Glimpse of the Trials Presented at TCT and AHA 2023

Abstract

In this article, the late-breaking trials presented at TCT and AHA 2023 are briefly described. The trials are described under the headings according to the area of interest of the trial.

TCT 2023

Valvular Heart Disease

PARTNER 3 Trial

Five-year Clinical And Echocardiographic Outcomes from the PARTNER 3 Low-risk Randomized Trial

This trial compared transcutaneous aortic valve replacement (TAVR) with surgical aortic valve replacement (SAVR) in patients with severe symptomatic aortic stenosis (AS) who were at low surgical risk. The results at 1-year follow-up showed that TAVR was superior in terms of the primary composite end point of death, stroke, or rehospitalization compared to SAVR. There was a lower rate of new-onset atrial fibrillation (AF) at 30 days, a shorter duration of hospital stay, and a low Kansas City Cardiomyopathy Questionnaire (KCCQ) score in the TAVR group. Rapid improvement in the New York Heart Association (NYHA) class and 6-minute walk test distance was also noticed. The 5-year follow-up did not show any change in the primary end point. Two important points to be noted here are that the hemodynamic performance of the valve and the occurrence of paravalvular leaks were not significant between the two groups compared to SAPIEN XT, which had a rate of 4.9% at 5 years. Apart from the positive results of the trial, the limitations are also to be considered. The long-term structural valve deterioration was not studied. A follow-up of up to 10 years is needed to conclude the safety of the TAVR valve in these young patients. As the assessment of the end points was not blinded, there can be a bias in the interpretation of the outcome among both groups. The results cannot be generalized, as they apply only to experienced operators and in patients with good transfemoral access and tricuspid aortic valve. This cannot be extrapolated to operators with less experience. The relevance of asymptomatic valve thrombosis was not evaluated, as hypo-attenuated leaflet thickening (HALT) was high at 30 days and at 1 year in the TAVR group compared to the SAVR group. These need to be addressed in the future.

Evolut Low-risk Trial

Evolut Surgical Replacement and Transcatheter Aortic Valve Implantation in Low-risk Patients

After the positive results of the PARTNER 3 trial, this trial of the self-expanding core valve Evolut showed it was non inferior to SAVR regarding the end point of mortality or disabling stroke at 24 months in low-risk severe symptomatic AS (median Society of Thoracic Surgeons Pre Operative Risk of Mortality (STS PROM) > 1.9%). The concerns different from the PARTNER 3 trial were the need for a permanent pacemaker and the occurrence of moderate to severe paravalvular leaks, which were higher with TAVR at 30 days. Disabling strokes, new onset of AF, acute kidney injury, and severe bleeding were higher in the SAVR arm. The gradients were low, and a higher effective orifice area was noted in the TAVR group. These findings were sustained in follow-up for 4 years, with the separation occurring over time.

Both trials emphasize that in patients with severe symptomatic AS and low surgical risk, TAVR performs better than SAVR. Fixing the issue of performance in the long term beyond 10 years is required (efficacy), and the risk of subclinical leaflet degeneration (performance) needs to be studied.

Align Aortic Regurgitation Trial

The JenaValve Trilogy™ Heart Valve System in High Surgical Risk Patients with Symptomatic, Severe Aortic Regurgitation

In this trial, TAVR using the Trilogy transcatheter heart valve (THV) achieved prespecified safety outcomes at 30 days in a cohort of symptomatic patients with severe aortic regurgitation (AR) at high surgical risk. The multicenter, nonblind, single-arm trial included 180 patients with symptomatic AR (3+) who were at high risk for SAVR. Similarly, in a second sample of 180 patients, the 1-year primary efficacy outcome for all-cause death was evaluated. Overall, TAVR employing the Trilogy THV fulfilled the 30-day performance target for safety outcomes (26.7%, p for non-inferiority = .0001), as well as the 12-month performance goal for all-cause mortality (7.8%, p for non-inferiority = .0001). In the final one-third of patients included, the necessity for pacemaker implantation fell to 14% from 26% previously. Similarly, at 1 year, echocardiographic performance and sustained improvement in quality of life and heart failure functional status were observed.

