Two trials presented at the American College of Cardiology meeting expose the tension between asking important scientific questions and simply getting positive results.
The DapaTAVI trial studied use of dapagliflozin after transcatheter aortic valve implantation (TAVI), and the STRIDE trial assessed semaglutide for the relief of claudication in patients with peripheral artery disease.
At quick glance, both trials seem reasonable. There are manuscripts in The New England Journal of Medicine and Lancet, placebo groups, randomization, and typical looking statistics. I will argue that neither trial asks important scientific questions. Instead, they are designed to get positive results and expand indications for the drugs tested.
DapaTAVI: SGLT2 Inhibitor Post Aortic Stenosis Intervention
In DapaTAVI, just over 600 patients with aortic stenosis who underwent TAVI in numerous Spanish centers were randomized to receive dapagliflozin or standard care at hospital discharge.
Included patients had a history of heart failure plus at least one of the following conditions: chronic kidney disease, diabetes, or left ventricular systolic dysfunction.
These were elderly patients (mean age, 82 years), about half were women, about 1 in 5 patients had a left ventricular ejection fraction < 40%, and nearly 90% had eGFR of 25-75 mL/min/1.73 m2.
The primary endpoint was a composite of all-cause death or worsening of heart failure, defined by hospitalization or an urgent visit at 1 year. The trial delivered positive results — as expected.
There was a 28% reduction in the composite primary outcome in the dapagliflozin arm. (hazard ratio, 0.72; 95% CI, 0.55-0.95; P =.02). The absolute risk reduction was 5.1% (15% vs 20.1%), providing a needed to treat number of 20.
The driver of the composite endpoint was a 37% reduction in worsening heart failure. (9.4% vs 14.4%). The lower rate of all-cause death did not reach statistical significance (7.8% vs 8.9%). The lower rate of cardiovascular death also did not reach significance (4.5% vs 5.3%).
Genital infections and hypotension were higher in the dapagliflozin arm. The authors concluded that dapagliflozin treatment after TAVI led to lower rates of a composite of death and heart failure events.
STRIDE Trial: Semaglutide in Peripheral Arterial Disease
Patients with peripheral artery disease and diabetes who have claudication have few treatment options. In multiple centers in many countries, STRIDE investigators screened more than 1300 patients to enroll 790 in a trial comparing semaglutide to placebo for the treatment of claudication.
Inclusion criteria were quite strict: Patients had to be able to walk pain-free for 200 m on a flat surface at a fixed speed of 3.2 km/h (2 mph) but also had to be symptom limited by 600 m and a fixed incline of 12%.
The primary endpoint was the ratio to baseline of the maximum walking distance at week 52 measured by the constant load treadmill with fixed speed and fixed incline (as above). There were many secondary endpoints, including physical function questionnaires. The median age of patients was 68 years, 27% were female, and the median BMI was 28 kg/m2. About a third of patients were on SGLT2 inhibitors.
The primary endpoint was positive for semaglutide. The estimated median ratio to baseline in maximum walking distance at week 52 was significantly greater in the semaglutide group than the placebo group.
To translate the somewhat complicated results, the semaglutide arm had a 21% increase in maximum walking distance vs an 8% increase in the placebo arm. That is about 26 m or 87 ft more distance with semaglutide. Semaglutide also improved the pain-free walking distance. (median of 14 meters extra). Quality of life scores improved more with semaglutide though the differences were modest. Participants in both treatment groups lost weight between baseline and week 52: There was a mean difference of 4.1kg in the semaglutide vs placebo arm.
The authors concluded that semaglutide increased walking distance and called for more research on the mechanisms of benefit as well as further trials in patients without diabetes.
Comments
I present these two trials in the same column because both were designed for positive results. Both delivered positive results, which will likely lead proponents to seek expanded indications for the two drugs. Yet neither trial added substantially to patient care.
In the DapaTAVI trial, elderly patients with a high prevalence of cardiorenal co-morbidity were given dapagliflozin in an unblinded manner. After a year, dapagliflozin led to fewer heart failure events. There were no significant effects on cardiovascular death or all-cause death. Since “heart failure events” require clinical judgement, the lack of blinding could have affected the results. Drug trials need placebo comparisons.
