Scientific Session in Chicago to talk about women's heart health and, importantly, the results of the WARRIOR trial. Joining me today are Dr Noel Bairey-Merz, who is from the Barbra Streisand Women's Heart Center at Cedars-Sinai, as well as Eileen Handberg, who is at the University of Florida and is director of cardiovascular research there. Thank you both for joining me.
Understanding INOCA
Taking a step back before we talk about WARRIOR specifically, let's think about where we are in terms of the management of women who have different types of heart disease. We have a well-trodden path for management of coronary disease that is visible to the eye on epicardial imaging, but we have been running into challenges in terms of understanding how to best manage patients, both women and men, who have evidence of ischemia but no clear epicardial disease, at least to the naked eye. What are your thoughts on where the gap has been in our knowledge base, and whether there are differences between women and men in that regard?
C. Noel Bairey-Merz, MD: Thanks for asking. The WISE study, but many studies across the globe now, demonstrate this is a burgeoning epidemic. It's probably about half of ischemic heart disease in women. And men are closely in pursuit, with many angiograms now in the VA CART program demonstrating that almost half also lack obstructive coronary disease, despite evidence of ischemia. So this is a big problem.
We've been studying small-vessel dysfunction for 25-plus years. We did some pharmacologic PROBE trials suggesting that high-intensity statins and a maximally tolerated angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) could be effective treatment because of the often concomitant, nonobstructive coronary disease, as you alluded to. That was the rationale for this, because most of these patients are not treated. Clinical guidelines are lacking; they’re given reassurance, “we’ll treat the risk factors, there’s probably nothing to worry about.”
O’Donoghue: You make such an important point that for all too long, we've been patting people on the back well after they have a coronary angiogram that doesn't demonstrate any clear obstructive coronary disease, but yet we know that ischemia with no obstructive coronary arteries (INOCA) is associated with worse outcomes. It has been a real challenge to know how best to try to reduce risk once that diagnosis is made.
Pivoting to the WARRIOR trial, what was the idea behind the design there?
The WARRIOR Trial
Eileen Handberg, PhD: We wanted to test the question that Noel raised about what's optimal treatment for this population of women. At specialized centers, who've been seeing these women for the past 25 years, we see recurrent hospitalizations use of healthcare resources and have had success with use of high-intensity statin and moderate-dose ACEI or ARB therapy, but never in a randomized trial to prove that the way we manage is correct.
The trial we designed to be pragmatic and real-world, randomizing participants to a high-intensity statin, a moderate-dose ACEI or ARB, and baby aspirin compared with usual care. This was funded by the Department of Defense because about 20% of the military are women. They're trying to get ahead of the curve. They provide care for a lot of retirees and dependents, so they agreed to answer this question, because it could be that therapy is good or not good, but you have to do the trial to get that answer.
O'Donoghue: It's such an important question. How many patients ultimately were enrolled, and how long were we able to follow them for?
Handberg: Our intention was to enroll 4422 people, but then COVID-19 happened, as it happened in many clinical trials in the past several years. We were able to enroll 2476 participants, so we did not meet our recruitment goal owing to all of the issues around access to healthcare institutions and research staff. We were able to follow them out to about 5-6 years. Our original intention was 3 years of follow up on all, but we were not able to make that goal.
O’Donoghue: That is a remarkable duration of follow-up, and certainly a very large trial in this space where we've really been woefully lacking data.
Handberg: Absolutely. It is the largest INOCA trial that exists, and it will provide us the opportunity to give a lot of information about INOCA. It will not be the definitive trial, but it will frame what happens next and where we go from here.
O’Donoghue: What were the topline results?
Handberg: The topline result was that there was no difference between the two arms across the follow-up period, and so we were not able to demonstrate a difference between usual care and intensive medical therapy. But again, we're underpowered, and we had a high contamination rate. We planned for that a priori. We anticipated that about 30% in each group might go the opposite way; we didn't get that high in the usual care group, but it was high enough that, combined with not enough power, we were not able to come up with a definitive answer. So we see this as a neutral trial.