Watch TAVR Trial

Concomitant Left Atrial Appendage Occlusion and Transcatheter Aortic Valve Replacement Among Patients with Atrial Fibrillation

This is the first prospective, randomized controlled trial to investigate a combination of TAVR and Left atrial appendage occlusion (LAAO) methods. The combination of Aortic stenosis (AS) and atrial fibrillation (AF) has been underrepresented in prior LAAO trials, and this trial has filled the management gap. WATCHMAN implantation during TAVR was found to be non-inferior to medical therapy with anticoagulation in patients with severe AS and concomitant AF in terms of the primary composite outcome (all-cause death, stroke, and major bleeding) at 2 years. Despite the increased periprocedural duration and intravenous contrast administration in the TAVR group, the incidence of acute renal damage was comparable across the two arms. At 2 years, only two-thirds of the medical therapy group were taking anticoagulants, and about 8% had switched to LAAO. This indirectly supports the use of the LAAO method in this older population (anticoagulation concerns) to reduce the risk of cardioembolic stroke. The latest generation WATCHMAN FLX implant has the advantage of less post-procedure bleeding and a shorter term of antithrombotic medication (a weakness of previous devices). The downsides are cost-effectiveness and the need for general anesthesia for LAAO in patients with AS, whereas TAVR is performed under moderate conscious sedation. These difficulties should be addressed in future research.

Triscend II Trial

Edwards EVOQUE Tricuspid Valve Replacement: Investigation of Safety and Clinical Efficacy After Replacement of Tricuspid Valve with a Transcatheter Device

In this trial, the safety and efficacy of Transcutaneous tricuspid valve therapy (TTVT) with the EVOQUE system was assessed. Despite more than half having huge or torrential tricuspid regurgitation (TR), the majority saw TR, being eliminated after percutaneous treatment. At 6 months, there was improvement in patient profile considerably. In the upcoming trials, mortality and rates of HF hospitalization are required.

Coronary Artery Disease

Agent IDE Trial

A Clinical Trial to Assess the Agent Paclitaxel-coated PTCA Balloon Catheter for the Treatment of Subjects with In-stent Restenosis

The findings of this research led to the introduction of drug-coated balloons in the United States. In individuals with coronary in-stent restenosis (ISR), drug coated balloons (DCB)s outperformed traditional balloon angioplasty in terms of target lesion failure. More than 40% of patients had several stent layers. When compared to others (SeQuent Please [3 ug mm⁻²]), the agent has a lower dose of Paclitaxel (2 mcq mm⁻²). There is no drug eluting stent (DES) arm for comparison, which is the preferred method in patients with ISR and one layer of stent.

T-PASS Trial

Ticagrelor Monotherapy in Patients Treated with New-generation Drug-eluting Stents for Acute Coronary Syndrome

When compared to 12 months of dual antiplatelet therapy (DAPT), ticagrelor monotherapy after less than a month of DAPT (median of 16 days) was non-inferior in terms of ischemic events and superior in terms of bleeding events in patients with ACS receiving PCI with bioresorbable polymer sirolimus-eluting stents in ACS. As the major adverse cardiac and cerebrovascular events (MACCE) were comparable, the reduction in bleeding episodes was the key cause for the superiority in primary composite outcomes. At 30 days, <10% of individuals in the experimental group were on DAPT. This trial extends the findings of the TICO and TWILIGHT studies, which found that ticagrelor monotherapy after 3 months of DAPT was superior to 12 months in ACS. TICO and T-PASS were conducted only in South Korean centers; hence, the findings cannot be generalized globally. The benefit of abbreviated DAPT in the STEMI subset was demonstrated in additional trials (safety signals). The scaffold is the difficulty of DAPT’s continuation. If no scaffold is present, the DAPT can be as simple as possible.

PICSO AMI I Trial

Pressure-controlled Intermittent Coronary Sinus Occlusion in Acute Myocardial Infarction

Even though primary PCI is beneficial in lowering STEMI symptoms, around 50% of patients have decreased myocardial perfusion and significant myocardial necrosis, which can contribute to elevated major adverse cardiovascular events (MACE). The attempts to minimize the size of the infarct were futile. Following its success in the treatment of refractory angina, the coronary sinus reducer was hypothesized to minimize the infarct size as measured by cardiac magnetic resonance imaging (MRI) when used in conjunction with primary percutaneous coronary intervention (PCI). Its use did not lessen the size of the infarct and resulted in increased procedure duration and contrast utilization (which is not acceptable in acute MI). The gadget, however, proved safe, with no device-related issues.

