Abstract
In this second part of the Journal scan of this issue, we provide a brief overview of the late-breaking trials presented at the American College of Cardiology (ACC) Conference held in Atlanta, Georgia, from April 6 to 8, 2024, and their relevance to our daily clinical practice. The trials are categorized under the following headings:
F. Lipidology (VICTORION INITIATE, SHASTA2, Liberate HR, Bridge-TIMI 73A, AEGIS II,)
G. Artificial Intelligence (TACTic, Be Active, Tele ACS)
H. Others (Deposition, Crescent, TACT2)
Lipidology
VICTORION INITIATE Trial
Use of Inclisiran in patients with CVD as an initial strategy
Most patients with atherosclerotic cardiovascular disease (CVD) fail to reach the targeted low-density lipoprotein (LDL) cholesterol levels and are at high risk of recurrent events. This trial evaluated whether initiating Inclisiran immediately as an add-on drug in patients who are unable to reach the targeted levels versus the usual standard of care approach is beneficial. A total of 450 patients were randomized to placebo or inclisiran (284 mg at 0, 90, and 270 days). The primary end point was a change in LDL cholesterol from baseline and statin discontinuation rates. The reduction in LDL cholesterol was 60% versus 7% (placebo). The statin discontinuation rate was 6.0% versus 16.7% in usual care. Inclisiran patients achieved LDL cholesterol < 70 mg/dL in 80% versus 22.4% in usual care and achieved LDL cholesterol < 55 mg/dL 71.6% versus 8.9% in usual care, which was statistically significant.
SHASTA2
Triglyceride clearance drug in hypertriglyceridemia
In a recent trial, the effect of decreasing the production of the apolipoprotein C3 (APOC3) protein on reducing triglyceride (TG) levels was studied. The APOC3 protein is produced in liver cells and inhibits the clearance of TGs from the body. The trial included patients with severe hypertriglyceridemia (>900 mg/dL), most of whom had a history of CVD, diabetes, low high-density lipoprotein (HDL) cholesterol, and high body mass index. The patients were randomly assigned to one of 4 groups, with 3 groups receiving 2 injections of plozasiran at one of 3 doses (10, 25, or 50 mg) and the fourth group receiving 2 injections of a placebo. The study was double-blinded. The primary end point of the study was the per cent change in fasting TG levels from study entry to 24 weeks. Secondary end points included the per cent change in APOC3 at 24 weeks and fasting TG levels at 48 weeks. All patients were followed for 36 weeks after the second dose, for a total of 48 weeks. Only high doses of the drug caused significant changes in TGs. At 24 weeks, plozasiran-treated patients (25 or 50 mg) saw an average reduction in TG levels of 74% compared to the placebo (17%). At 48 weeks, the average reduction was 58% versus 7%. The average reduction in APOC3 was 78% vs 1% at 24 weeks and 48% vs +4% at 48 weeks respectively. Regarding the TG levels, at 24 weeks, 90% had TG levels < 500 mg/dL, and at 48 weeks, it was 77%. The TG levels < 150 mg/dL were achieved in >50% of patients at 24 weeks. Significant and durable dose-dependent reductions in APOC3 and TGs persisted through weeks 48. Overall, the study shows that plozasiran is an effective agent in reducing the risk of hypertriglyceridemia.
Liberate HR
Use of Lerodalcibep in patients at very high risk or high risk for CVD
Lerodalcibep, the third-generation PCSK9 inhibitor, was evaluated for its efficacy in lowering the LDL cholesterol in this placebo-controlled double-blinded trial enrolling patients with high or very high risk of CVD and stable LDL lowering therapy. A total of 966 patients were randomized in 2:1 fashion to placebo or the drug. The mean LDL cholesterol was 116 mg/dL despite >80% being on statins and 16% being on ezetimibe. Compared to the placebo, patients taking lerodalcibep (300 mg, 1.2 mL SC dose once a month for 52 weeks) had a significant reduction in their LDL-C levels and more than 50% of patients achieved a 50% reduction in LDL-C. The drug also reduced non-HDL (47%), apolipoprotein B (APOB, 43%), and lipoprotein a (33%). The study drug was well tolerated with minimal side effects (reactions at the injection site).
Bridge-TIMI 73A
Olezarsen use in Dyslipidemia
Olezarsen targets APOC3, a protein that increases the level of circulating TGs and is linked to an increased risk of CVD. In the Bridge-TIMI 73A study, olezarsen effectively reduced TG levels by at least 50% in patients with hypertriglyceridemia and/or established CVD. Unlike other lipid-lowering therapies, olezarsen also lowered other atherogenic lipoproteins, such as APOB and VLDL, and increased HDL-C levels. The drug was generally well tolerated and did not carry the same risk of thrombocytopenia as its predecessor volanesorsen. Phase 3 trials will investigate whether olezarsen’s effects on atherogenic lipoproteins translate into a reduced risk of CVD, which is still a challenge for current TG-lowering treatments.
AEGIS II
Infusions of CSL 112 APOA1 in Acute MI
Cholesterol efflux is a process where cholesterol is transported from the plaque to the liver for excretion, and it is mediated by apolipoprotein A1 (APOA1). When this process is impaired, patients remain at risk of recurrent events. This is especially the case for patients who have had an acute myocardial infarction (AMI). This clinical trial was conducted to evaluate the effectiveness of a new intravenous formulation of APOA1 in patients who had an AMI and multivessel disease along with other cardiovascular (CV) risk factors. The trial involved 4 weekly infusions of APOA1 (6 g) in these patients. The study found that this treatment did not result in a reduction of major adverse CV events (which include CV death, myocardial infarction, or stroke) over 90 days when compared to the placebo. However, the study did suggest that the treatment could be beneficial for those with elevated baseline LDL-C. It is important to note that this observation is hypothesis-generating, and further research is required to confirm this suggestion.