We have learned a lot about prescribing medications, tolerability of these types of medications, and the ability to determine the right population. We enrolled women who had their anatomy defined by coronary angiography or coronary CT angiography (CTA), and what we found was the women who had coronary CTA have fewer comorbidities and a lower-risk profile than the women with coronary angiography. So if we are going to design the next trial to get a definitive answer, we probably have to go after more symptomatic women. We didn't see as much angina as we had anticipated and we had seen in our WISE projects.
Lipids and Blood Pressure
O’Donoghue: One challenge, of course, is to enroll exactly the right patient population in whom you expect to see perhaps the most benefit. Then you have the challenges of COVID that may have also have had an effect, perhaps even on a patient's willingness to follow up on a regular basis.
What do you know about achieved blood pressure and low-density lipoprotein cholesterol values (LDL-C)? Was there a differential achieved between the groups?
Handberg: No. Interestingly, this population was predominantly White, overweight, and postmenopausal. They had comorbidities, but their blood pressures were well controlled. The blood pressures were about 120-125 mm Hg systolic to begin with. They were not overly hypertensive, and their LDL-C was about 96 mg/dL on average. We did see about a 7 mg/dL decrease in LDL-C, but we saw no difference between the two groups in terms of systolic or diastolic blood pressure.
O’Donoghue: Do you know if providers were, in fact, prescribing high-intensity statins? Do you know the intensity of the medical therapy?
Handberg: We do think that would have made a difference. We haven't done all the analysis, but we looked at contamination and did an analysis indicating that if therapy had been optimally deployed, there would be a nonsignificant 25% reduction in major adverse cardiovascular events in the sensitivity analysis.
But again, there was patient inertia. A woman with a systolic blood pressure of 120 mm Hg who's being put on a moderate-dose ACEI might ask, “Why do I need to go on this medication? I'm worried my blood pressure is going to drop too low.” All of this will inform the next trial about how to do this.
We did a smaller PROBE trial where women were on the maximum dose of quinapril, but it was blinded; they didn't know, and they tolerated it, and they had the same kind of blood pressures. I think it's about trial design. This will help us go forward with the next trial.
Next Steps
O’Donoghue: As we think about next steps for the healthcare provider who is caring for a patient with presumed INOCA, would you recommend that they continue the path of first thinking about aggressive statin therapy?
Bairey-Merz: I think this trial should not be interpreted as a reason to pull people off effective ACEI, ARB, or statin medication. Again, we saw no benefit, but we saw no harm, and the majority of these women did have risk factors. And as Dr Handberg says, they came in with very well-controlled blood pressure and lipid levels, frequently already on those medications. So this is not an endorsement, again, to pull people off of medications.
Number two is that this will inform the next trial design. It's an intermediate-risk group, so we're going to need to be thoughtful about enriching a population for risk and whether we try this off-the-shelf strategy. Trying to discriminate groups with generic, easily available meds that are being used for other reasons may be a challenge.
Maybe we have to think about additional strategies. [One may be] ancillary trials, where we will look at plaque composition change in response to the two arms, as well as a secondary analysis looking at artificial intelligence, machine learning on the baseline coronary CTA, as well as the biorepository. We need to find the 0.5% of people who die annually because there are patients at risk in this population.
O’Donoghue: So much important work to do. Congratulations, both, for completing this study, and thank you for all that you're doing to improve women’s health.
Signing off for Medscape. This is Dr Michelle O'Donoghue.
Michelle O'Donoghue is a cardiologist at Brigham and Women's Hospital and senior investigator with the TIMI Study Group. A strong believer in evidence-based medicine, she relishes discussions about the published literature. A native Canadian, Michelle loves spending time outdoors with her family but admits with shame that she's never strapped on hockey skates.
COMMENTARY
Keep Fighting INOCA After Neutral WARRIOR Trial
DISCLOSURES
| April 04, 2025This transcript has been edited for clarity.
