Here are the trials that I’m looking forward to at the upcoming American College of Cardiology (ACC) Scientific Sessions in Chicago.
The WARRIOR Trial
I am not sure why it is so but about half of all women who present with signs or symptoms of ischemia have no significant epicardial coronary stenosis on angiography. While these patients are often labeled as “normal,” the syndrome named INOCA, or ischemia and no obstructive coronary artery disease, confers an increased future cardiovascular risk.
Only theories exist to explain this increased risk. Perhaps it is microvascular disease, endothelial dysfunction, or some other inflammatory condition.
Investigators from the WARRIOR trial decided not to wait for the biology of INOCA to be sorted out. Instead they will test the value of intensive medical therapy vs usual care in a properly powered outcomes trial. WARRIOR is important not only because it will inform the efficacy of intensive medical therapy in a syndrome that affects millions of patients, but it will also help us understand something not previously understood.
I look forward to the results of this non-industry-funded study of generic inexpensive medicines. We will have to put on our thinking hats though, because we already know that high-dose statin therapy reduces non-fatal cardiac outcomes by about 20%. The three-point endpoint of death, myocardial infarction and stroke, may be statistically positive, but will it be clinically meaningful?
Secondary outcomes of quality of life, healthcare use, and time to return to work may also provide important information about INOCA.
The STRIDE Trial
ACC organizers placed STRIDE, a placebo-controlled randomized trial of semaglutide for the treatment of claudication in patients with peripheral artery disease and diabetes, after WARRIOR in the opening late breaker session. The two trials represent disparate types of medical science. While WARRIOR seeks to understand a common condition and its potential treatment, STRIDE seeks to expand an indication for an expensive drug. One is science, the other marketing.
Among the authors of the rationale and design paper are three Novo-Nordisk employees. STRIDE enrolls about 800 patients with peripheral artery disease and diabetes. The mean BMI is 30 kg/m2.The primary endpoint is walking distance — which is sensitive to blinding. Owing to gastrointestinal symptoms, decreased appetite, and weight loss, patients on GLP-1s are very likely to know their treatment assignment. When patients on semaglutide walk longer distances, it is likely a placebo effect.
The trialists know this. Like many GLP-1 trials (see also SUMMIT), bias-sensitive endpoints — such as walking distance, hospitalization for heart failure, or quality-of-life questionnaires — make positive outcomes (and new indications) more likely. Positive outcomes enhances profit. It’s not nefarious; it’s what industry-led science does. Our job is to avoid being bamboozled.
PROTECT-TAVI Trial
The British Heart Foundation PROTECT TAVI hopes to settle the ongoing uncertainty with embolic stroke protection during transcatheter aortic valve implantation/replacement (TAVI, or TAVR in US parlance). It likely will not.
Embolic protection of the brain after TAVI is one of my favorite areas of evidence-based medicine for two reasons: One is that few trials yield more surprising results than the previous PROTECTED TAVR trial. It’s as if photographic evidence lies. Despite obvious debris on the device after its use, the stroke rates in the 3000-patient PROTECTED TAVR did not significantly differ (2.3% vs 2.9% in the control group). One positive from the “negative” trial was a signal of device benefit for disabling stroke (0.5% vs 1.3%).
The second reason to like this topic is that observational studies suggest both benefit from the device as well as the reason PROTECTED TAVR didn’t show it — namely, a lack of power. David Cohen and colleagues used the STS/ACC/TVT registry to compare outcomes after TAVR with and without embolic protection in more than 414,000 patients. In a clever design using an instrumental variable analysis (site-level preference for device use as the instrument), they found a 13% statistically significant reduction in disabling stroke and a nonsignificant 10% reduction in all strokes with the device.
These findings suggest that PROTECT TAVI will likely be underpowered, despite its planned enrollment of more than 7000 patients (double that of PROTECTED TAVR). If you assume a stroke rate of 3% and relative risk reduction of 10% from the observational study, a trial would have to have nearly 100,000 patients to detect a difference — well short of the 7000 planned enrollment of PROTECT TAVI.
We can hope for signals in disabling stroke or subgroups that may benefit more from embolic protection.
PRAGUE-25 – AF Ablation Faces Another Test
The market share for atrial fibrillation (AF) ablation has grown into the billions. The advent of pulsed field ablation, which makes the procedure faster and perhaps safer, has only enhanced its popularity. For hospitals and industry, AF ablation is akin to a money printing machine. Yet we still do not know the causes of AF, and, as such, procedural efficacy remains flat over the past 20 years.