Yet, I see an even more glaring limitation with DapaTAVI. We know that the SGLT2 inhibitors have a diuretic effect. If you give such a drug to any post-cardiac-procedure patient who has a high prevalence of cardiac or renal disease, you should expect a reduction in future heart failure encounters. We know this from previous trials. The specific procedure in this trial was TAVI, but it could have been cardiac bypass, atrial fibrillation ablation, coronary stenting, or any number of others.
I worry that DapaTAVI will be used to expand the indication to post-TAVI patients. I do not believe the level of evidence supports the indication.
The STRIDE trial tested the effect of semaglutide on a subjective endpoint of walking distance.
When I queried both my vascular surgeon friend and my large language model AI program (Claude), both emphasized the importance of blinding when measuring walking distance on a treadmill. Blinding is important because exercise time is subjective. A motivated patient or treadmill supervisor could easily eek out another few meters — which was the delta in this trial.
Blinding is a big challenge in trials of GLP-1 drugs. The weight loss and gastrointestinal symptoms of this drug class are well established — and likely allow patients to know their treatment arm. The placebo effect then makes assessing something like walking time (and quality of life) difficult. Yet even with possible placebo effects, the increase in walking time and quality of life scores with semaglutide are decidedly modest, and essentially similar to the old drug cilostazol.
Semaglutide proponents would argue that its proven cardiovascular benefits make it a better choice for claudication than the black-boxed-labeled cilostazol. I counter that the small increases in STRIDE could have been due to placebo effect. And semaglutide costs many fold more than cilostazol — or a supervised exercise program.
Do Better
Drug developers can be proud of SGLT2 inhibitors and GLP-1 agonists. It’s good that we have these new treatment options.
While we laud investigators for conducting trials, expansion of drug indications should require methodologically robust studies which deliver clinically meaningful effect sizes.
Neither DapaTAVI nor STRIDE rise to this level.
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
Little Learned From Trials That Are Positive by Design
DapaTAVI and STRIDE
DISCLOSURES
| April 10, 2025Two trials presented at the American College of Cardiology meeting expose the tension between asking important scientific questions and simply getting positive results.
The DapaTAVI trial studied use of dapagliflozin after transcatheter aortic valve implantation (TAVI), and the STRIDE trial assessed semaglutide for the relief of claudication in patients with peripheral artery disease.
At quick glance, both trials seem reasonable. There are manuscripts in The New England Journal of Medicine and Lancet, placebo groups, randomization, and typical looking statistics. I will argue that neither trial asks important scientific questions. Instead, they are designed to get positive results and expand indications for the drugs tested.
DapaTAVI: SGLT2 Inhibitor Post Aortic Stenosis Intervention
In DapaTAVI, just over 600 patients with aortic stenosis who underwent TAVI in numerous Spanish centers were randomized to receive dapagliflozin or standard care at hospital discharge.
Included patients had a history of heart failure plus at least one of the following conditions: chronic kidney disease, diabetes, or left ventricular systolic dysfunction.
These were elderly patients (mean age, 82 years), about half were women, about 1 in 5 patients had a left ventricular ejection fraction < 40%, and nearly 90% had eGFR of 25-75 mL/min/1.73 m2.
The primary endpoint was a composite of all-cause death or worsening of heart failure, defined by hospitalization or an urgent visit at 1 year. The trial delivered positive results — as expected.
There was a 28% reduction in the composite primary outcome in the dapagliflozin arm. (hazard ratio, 0.72; 95% CI, 0.55-0.95; P =.02). The absolute risk reduction was 5.1% (15% vs 20.1%), providing a needed to treat number of 20.
The driver of the composite endpoint was a 37% reduction in worsening heart failure. (9.4% vs 14.4%). The lower rate of all-cause death did not reach statistical significance (7.8% vs 8.9%). The lower rate of cardiovascular death also did not reach significance (4.5% vs 5.3%).
Genital infections and hypotension were higher in the dapagliflozin arm. The authors concluded that dapagliflozin treatment after TAVI led to lower rates of a composite of death and heart failure events.