Michelle L. O’Donoghue, MD, MPH: Hi. This is Dr Michelle O'Donoghue, reporting for Medscape. I'm here at the 2025 American College of Cardiology Scientific Session in Chicago to talk about women's heart health and, importantly, the results of the WARRIOR trial. Joining me today are Dr Noel Bairey-Merz, who is from the Barbra Streisand Women's Heart Center at Cedars-Sinai, as well as Eileen Handberg, who is at the University of Florida and is director of cardiovascular research there. Thank you both for joining me.
Understanding INOCA
Taking a step back before we talk about WARRIOR specifically, let's think about where we are in terms of the management of women who have different types of heart disease. We have a well-trodden path for management of coronary disease that is visible to the eye on epicardial imaging, but we have been running into challenges in terms of understanding how to best manage patients, both women and men, who have evidence of ischemia but no clear epicardial disease, at least to the naked eye. What are your thoughts on where the gap has been in our knowledge base, and whether there are differences between women and men in that regard?
C. Noel Bairey-Merz, MD: Thanks for asking. The WISE study, but many studies across the globe now, demonstrate this is a burgeoning epidemic. It's probably about half of ischemic heart disease in women. And men are closely in pursuit, with many angiograms now in the VA CART program demonstrating that almost half also lack obstructive coronary disease, despite evidence of ischemia. So this is a big problem.
We've been studying small-vessel dysfunction for 25-plus years. We did some pharmacologic PROBE trials suggesting that high-intensity statins and a maximally tolerated angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) could be effective treatment because of the often concomitant, nonobstructive coronary disease, as you alluded to. That was the rationale for this, because most of these patients are not treated. Clinical guidelines are lacking; they’re given reassurance, “we’ll treat the risk factors, there’s probably nothing to worry about.”
O’Donoghue: You make such an important point that for all too long, we've been patting people on the back well after they have a coronary angiogram that doesn't demonstrate any clear obstructive coronary disease, but yet we know that ischemia with no obstructive coronary arteries (INOCA) is associated with worse outcomes. It has been a real challenge to know how best to try to reduce risk once that diagnosis is made.
Pivoting to the WARRIOR trial, what was the idea behind the design there?
The WARRIOR Trial
Eileen Handberg, PhD: We wanted to test the question that Noel raised about what's optimal treatment for this population of women. At specialized centers, who've been seeing these women for the past 25 years, we see recurrent hospitalizations use of healthcare resources and have had success with use of high-intensity statin and moderate-dose ACEI or ARB therapy, but never in a randomized trial to prove that the way we manage is correct.
The trial we designed to be pragmatic and real-world, randomizing participants to a high-intensity statin, a moderate-dose ACEI or ARB, and baby aspirin compared with usual care. This was funded by the Department of Defense because about 20% of the military are women. They're trying to get ahead of the curve. They provide care for a lot of retirees and dependents, so they agreed to answer this question, because it could be that therapy is good or not good, but you have to do the trial to get that answer.
O'Donoghue: It's such an important question. How many patients ultimately were enrolled, and how long were we able to follow them for?
Handberg: Our intention was to enroll 4422 people, but then COVID-19 happened, as it happened in many clinical trials in the past several years. We were able to enroll 2476 participants, so we did not meet our recruitment goal owing to all of the issues around access to healthcare institutions and research staff. We were able to follow them out to about 5-6 years. Our original intention was 3 years of follow up on all, but we were not able to make that goal.
O’Donoghue: That is a remarkable duration of follow-up, and certainly a very large trial in this space where we've really been woefully lacking data.
Handberg: Absolutely. It is the largest INOCA trial that exists, and it will provide us the opportunity to give a lot of information about INOCA. It will not be the definitive trial, but it will frame what happens next and where we go from here.
O’Donoghue: What were the topline results?