I am drawn to PRAGUE-25 because it will test ablation against an aggressive program of risk factor management in patients with obesity and AF. The aims in the risk factor management group will be a 10% weight loss, increased physical fitness, and reduction of alcohol consumption. I don’t know about the Czech Republic, where the trial will take place, but this would be a hard trial to do in the US.
The primary outcome will be an episode of AF. Secondary endpoints include AF burden, changes in quality of life and cardiorespiratory fitness, as well as metabolic measures. The design is non-inferiority, which I like, because the risk factor group avoids a major procedure.
AF ablation is a tough intervention to beat when the primary outcome is an episode of AF. Cardiovascular outcomes or quality of life would be better. I give kudos to Pavel Osmancik and his team, because to date, most of the risk factor management evidence is observational. A surprise positive result would surely shake up the electrophysiology field.
FRESH UP Trial –Testing the Dogma of Fluid Restriction
Another of my favorite categories of evidence-based medicine is the testing of dogmas — especially when a less disruptive intervention wins. In 2022, Justin Ezekowitz and colleagues upended the dogma of salt restriction in patients with heart failure when the SODIUM HF trial of low sodium diet found no difference in outcomes.
Fluid restriction is another one of those maximally disruptive principles set out by authority. At ACC, A Dutch team will present results of the FRESH UP trial comparing fluid restriction (1500 cc per day) vs no restriction in stable outpatients with chronic heart failure.
The primary outcome is quality of life assessed by the KCCQ summary score. Secondary outcomes include thirst distress and clinical events. I’d bet on the trial favoring the no-restriction arm.
While I love seeing dogmas reversed, quality-of-life measures have limited value in unblinded studies. And there will not likely be enough clinical events to reassure treatment maximizers that liberal fluid intake is safe. If we are to upend dogma, I wish for trials powered for clinical outcomes.
Overlapping Meetings
I will not be in Chicago because the European Heart Rhythm Association meeting conflicts with ACC. Someday soon, I hope the two organizations fix this problem. Follow theheart.org | Medscape Cardiology for meeting coverage.
John Mandrola practices cardiac electrophysiology in Louisville Kentucky and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence.
COMMENTARY
Mandrola’s 5 Trials to Look for at the 2025 American College of Cardiology Scientific Sessions
DISCLOSURES
| March 25, 2025Here are the trials that I’m looking forward to at the upcoming American College of Cardiology (ACC) Scientific Sessions in Chicago.
The WARRIOR Trial
I am not sure why it is so but about half of all women who present with signs or symptoms of ischemia have no significant epicardial coronary stenosis on angiography. While these patients are often labeled as “normal,” the syndrome named INOCA, or ischemia and no obstructive coronary artery disease, confers an increased future cardiovascular risk.
Only theories exist to explain this increased risk. Perhaps it is microvascular disease, endothelial dysfunction, or some other inflammatory condition.
Investigators from the WARRIOR trial decided not to wait for the biology of INOCA to be sorted out. Instead they will test the value of intensive medical therapy vs usual care in a properly powered outcomes trial. WARRIOR is important not only because it will inform the efficacy of intensive medical therapy in a syndrome that affects millions of patients, but it will also help us understand something not previously understood.
I look forward to the results of this non-industry-funded study of generic inexpensive medicines. We will have to put on our thinking hats though, because we already know that high-dose statin therapy reduces non-fatal cardiac outcomes by about 20%. The three-point endpoint of death, myocardial infarction and stroke, may be statistically positive, but will it be clinically meaningful?
Secondary outcomes of quality of life, healthcare use, and time to return to work may also provide important information about INOCA.
The STRIDE Trial
ACC organizers placed STRIDE, a placebo-controlled randomized trial of semaglutide for the treatment of claudication in patients with peripheral artery disease and diabetes, after WARRIOR in the opening late breaker session. The two trials represent disparate types of medical science. While WARRIOR seeks to understand a common condition and its potential treatment, STRIDE seeks to expand an indication for an expensive drug. One is science, the other marketing.
Among the authors of the rationale and design paper are three Novo-Nordisk employees. STRIDE enrolls about 800 patients with peripheral artery disease and diabetes. The mean BMI is 30 kg/m2.The primary endpoint is walking distance — which is sensitive to blinding. Owing to gastrointestinal symptoms, decreased appetite, and weight loss, patients on GLP-1s are very likely to know their treatment assignment. When patients on semaglutide walk longer distances, it is likely a placebo effect.
