Many trials are published each year, and it can be hard to keep up with their results and separate the proverbial wheat from the chaff. These are my takes on some major trials from last year.
SELECT trial
Semaglutide 2.4mg in a large 17,604 RCT with established CAD, without diabetes and a BMI greater than 27 showed a 20% reduction in CV death, non-fatal MI or non-fatal stroke at a mean follow-up of 40 months. Oral Semaglutide is now available in other countries with similar HbA1c reductions compared to liraglutide with greater reductions in HbA1c compared to SGLT2 antagonists.
Greater weight loss was achieved with Semaglutide compared to liraglutide. Downsides include GI intolerance and cost. The recently published results of the SURMONT-4 withdrawal trial underscores the challenge of weight regain when the drug is stopped.
Two meta-analyses have shown that Tirzepatide (dual GLP-1 and GIP receptor agonist) to be more effective in weight loss. We eagerly await trials on Tirzepatide demonstrating CV protection.
NOAF-AFNET 6 and ARTESIA
These two trials have challenged the idea of anticoagulation in patients with subclinical AF detected on implantable cardiac devices.
NOAF-AFNET randomly assigned 2500 patients over the age of 65 lasting for at least six minutes detected by cardiac implanted devices who had at least one additional risk factor for stroke. The mean duration of AF was 2.8 hours. The trial was stopped early at 21 months because of perceived excess bleeding in the Edoxaban arm (31% increased risk, or 5.9% per patient-year vs 4.5% per patient-year). There was a small 19% reduction (4% vs 3.2% per patient-year) in the primary endpoint of stroke, systemic embolism and CV death.
ARTESIA randomly assigned 4000 older patients with a short-lived device detecting AF to apixaban vs aspirin (median duration, 1.5hours). After 3.5 years, Apixaban reduced the primary endpoint of stroke and systemic embolism by 37% (0.78% per patient-year vs 1.24% per patient-year) but increased major bleeding by 80% (1.71% per patient-year vs 0.94% per patient-year).
Both trials demonstrated a reduction in thrombotic events but an increase in bleeding rates. The biggest discovery was the low stroke rates in both trials. What we need now is an analysis correlating duration of AF and net clinical benefit. Some experts have suggested using 24 hours as a cut-off.
ORBITA-2
This trial randomised 300 patients with stable coronary artery disease without anti-anginal therapy to Percutaneous Coronary Intervention (PCI) or placebo-PCI (sham control arm). Not surprisingly, the mean anginal symptom score was significantly lower in the PCI group.
PARTNER three-five year follow up and EVOLUT four year results
Longer term data on TAVR (Transcatheter aortic valve replacement) in low-risk surgical patients were published. In the PARTNER 3 trial of balloon expandable TAVR, the short-term benefit of TAVR neutralised over time. Death, stroke and rehospitalisation were all similar and valve haemodynamics matched those of surgical implanted valves. There was more aortic regurgitation in the TAVR arm.
The Evolut low risk four-year results for self-expandable TAVR still demonstrated a benefit for death and stroke compared to SAVR (Surgical aortic valve replacement). Valve haemodynamics were also better in the TAVR arm. New permanent pacemaker rates remained higher in the TAVR arm.
Both trials will continue to follow patients.
It is hard not to be impressed with the technological advancements in the transcatheter aortic valve space and it will be interesting to see the results of the seven and ten-year follow-up.
CLEAR-OUTCOMES Trial
This trial randomised 14,000 patients at increased CV risk, who were intolerant or unwilling to take statins to Bempedoic acid vs placebo. At a median duration of 40.6 months, there was a 0.75mmol/L reduction in LDL. There was a 13% relative reduction in death, MI stroke and revascularisation – 1.6% absolute risk reduction. This gives us another alternative to those who are unable to take statins. Other options now include Inclisiran (awaiting large ORION-4 trial) and oral PCSK9 inhibitors (showed good reductions in LDL in phase 2 trial).
Key messages
- Obesity poses a significant challenge, and it is crucial to underscore the numerous benefits offered by GLP-1 agonists
- Not all AF is the same and those subclinical episodes detected on devices seem to confer a low stroke rate. Analysis correlating duration and net clinical benefit of anticoagulation is needed
- PCI can be offered for stable coronary artery disease for symptom relief particularly those who fail medical therapy or are intolerant of medications.
Author competing interests