AHA 2023

Preventive Cardiology

SELECT Trial

Semaglutide and Cardiovascular Outcomes in Overweight or Obese Patients Who Do Not Have Diabetes

Once-weekly subcutaneous semaglutide was linked to a 20% lower incidence of MACE (CV mortality, nonfatal MI, and stroke) during 36 months in overweight or obese patients and established cardiovascular disease (CVD) who did not have diabetes, according to the SELECT trial. Patients who were already taking statins experienced this impact. In the semaglutide arm, drug discontinuation was prevalent due to gastrointestinal intolerance. Prior studies of lifestyle and pharmacologic treatments did not show a significant reduction in the CV risk linked with overweight and obesity. The SELECT trial extends the findings of SUSTAIN-6 and other GLP-1 RA trials, which have shown CV improvement in DM, to this higher-risk cohort. The cardioprotective benefits of GLP-1 RA are not fully understood and are likely complex, as evidenced by the treatment arm’s larger reduction in both systolic blood pressure and incident DM. Given the incidence of prediabetes in the study cohort, as well as the associated interaction on exploratory subgroup analysis, the latter is significant. Based on these findings, subcutaneous semaglutide may play a larger role in secondary CVD prevention in patients without diabetes who are overweight or obese.

Coronary Artery Disease

DAPA MI Trial

A Registry-based Randomized Trial of Dapagliflozin in Patients With Acute Myocardial Infarction Without Diabetes

The findings of this trial shows that dapagliflozin when used in individuals with acute MI (with no history of diabetes or chronic heart failure) has superior cardiometabolic outcomes than placebo. Cardiovascular outcomes, including HF hospitalization, were comparable, although patients on dapagliflozin were less likely to acquire diabetes and lost 1.65 kg over about 2 years of follow-up. 75% of the population had an EF of 50%. The cardiovascular advantages in an acute coronary syndrome group appears to be limited.

MINT Trial

Restrictive Versus Liberal Blood Transfusion in Patients with Myocardial Infarction and Anemia: Results of the MINT Trial

In patients with acute MI and comorbid anemia, the MINT trial found that a liberal transfusion strategy targeting Hb of 10 g dL⁻¹ was not superior to a restrictive target of 7–8 g dL⁻¹ in terms of all-cause death or nonfatal MI at 30 days, despite increased events in the restrictive strategy. There is a scarcity of data to recommend transfusion for acute MI aggravated by anemia. The REALITY trial (n = 668) previously demonstrated the non-inferiority of a restrictive transfusion strategy in MI concerning 30-day major adverse cardiovascular events. However, the study’s authors highlighted that the non-inferiority margin of 1.25 may include clinically meaningful harm. Furthermore, after 1 year, the limited method was no longer non-inferior in a prespecified analysis. Given these findings, the trend toward clinical benefit found in MINT shows that a liberal transfusion strategy in MI may be reasonable to pursue without a considerably higher risk of damage.

ORBITA 2 Trial

Percutaneous Coronary Intervention for Stable Angina: A Randomized, Placebo-controlled Trial

This trial showed that PCI scores over the medical management in improving anginal frequency and exercise times in patients with stable angina. This is in contrast with the ORBITA trial, which found no advantage from PCI in addition to appropriate medical therapy for the primary goal of improving treadmill exercise time. The short duration of follow-up (12 weeks) and relatively small sample size hinder the assessment of important clinical outcomes.