Handberg: The topline result was that there was no difference between the two arms across the follow-up period, and so we were not able to demonstrate a difference between usual care and intensive medical therapy. But again, we're underpowered, and we had a high contamination rate. We planned for that a priori. We anticipated that about 30% in each group might go the opposite way; we didn't get that high in the usual care group, but it was high enough that, combined with not enough power, we were not able to come up with a definitive answer. So we see this as a neutral trial.
We have learned a lot about prescribing medications, tolerability of these types of medications, and the ability to determine the right population. We enrolled women who had their anatomy defined by coronary angiography or coronary CT angiography (CTA), and what we found was the women who had coronary CTA have fewer comorbidities and a lower-risk profile than the women with coronary angiography. So if we are going to design the next trial to get a definitive answer, we probably have to go after more symptomatic women. We didn't see as much angina as we had anticipated and we had seen in our WISE projects.
Lipids and Blood Pressure
O’Donoghue: One challenge, of course, is to enroll exactly the right patient population in whom you expect to see perhaps the most benefit. Then you have the challenges of COVID that may have also have had an effect, perhaps even on a patient's willingness to follow up on a regular basis.
What do you know about achieved blood pressure and low-density lipoprotein cholesterol values (LDL-C)? Was there a differential achieved between the groups?
Handberg: No. Interestingly, this population was predominantly White, overweight, and postmenopausal. They had comorbidities, but their blood pressures were well controlled. The blood pressures were about 120-125 mm Hg systolic to begin with. They were not overly hypertensive, and their LDL-C was about 96 mg/dL on average. We did see about a 7 mg/dL decrease in LDL-C, but we saw no difference between the two groups in terms of systolic or diastolic blood pressure.
O’Donoghue: Do you know if providers were, in fact, prescribing high-intensity statins? Do you know the intensity of the medical therapy?
Handberg: We do think that would have made a difference. We haven't done all the analysis, but we looked at contamination and did an analysis indicating that if therapy had been optimally deployed, there would be a nonsignificant 25% reduction in major adverse cardiovascular events in the sensitivity analysis.
But again, there was patient inertia. A woman with a systolic blood pressure of 120 mm Hg who's being put on a moderate-dose ACEI might ask, “Why do I need to go on this medication? I'm worried my blood pressure is going to drop too low.” All of this will inform the next trial about how to do this.
We did a smaller PROBE trial where women were on the maximum dose of quinapril, but it was blinded; they didn't know, and they tolerated it, and they had the same kind of blood pressures. I think it's about trial design. This will help us go forward with the next trial.
Next Steps
O’Donoghue: As we think about next steps for the healthcare provider who is caring for a patient with presumed INOCA, would you recommend that they continue the path of first thinking about aggressive statin therapy?
Bairey-Merz: I think this trial should not be interpreted as a reason to pull people off effective ACEI, ARB, or statin medication. Again, we saw no benefit, but we saw no harm, and the majority of these women did have risk factors. And as Dr Handberg says, they came in with very well-controlled blood pressure and lipid levels, frequently already on those medications. So this is not an endorsement, again, to pull people off of medications.
Number two is that this will inform the next trial design. It's an intermediate-risk group, so we're going to need to be thoughtful about enriching a population for risk and whether we try this off-the-shelf strategy. Trying to discriminate groups with generic, easily available meds that are being used for other reasons may be a challenge.
Maybe we have to think about additional strategies. [One may be] ancillary trials, where we will look at plaque composition change in response to the two arms, as well as a secondary analysis looking at artificial intelligence, machine learning on the baseline coronary CTA, as well as the biorepository. We need to find the 0.5% of people who die annually because there are patients at risk in this population.
O’Donoghue: So much important work to do. Congratulations, both, for completing this study, and thank you for all that you're doing to improve women’s health.
Signing off for Medscape. This is Dr Michelle O'Donoghue.
Michelle O'Donoghue is a cardiologist at Brigham and Women's Hospital and senior investigator with the TIMI Study Group. A strong believer in evidence-based medicine, she relishes discussions about the published literature. A native Canadian, Michelle loves spending time outdoors with her family but admits with shame that she's never strapped on hockey skates.
Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.
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