The trialists know this. Like many GLP-1 trials (see also SUMMIT), bias-sensitive endpoints — such as walking distance, hospitalization for heart failure, or quality-of-life questionnaires — make positive outcomes (and new indications) more likely. Positive outcomes enhances profit. It’s not nefarious; it’s what industry-led science does. Our job is to avoid being bamboozled.
PROTECT-TAVI Trial
The British Heart Foundation PROTECT TAVI hopes to settle the ongoing uncertainty with embolic stroke protection during transcatheter aortic valve implantation/replacement (TAVI, or TAVR in US parlance). It likely will not.
Embolic protection of the brain after TAVI is one of my favorite areas of evidence-based medicine for two reasons: One is that few trials yield more surprising results than the previous PROTECTED TAVR trial. It’s as if photographic evidence lies. Despite obvious debris on the device after its use, the stroke rates in the 3000-patient PROTECTED TAVR did not significantly differ (2.3% vs 2.9% in the control group). One positive from the “negative” trial was a signal of device benefit for disabling stroke (0.5% vs 1.3%).
The second reason to like this topic is that observational studies suggest both benefit from the device as well as the reason PROTECTED TAVR didn’t show it — namely, a lack of power. David Cohen and colleagues used the STS/ACC/TVT registry to compare outcomes after TAVR with and without embolic protection in more than 414,000 patients. In a clever design using an instrumental variable analysis (site-level preference for device use as the instrument), they found a 13% statistically significant reduction in disabling stroke and a nonsignificant 10% reduction in all strokes with the device.
These findings suggest that PROTECT TAVI will likely be underpowered, despite its planned enrollment of more than 7000 patients (double that of PROTECTED TAVR). If you assume a stroke rate of 3% and relative risk reduction of 10% from the observational study, a trial would have to have nearly 100,000 patients to detect a difference — well short of the 7000 planned enrollment of PROTECT TAVI.
We can hope for signals in disabling stroke or subgroups that may benefit more from embolic protection.
PRAGUE-25 – AF Ablation Faces Another Test
The market share for atrial fibrillation (AF) ablation has grown into the billions. The advent of pulsed field ablation, which makes the procedure faster and perhaps safer, has only enhanced its popularity. For hospitals and industry, AF ablation is akin to a money printing machine. Yet we still do not know the causes of AF, and, as such, procedural efficacy remains flat over the past 20 years.
I am drawn to PRAGUE-25 because it will test ablation against an aggressive program of risk factor management in patients with obesity and AF. The aims in the risk factor management group will be a 10% weight loss, increased physical fitness, and reduction of alcohol consumption. I don’t know about the Czech Republic, where the trial will take place, but this would be a hard trial to do in the US.
The primary outcome will be an episode of AF. Secondary endpoints include AF burden, changes in quality of life and cardiorespiratory fitness, as well as metabolic measures. The design is non-inferiority, which I like, because the risk factor group avoids a major procedure.
AF ablation is a tough intervention to beat when the primary outcome is an episode of AF. Cardiovascular outcomes or quality of life would be better. I give kudos to Pavel Osmancik and his team, because to date, most of the risk factor management evidence is observational. A surprise positive result would surely shake up the electrophysiology field.
FRESH UP Trial –Testing the Dogma of Fluid Restriction
Another of my favorite categories of evidence-based medicine is the testing of dogmas — especially when a less disruptive intervention wins. In 2022, Justin Ezekowitz and colleagues upended the dogma of salt restriction in patients with heart failure when the SODIUM HF trial of low sodium diet found no difference in outcomes.
Fluid restriction is another one of those maximally disruptive principles set out by authority. At ACC, A Dutch team will present results of the FRESH UP trial comparing fluid restriction (1500 cc per day) vs no restriction in stable outpatients with chronic heart failure.
The primary outcome is quality of life assessed by the KCCQ summary score. Secondary outcomes include thirst distress and clinical events. I’d bet on the trial favoring the no-restriction arm.
While I love seeing dogmas reversed, quality-of-life measures have limited value in unblinded studies. And there will not likely be enough clinical events to reassure treatment maximizers that liberal fluid intake is safe. If we are to upend dogma, I wish for trials powered for clinical outcomes.
Overlapping Meetings
I will not be in Chicago because the European Heart Rhythm Association meeting conflicts with ACC. Someday soon, I hope the two organizations fix this problem. Follow theheart.org | Medscape Cardiology for meeting coverage.
John Mandrola practices cardiac electrophysiology in Louisville Kentucky and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence.
Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.
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