Heart Failure

ARIES HM3 Trial

Avoidance of Aspirin with Left Ventricular Assist Devices in Advanced Heart Failure: Primary Results of the International, Double-blind, Placebo-controlled ARIES HM3 Trial

The ARIES HM3 trial showed that in patients with a HeartMate (HM3) device, a management strategy eliminating aspirin was non-inferior to the combination therapy of vitamin k antagonist (VKA) and aspirin in terms of bleeding and thrombotic events up to 1 year after implantation. Although it is a superiority trial by design, the composite hemocompatibility end point and survival free of bleeding and stroke appeared to favor the placebo group. The authors also found that significant bleeding events reduced cumulative cost and duration of stay in the hospital by 41% and 47%, respectively. Antithrombotic therapy after LVAD implantation has traditionally included both a VKA and an aspirin. The HM3 pump is a magnetically levitated device that has good hemocompatibility when compared to HeartMate II. Previous short observational studies assessing aspirin cessation in HM3 patients with a high risk of bleeding found outcomes equal to the controls for 2 years. ARIES HM3 is the first randomized study to support an aspirin-free regimen in HM3 patients, particularly those at high risk of significant bleeding.

Arrhythmia

AZALEA Trial

Abelacimab, a Novel Factor XI/XIa Inhibitor, Versus Rivaroxaban in Patients with Atrial Fibrillation: Primary Results of the AZALEA-TIMI 71 Randomized Trial

The findings of this phase II trial showed that abelacimab (90 and 150 mg monthly, subcutaneously) is superior to rivaroxaban (20 mg daily) in reducing bleeding episodes in individuals with AF and a high CHA2DS2-VASc score. Abelacimab is a highly selective completely human monoclonal antibody to factor XI. It blocks the activation after binding to Factor XI, which is required for the intrinsic clotting pathway. The benefit is that pathological thrombosis is prevented while physiological hemostasis is maintained.

Another phase II trial found that abelacimab 75 and 150 mg dosages were superior to enoxaparin in preventing VTE after total knee replacement. These are encouraging findings. A phase III trial (LILAC-TIMI 76) compares the safety and efficacy of abelacimab 150 mg to placebo in individuals with AF who are not candidates for anticoagulation.

ARTESIA Trial

Apixaban for the Prevention of Stroke in Patients with Subclinical Atrial Fibrillation

Subclinical AF (including people on ICD who have documented AF) has a 2.5-fold increased risk of stroke or systemic embolism. It is not known whether the use of anticoagulants to prevent them is beneficial or not. This trial offered the solution. Apixaban, as compared to aspirin, lowered the risk of stroke or systemic embolism but raised the risk of serious bleeding in this subset of patients. In these patients, the risk of bleeding with stroke protection will be evaluated.

Lipidology

VERVE 101 Trial

Safety and Pharmacodynamic Effects of VERVE-101, an Investigational DNA Base Editing Medicine Designed to Durably Inactivate the PCSK9 Gene and Lower LDL Cholesterol: Interim Results of the Phase 1b Heart 1 Trial

A single infusion of a CRISPR-based gene editing treatment dramatically lowered LDL-C and PCSK9 levels in patients with heterozygous familial hypercholesterolemia (HeFH) in this new route study. Ten patients with HeFH (average LDL of 201 mg dl⁻¹) from the United Kingdom and New Zealand (8 men/2 women, mean age 54 years) were included in the study. Most of the individuals in this initial human research had pre-existing significant CAD and had already undergone coronary revascularization. Half of them experienced at least one myocardial infarction. All were taking statins, but none were taking PCSK9 inhibitors. Following consultation with an independent safety monitoring board, all patients received a single intravenous infusion of VERVE-101, with the first group (n = 3) getting a low dose of 0.1 mg kg⁻¹ and subsequent cohorts receiving increasing doses. The greatest dose administered was 0.6 mg kg⁻¹. Overall, three individuals who received the highest two VERVE-101 dosages (0.45 and 0.6 mg kg⁻¹) experienced the greatest decreases in LDL-C and PCSK9 protein levels. LDL-C was reduced by 39% and 48% in the 0.45 mg kg⁻¹ group, respectively, as was PCSK9 by 47% and 59%. One patient in the 0.6 mg kg⁻¹ group saw a 55% reduction in LDL-C and an 84% reduction in PCSK9. The reduction in LDL was sustained for 6 months. A new treatment approach with no lipid-lowering drug side effects. It is a single course therap that lowers LDL-C for decades. What is the personal impact? Will the patient still require statins or other medications in the future? What are the consequences of polygenic dyslipidemia? Future experiments will address this issue.