STRIDE Trial: Semaglutide in Peripheral Arterial Disease
Patients with peripheral artery disease and diabetes who have claudication have few treatment options. In multiple centers in many countries, STRIDE investigators screened more than 1300 patients to enroll 790 in a trial comparing semaglutide to placebo for the treatment of claudication.
Inclusion criteria were quite strict: Patients had to be able to walk pain-free for 200 m on a flat surface at a fixed speed of 3.2 km/h (2 mph) but also had to be symptom limited by 600 m and a fixed incline of 12%.
The primary endpoint was the ratio to baseline of the maximum walking distance at week 52 measured by the constant load treadmill with fixed speed and fixed incline (as above). There were many secondary endpoints, including physical function questionnaires. The median age of patients was 68 years, 27% were female, and the median BMI was 28 kg/m2. About a third of patients were on SGLT2 inhibitors.
The primary endpoint was positive for semaglutide. The estimated median ratio to baseline in maximum walking distance at week 52 was significantly greater in the semaglutide group than the placebo group.
To translate the somewhat complicated results, the semaglutide arm had a 21% increase in maximum walking distance vs an 8% increase in the placebo arm. That is about 26 m or 87 ft more distance with semaglutide. Semaglutide also improved the pain-free walking distance. (median of 14 meters extra). Quality of life scores improved more with semaglutide though the differences were modest. Participants in both treatment groups lost weight between baseline and week 52: There was a mean difference of 4.1kg in the semaglutide vs placebo arm.
The authors concluded that semaglutide increased walking distance and called for more research on the mechanisms of benefit as well as further trials in patients without diabetes.
Comments
I present these two trials in the same column because both were designed for positive results. Both delivered positive results, which will likely lead proponents to seek expanded indications for the two drugs. Yet neither trial added substantially to patient care.
In the DapaTAVI trial, elderly patients with a high prevalence of cardiorenal co-morbidity were given dapagliflozin in an unblinded manner. After a year, dapagliflozin led to fewer heart failure events. There were no significant effects on cardiovascular death or all-cause death. Since “heart failure events” require clinical judgement, the lack of blinding could have affected the results. Drug trials need placebo comparisons.
Yet, I see an even more glaring limitation with DapaTAVI. We know that the SGLT2 inhibitors have a diuretic effect. If you give such a drug to any post-cardiac-procedure patient who has a high prevalence of cardiac or renal disease, you should expect a reduction in future heart failure encounters. We know this from previous trials. The specific procedure in this trial was TAVI, but it could have been cardiac bypass, atrial fibrillation ablation, coronary stenting, or any number of others.
I worry that DapaTAVI will be used to expand the indication to post-TAVI patients. I do not believe the level of evidence supports the indication.
The STRIDE trial tested the effect of semaglutide on a subjective endpoint of walking distance.
When I queried both my vascular surgeon friend and my large language model AI program (Claude), both emphasized the importance of blinding when measuring walking distance on a treadmill. Blinding is important because exercise time is subjective. A motivated patient or treadmill supervisor could easily eek out another few meters — which was the delta in this trial.
Blinding is a big challenge in trials of GLP-1 drugs. The weight loss and gastrointestinal symptoms of this drug class are well established — and likely allow patients to know their treatment arm. The placebo effect then makes assessing something like walking time (and quality of life) difficult. Yet even with possible placebo effects, the increase in walking time and quality of life scores with semaglutide are decidedly modest, and essentially similar to the old drug cilostazol.
Semaglutide proponents would argue that its proven cardiovascular benefits make it a better choice for claudication than the black-boxed-labeled cilostazol. I counter that the small increases in STRIDE could have been due to placebo effect. And semaglutide costs many fold more than cilostazol — or a supervised exercise program.
Do Better
Drug developers can be proud of SGLT2 inhibitors and GLP-1 agonists. It’s good that we have these new treatment options.
While we laud investigators for conducting trials, expansion of drug indications should require methodologically robust studies which deliver clinically meaningful effect sizes.
Neither DapaTAVI nor STRIDE rise to this level.
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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