Artificial Intelligence
TACTic
Use of AI app in prescribing statin over-the-counter
A recent study by the Cleveland Clinic looked into whether statins could be given over the counter to patients using an app that assesses their need for the medicine in line with a physician’s opinion. The study included around 1200 patients who entered their personal information into the app. The app then used guidelines to assess their risk and determine whether or not they required statins. The decision made by the app was confirmed by a physician who was not aware of the app’s decision. In 91% of cases, the self-assessment made by the app aligned with the physician’s decision on whether the patient required statins. The study also found that using 5 mg of rosuvastatin resulted in a 31% reduction in LDL. These results may pave the way for the US Food and Drug Administration approval of 5 mg rosuvastatin as a nonprescription drug.
Be Active
To be active, we have to walk
Regular walking can be beneficial for your heart health. To encourage patients at high risk of heart disease or stroke to walk more, different strategies have been tried. These included gamification (which involves gameplaying, competition, and point scoring) and financial incentives (where people gain or lose money on the basis of their behavior). In this study involving 1062 participants, a wearable device was given to track their daily steps. Participants were randomly divided into 4 groups: controls, behaviorally designed gamification, loss-framed financial incentives, or both. This lasted for 12 months, with an additional 6 months assessed for the sustainability of changes. The step count increased significantly compared to the baseline. At 6 months, the sustained improvement was seen only in the gamification and financial incentive arm. This trial of a home-based intervention to promote physical activity showed that with appropriate techniques, CV risk can be reduced.
Tele ACS
Use of telemedicine in post-ACS patients
This trial was conducted between 2022 and 2023 in London with 337 participants who had an ACS and at least 1 CV risk factor. The trial investigated the use of telemedicine in post-ACS patients and found that the telemedicine arm had lower rates of hospital readmissions, emergency department (ED) visits, unplanned coronary revascularizations, chest pain, and dizziness. The patients in the telemedicine arm were given an ECG belt linked to their smart device, an ambulatory blood pressure monitoring (ABPM) monitor, and a pulse oximeter. Remote assessment by a cardiologist was done in the case of symptoms before referring them to ED. The time to first readmission at 6 months was lower in the telemedicine arm, and the reduction in myocardial infarction was by 15%. Post-ACS patient care can be enhanced by the use of telemedicine and by reducing the need for hospital care.
Others
Deposition
Does topical application of TXA have any benefit over IV TXA perioperatively?
Perioperative bleeding is a significant complication of cardiac surgery, especially when cardiopulmonary bypass (CPB) is used. CPB can trigger inflammation and coagulopathy, leading to more severe bleeding. Intravenous administration of Tranexamic acid (TXA) is a common treatment for perioperative bleeding, but it carries a small risk of seizures. To avoid this risk, topical TXA has been suggested as an alternative. The largest randomized trial to compare both methods was conducted, but it was terminated early because of the increased need for blood transfusions (more than 4 RBC units). The trial would have assessed whether topical TXA offered any neurological benefits (ie, preventing seizures), but the overall primary event rate was much lower in both treatment groups. Therefore, this trial does not provide support for or against the use of topical TXA over intravenous TXA to control perioperative bleeding in cardiac surgery.
Crescent
Mandibular assist device in OSA
In patients with obstructive sleep apnea, the use of continuous positive airway pressure (CPAP) devices can be difficult. However, the use of mandibular advancement devices (MADs) was found to be noninferior to CPAP devices. This trial was conducted in 3 medical centers in Singapore between 2019 and 2022, involving a total of 220 patients with moderate to severe OSA and hypertension. The patients were randomized into 2 groups, one using a MAD device and the other using a CPAP device. The study followed the patients for 6 months, during which they underwent assessments at baseline and 6 months, including ABPM, an Epworth Sleepiness Scale Questionnaire, and blood tests for CV markers. The median age of the patients was 61 years, and 85.5% of them were men. The study found a significant change in MABP in the MAD group compared with the CPAP group, and the adherence to the MAD device was significantly better (56.5% vs 23.2%).
TACT2
Chelation therapy in diabetes: Does the benefit extend from the TACT trial?
The chelating agents are the mainstay of the treatment of metal poisoning. Ethylenediaminetetraacetic acid is the classical chelating agent used for chelating lead and cadmium. Lead replaces the calcium ion and cadmium replaces the zinc. The Trial to Assess Chelation Therapy 2 (TACT2) trial analyzed the effects of edetate disodium-based chelation therapy in diabetic patients who previously suffered from a heart attack. Compared to the TACT trial, which showed moderate benefits at 55 months, TACT 2 did not show improved outcomes. The treatment was given weekly for 40 weeks to 68% of the patients, and at least 20 infusions were received by 78% of them. At a 48-month follow-up, there was no significant difference in the primary outcome between the two groups. This treatment, however, was found to be safe and reduced lead levels at follow-up by 60% compared to placebo. The reason for the varied results between the 2 studies was that the population in TACT 2 had severe diabetes and comorbidities, and low baseline lead levels. It was concluded that this treatment could be beneficial in areas where lead is a major CV and neurological problem, but further large-scale studies are necessary to confirm this hypothesis.
