Brief Overview of the Late-Breaking Trials Presented at ACC’24: Part 1

Ultimate DAPT

After DAPT for 1 month, is monotherapy as efficacious as DAPT for the next 12 months?

Results of this clinical trial showed that ticagrelor monotherapy is safe and does not increase the risk of bleeding or thrombosis in patients who have undergone percutaneous coronary intervention (PCI), following 1 month of dual antiplatelet therapy (DAPT). The trial was conducted across 58 medical centers in China, Pakistan, Italy, and the United Kingdom, and included a randomized sample of 3400 patients. Participants were predominantly Chinese (88%), with a median age of 62 years and 74% being men. Most patients had single-vessel disease, and 97% underwent transradial access. The incidence of clinically relevant bleeding was almost 50% lower in the monotherapy group than the DAPT group (2.1% vs. 4.6%, P < .0001), whereas major adverse cardiac event (MACE) rates did not differ significantly between the two groups. Patients who were stable after 1 month of DAPT were found to benefit from switching to ticagrelor monotherapy, but the study did not investigate patients with diffuse disease, multivessel disease, use of more than 2 stents, or with unaddressed lesions. It is important to note that the majority of participants were from China and Pakistan, limiting the global applicability of the study. For now, as per the trial in stable patients with single-vessel disease post PCI, after one month of DAPT can be safely switched over to ticagrelor monotherapy .

DanGer Shock

Impella CP in patients with cardiogenic shock: Benefit or harm?

This is an important trial that studied a population that has been difficult to research. Many observational studies have indicated harm with Impella CP use in this patient population. Other mechanical circulatory support devices such as intra-aortic balloon pump and venoarterial extracorporeal membrane oxygenation failed to show a benefit with routine use in this group. However, the results of this trial showed that implanting Impella CP routinely in addition to standard care is more effective in reducing 6-month mortality among patients with ST-segment elevation myocardial infarction (STEMI) and cardiogenic shock than the standard care alone. In over 50% of patients, Impella CP was placed before revascularization. One limitation is that it took the investigators 10 years to enroll 355 patients across 3 countries. Inclusion criteria were strict, and blinding was not possible. The risk of complications (bleeding, limb ischemia, need for renal replacement therapy, and sepsis) was higher with Impella CP. Among the patients who survived, these complications could impact long-term mortality. Future utility analysis from a patient-centered standpoint will be helpful. Using smaller Impella CP sheaths may help reduce these complications in the future. Overall, contrary to the literature available in this subset, this trial supports the careful use of Impella CP among patients with STEMI and cardiogenic shock.

REDUCE AMI

Beta-blockers in acute MI with preserved LVEF

This clinical trial conducted in Sweden, Estonia, and New Zealand enrolled around 5000+ patients (median age of 65 years, and 22.5% women) between 2017 and 2023 at 45 centers. The patients had a history of myocardial infarction with preserved left ventricular ejection fraction (LVEF > 50%) and coronary artery disease (CAD). The trial aimed to study the effect of long-term treatment with beta-blockers (metoprolol or bisoprolol) on the risk of death or myocardial infarction (MI). The results showed that after a follow-up of 3.5 years, the primary composite endpoint of death from any cause or new MI did not differ between the 2 groups (HR 0.96, P = .06). There was no significant difference in the secondary endpoints either. Therefore, the study concluded that beta-blockers do not lower the risk of death or myocardial infarction in such patients. However, it is important to note that beta-blockers have other benefits and should not be removed from secondary prevention aspects without further evaluation.

EMPACT-MI

Early initiation of Empagliflozin in acute MI for HF prevention: Any benefit?

The EMPACT-MI study was conducted between 2020 and 2023 at 451 sites in 22 countries to determine whether the SGLT2 inhibitor empagliflozin can reduce the risk of hospitalization for heart failure (HF) or death from any cause among patients with an increased risk for HF following acute myocardial infarction (MI). The study included 6522 patients with a median age of 63 years, of which 24.9% were women and most were White (83.6%). All patients had been hospitalized for an acute MI and were at risk of HF caused by a newly reduced LVEF (<45%) -78.4% or congestion (57%). Within 14 days of admission, patients were given either 10 mg of empagliflozin or a placebo in addition to standard care. After 17.9 months, the study found that the first HF hospitalization or any cause of death did not differ among both groups (8.2% vs. 9.1%). However, when analyzed for the reduction in first HF hospitalization, it was found to be reduced 25–30% in empagliflozin group (3.5% vs 4.7%, HR –0.77). Adverse events were similar in both groups and consistent with the known safety profile of empagliflozin. Among patients at increased risk for heart failure after AMI, treatment with empagliflozin did not lead to a significantly lower risk of a first hospitalization for heart failure or death from any cause than placebo.