REMAIN Trial 2

Recaticimab Add-on Therapy in Patients with Non-familial Hypercholesterolemia and Mixed Hyperlipidemia: A Multicenter, Randomized, Double-blind, Placebo-controlled Phase 3 Trial

This trial established the long-term efficacy and safety of add-on recaticimab in patients with non-familial hypercholesterolemia and mixed hyperlipidemia who are not effectively managed on steady statin therapy. The medication is a novel PCSK9 inhibitor that is administered every 1–3 months. The trial in China featured 689 participants with an average age of 56 years, with 64% of them being men. This cohort was randomized into three groups, each receiving 150 mg of recaticimab or placebo injection every 4 weeks, 300 mg of drug or placebo every 8 weeks, and 450 mg of drug or placebo every 12 weeks. In terms of results, people who received the drug regardless of the condition had lower bad cholesterol levels at 24 weeks than those who received a placebo (62% vs 0%, 59% vs +1.4%, 51% vs +2%, respectively). At 48 weeks, the the levels remained low. Aside from the injection site reactions, no additional adverse events were observed. Additionally, lipoprotein (a) and apolipoprotein B levels were dramatically lowered. The effect was similar to that of other PCSK9 inhibitors, with the advantage of requiring less frequent doses.

REPRIEVE Trial

Effects of Pitavastatin on Coronary Artery Disease and Inflammatory Biomarkers in HIV: Mechanistic Sub-study of the Randomized Trial to Prevent Vascular Events in HIV

Pitavastatin treatment was superior to placebo in people with HIV who had a low-to-moderate risk of cardiovascular disease. The effect was mediated by lower plaque progression risk, lower lipid oxidation, and lower arterial inflammation. The findings were consistent across all subgroups (gender, geographical region, CD4 level, and so on). The degree of LDL-C decrease predicted the benefit more accurately. When compared to a placebo, muscle-related complaints were more common.

Artificial Intelligence

ARISE Trial

Artificial Intelligence–Enabled Rapid Identification of ST Elevation Myocardial Infarction Using Electrocardiogram: A Pragmatic Randomized-controlled Trial

This trial highlighted the significance of AI in cardiology practice. Following the trial evidence of the benefit of AI in pregnancy (SPEC AI trial: AI stethoscope identified double the number of cardiomyopathy cases compared to the conventional approach) and novel speech analysis technology in monitoring patients with heart failure (SPEECH trial detected 71% impending decompensation 3 weeks before the conventional approach), this trial with AI-driven ECG analysis has shown to shorten the time to arrival from the cath lab. Ejection fraction and length of stay were comparable among treatment groups. This experiment, which included 43,000 patients and used AI technology in conjunction with ECG testing, shortened the time it took to diagnose and transport participants with STEMI to the cardiac catheterization laboratory by 10 minutes. There is an 88% positive predictive value and a 99.9% negative predictive value.

ORFAN Trial

The Oxford Risk Factors and Non-invasive Imaging Study

This trial was a prospective, observational, multicenter research in the United Kingdom that enrolled 250,000 randomly selected patients from the study’s participating centers. The patients were evaluated for the presence of inflammation and the risk of CV events based on the imaging data and demographics provided. The AI-driven risk assessment used the perivascular fat score (fat attenuation index, FAI) to evaluate the inflammatory risk. Higher FAI levels indicate more vascular inflammation and are predictive of future CV events. The researchers validated the performance of FAI and an AI-assisted prognostic model in capturing 8-year residual inflammatory risk using CCTA-derived measures, plaque analysis, and individual risk factors. Patients with high levels of coronary inflammation as indicated by FAI were more likely than those with lower FAI scores to have a MACE event (cardiac death, nonfatal MI, or new HF). Those classified as high/very high risk by the AI-assisted prognostic model had a higher probability of MACE regardless of the existence of obstructive CAD. According to the authors, it resulted in the reclassification of around 30% of patients into a higher-risk category and approximately 10% into a lower-risk category. This experiment reinforces the use of AI in current cardiology practice and encourages cardiologists to look beyond plaque when assessing CV risk.