Experts Review Clinical Trials in Cardiovascular Death, Antiplatelet Therapies

In a session of featured clinical research at the American College of Cardiology 2022 Scientific Sessions (ACC.22), Deepak Bhatt, MD, MPH, reviewed data from both the SCORED trial of sotagliflozin and the REVERSE-IT trial investigating bentracimab to reverse the antiplatelet effects of ticagrelor.

In the first presentation, Bhatt said there have been multiple trials supporting the use of sodium-glucose co-transporter 2 (SGLT2) inhibitors, which protect the heart and the kidneys. Unlike typical SGLT2 inhibitors, however, sotagliflozin inhibits both SGLT2 and SGLT1, which is expressed in the kidneys and gut. By inhibiting SGLT1, Bhatt said the absorption of glucose is slowed.

The SOLOIST trial compared sotagliflozin versus placebo in patients with diabetes and hypertensive heart failure (HHR), which showed significant reductions in urgent cardiovascular-related visits in favor of sotagliflozin. The SCORED trial compared sotagliflozin versus placebo with the same primary endpoint, but included outpatients with diabetes and chronic kidney disease, as well.

According to new data presented at ACC.22, researchers in the SCORED trial found a similar result to the SOLOIST trial, with a large and significant benefit. Major adverse cardiovascular events (MACE) were significantly reduced in the SCORED trial, in addition to total cardiovascular deaths, non-fatal myocardial infarctions (MIs), and non-fatal strokes. Notably, researchers found an early effect significant by 94 days. Total fatal or non-fatal MIs and strokes were each significantly reduced, with 0.68 and 0.66 hazard ratios, respectively, in the overall trial.

The investigators also analyzed subgroups of patients either with or without a history of cardiovascular disease at baseline and found similar results in both groups. Each subgroup had more than 5000 patients and multiple post-hoc sensitivity analyses yielded similar results.

In the subgroup of patients with a history of cardiovascular disease, patients had a hazard ratio of 0.79 for MACE with sotagliflozin, compared to a hazard ratio of 0.74 in the subgroup of patients with no history of cardiovascular disease. Similarly, the hazard ratio for total MI was 0.69 in the group with a history of disease, compared to 0.66 in those without a history of cardiovascular disease. Finally, the hazard ratio for total stroke was 0.69 in the subgroup with a history of disease and 0.62 in the subgroup without a history of cardiovascular disease.

These findings were also consistent for MACE across vascular beds, with hazard ratios of 0.79 for those with coronary artery disease, 0.72 for those with cerebrovascular disease, and 0.77 for those with peripheral artery disease.

Adverse events (AEs) of special interest were similar with findings across the SGLT2 inhibitor class of medications. Bhatt noted that there was a significant increase in diarrhea from 6% to 8.5%, mostly likely due to the expression of SGLT1 in the gut. Proportions considered serious were similar between the subgroups and AEs generally did not lead to treatment discontinuation.

Importantly, Bhatt noted that the SCORE trial was stopped early in the context of COVID-19, which shortened the duration and limited the statistical power to see significant reductions in cardiovascular death. This also limited the magnitude of absolute risk reductions in MACE.

Next, Bhatt turned to a discussion of bentracimab, which was found to significantly reverse the antiplatelet effects of ticagrelor in older adults. Ticagrelor has substantial data with a broad label, Bhatt said. It is an oral P2Y¹² inhibitor that is effective in patients with acute coronary syndromes, prior myocardial infarction, high-risk coronary artery disease, transient ischemic attack, and stroke.

As with other antiplatelet drugs, however, spontaneous major bleeding and bleeding associated with urgent or emergent invasive procedures are significant concerns. Importantly, the antiplatelet effects of ticagrelor cannot be reversed with a platelet transfusion, necessitating a rapid-acting reversal agent, such as bentracimab.

Bentracimab is a recombinant human IgG1 monoclonal antibody fragment that binds to free ticagrelor with high affinity and specificity. This bonding allows adenosine diphosphate to activate platelets while the bentracimab:ticagrelor complex is eliminated from the bloodstream.

In the REVERSE-IT trial, researchers investigated the antiplatelet effects of ticagrelor with bentracimab in at least 200 patients who presented with uncontrolled major or life-threatening bleeding, or who require urgent surgery or invasive procedures. Enrollment is ongoing in North America and Europe, and patients with use of ticagrelor within the prior 3 days who require urgent reversal are eligible for enrollment.

According to an interim analysis summary, bentracimab provided immediate and sustained reversal of the antiplatelet effects of ticagrelor. Rate of effective hemostasis were adjudicated as good or excellent in more than 90% of cases, with no drug-related serious AEs or allergic or infusion-related reactions. These benefits were consistent in all prespecified subgroups, including those undergoing surgery or with major bleeding.

Based on the findings, Bhatt said bentracimab significantly restored platelet function as measured by multiple assays. No thrombotic events or serious AEs were reported in volunteers randomized to bentracimab, which Bhatt said confirms the safety profile. An assessment of bentracimab’s clinical effect on patients with bleeding will be undertaken after completion of the REVERSE-IT study.

REFERENCE

Bhatt, D. Featured Clinical Research. Presented at: American College of Cardiology 2022 Scientific Sessions. April 2, 2022.