ORBITA COSMIC 2

Coronary sinus reducer effect in refractory angina

In the ORBITA-COSMIC study, the coronary sinus reducer was found to be no better than a placebo procedure in improving the primary outcome of stress myocardial blood flow in ischemic segments in patients with angina (stable CAD), and no further options for antianginal therapy. However, the use of the device did show a reduction in anginal episodes, as detected on the ORBITA app. This effect was notable at 10 weeks and sustained for 6 months. It is worth noting that this reduction in angina was observed despite the patients already receiving intensive antianginal medication, with the median number of drugs taken during the trial being three.

PREVENT Trial

Is stenting non-flow limiting vessels beneficial for patients with vulnerable plaque compared to medical therapy?

Over the years, there has been a shift in coronary interventions from traditional anatomic-driven (stenosis-related, angiographic) to flow-driven (physiology, pressure change) and now to morphology-driven (imaging) concept. In this trial, patients with chronic coronary syndromes were randomized to preventive PCI plus optimal medical therapy (OMT) or OMT alone in patients with image-guided vulnerable plaques (non-flow limiting, fraction flow reserve (FFR) >0.80) but had a stenosis of more than 50%. At 2 years, the PCI was more effective than OMT in all subsets, which was statistically significant, thus supporting the benefit of preventive PCI (the effect was minimal). The trial cannot be generalized because the study cohort is of stable ischemic heart disease, it was conducted in four countries (not done globally), and the risk of events in vessels with stenosis < 50% (which can be vulnerable) was not assessed. Global studies and varied population studies (acute MI and severe CAD, with multiple comorbidities) would provide more information on the benefit of morphology-driven PCI over OMT.

IVUS-DCB

Intravascular imaging in peripheral arterial disease

The importance of intravascular ultrasound imaging (IVUS) in improving outcomes for peripheral arterial disease has been highlighted by this trial. The trial focused on patients with symptomatic femoropopliteal disease, 60% of whom were diabetic. The use of IVUS-guided stenting resulted in a patency rate at 1 year that was 14% higher than with angiography alone (83.8% vs. 70.1%). The advantage of using IVUS over angiography alone was particularly evident in patients with extensive disease.

RELIEVE HF

Atrial shunt device in heart failure

The advantage of decompressing the atria by an emergency balloon atrial septostomy in congenital heart disease is applied in patients with HF by use of an interatrial device. This is the first placebo procedure-controlled trial of interatrial shunting (with the Ventura shunt) in patients with HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). A total of 508 patients (74 years old, 64% men) at 94 sites in North America, Europe, Israel, Australia, and New Zealand were randomized to a shunt (n = 250) or placebo procedure (n = 258). All participants had symptomatic HF despite taking the medications at maximally tolerated doses. Only operators knew which procedure a patient received.

Results showed no significant difference between groups for the primary effectiveness endpoint (death from any cause, the need for a transplant or assist device, HF hospitalizations, worsening of outpatient events, and change in the quality of life). The win ratio of the interim analysis was 0.86 (0.61-1.22; P = .20). The annualized rate of events did not differ among the groups (55.7% vs. 56.0%, RRR 1.00; P = .96).

What was surprising was a marked improvement in the quality of life across all groups was observed, including those who received a placebo procedure, suggesting a placebo effect. The change from baseline through year 1 was 9.5 vs. 10.2 (P = .74). A tremendous placebo effect was noted in the HFpEF group compared with the device group. Outcomes based on the baseline left ventricular ejection fraction suggested improvement in HFrEF compared with the HFpEF. There were no device-related adverse events. This trial may not apply to other devices and the varied profiles of HF patients to be evaluated.

ARISE HF

Aldose reductase inhibitor in diabetic cardiomyopathy

One of the complications of diabetes mellitus is progression to symptomatic HF. Deterioration in exercise capacity precedes the onset of HF. This study evaluated the safety and efficacy of an aldose reductase inhibitor, AT 001 in patients with diabetic cardiomyopathy having reduced peak oxygen uptake in stabilizing the exercise capacity. A total of 691 patients were randomized to either a placebo or an increasing dose of AT 001 twice daily. The primary endpoint was a proportional change in peak VO₂ from baseline to 15 months. The mean age of the patients was 67.5 years, of which 50.4% were women. The difference in peak VO₂ between placebo and high dose AT 001 was 0.30 (P = .19). The drug was safe and well tolerated. On prespecified stratified subgroup analysis, the drug was associated with better exercise capacity at 15 months in patients not taking SGLTi and GLP-1RA at baseline. The diabetics were well controlled (HBA1C was 6.98%), which is not represented globally. More studies are required on this drug.

IMPROVE HCM

Ninerafaxstat in HCM

The cause of HF in nonobstructive hypertrophic cardiomyopathy (HCM) is diastolic dysfunction, which is because of various factors (hypertrophy, disarray, scar, and fibrosis) mostly dependent on the energy. A drug targeting the heart’s energy efficiency (mitotrope) can result in better exercise capacity, and outcomes were evaluated in this trial. The new mitotrope drug called ninerafaxstat was evaluated. This drug partially inhibits fatty acid oxidation and increases the use of glucose as fuel in the myocardium. The drug is hemodynamically safe and does not need any monitoring, which is of importance in current practice. Across 12 centers, a total of 67 patients with left ventricular outflow tract gradient < 30 mm Hg and peak VO₂ < 80% were enrolled. They were randomized to a placebo or ninerafaxstat 200 mg twice daily for 12 weeks. Approximately 60% were on beta-blockers and 30% were already on calcium channel blockers. At the end of 12 weeks, ninerafaxstat improved ventilating efficiency (VE/VCO₂ slope) compared to the placebo (P = 0.006). Additionally, the drug significantly improved KCCQ CCS (P = 0.04), resulting in reduced symptom burden and improved exercise capacity for those with HCM. The left atrial size decreased significantly in the group receiving the drug, however, no change in NT pro-BNP was noted. This novel drug is an important advancement in nonobstructive HCM management and needs long-term studies.

PROACT

Can ACEI prevent cardiotoxicity by anthracyclines?

In this trial, researchers studied whether ACE inhibitors would help prevent cardiotoxicity caused by anthracyclines. The study involved 111 patients with an average age of 57 years, 78% of whom were women and 98% were of White British origin. The patients were being treated for breast cancer (62%) or non-Hodgkin lymphoma (38%) and received 6 cycles of chemotherapy with a mean dose of 328 mg/m² of anthracyclines (equivalent to >300 mg/m² of doxorubicin). The drug evaluated in this study was enalapril, with a mean dose of 17.7 mg. At the start of the study, all patients had a negative troponin result. The results of the study did not show any difference between the groups in the proportion of patients who experienced troponin T or I release (P = NS). Therefore, ACE inhibitors did not appear to play a role in preventing cardiotoxicity from anthracyclines. Another drug to be explored in this cohort. More attention was drawn to the proportion of patients testing positive for troponin I, which was less than those testing positive for troponin T. The current guidelines do not differentiate between the two troponins (I or T), and both are associated with cardiotoxicity in observational studies. This finding raises the question of which troponin (I or T) should be used for the diagnosis of anthracycline cardiotoxicity. Troponin T has many manufacturers, whereas Troponin I has only a single manufacturer. It is unclear whether this difference should be considered before concluding one troponin is better than the other.

TARGET BP1

This study examines the potential benefits of renal denervation (RDN) using dehydrated alcohol in patients with resistant hypertension. The trial found that RDN was effective in reducing 24-hour ambulatory systolic blood pressure (ABPM SBP) after 3 months compared to the sham procedure, but there was no significant change in office systolic and diastolic blood pressure (office SBP or DBP). The placebo effect was found to be significant in the sham control group, but only 25% of patients were compliant with medications. Overall, the trial suggests that alcohol-mediated RDN is safe and has potential benefits, but further studies are needed to confirm these findings.

KARDIA 2 Study

Effect of small RNA interference drug in hypertension

Patients with uncontrolled hypertension often face difficulty in reaching their target blood pressure levels because of noncompliance with the prescribed medication regimen. This leads to a significant risk of adverse events. To address this issue, researchers conducted a phase-2 double-blind trial using a small RNA interference drug called Zilebesiran. Patients in the trial were given 4 weeks of optimal doses of the drugs indapamide (10 mg), amlodipine (5 mg), and olmesartan (40 mg), with discontinuation of other medications. They were then randomized into 3 groups (amlodipine, indapamide, and olmesartan). Half received a placebo, and others received zilebesiran in each group. After 3 months, the reduction in blood pressure was significant across all the groups, with the reduction in angiotensinogen and blood pressure being the most significant in the indapamide and amlodipine group. However, the reduction was not significant in the olmesartan group. A small risk of hyperkalemia and reduced renal function was noted. A larger population of high cardiovascular risk profile patients with chronic kidney disease will be evaluated in the KARDIA 3 study. A longer duration of study is required to note the safety profile of this novel drug.

FEEL Study

Any evidence for the effect of spirituality, and gratitude on the reduction of blood pressure?

This study aimed to investigate the effect of spirituality and gratitude on blood pressure reduction. The trial was conducted in Brazil and involved 100 patients with stage 1 and stage 2 hypertension. Participants were randomly assigned to either receive usual care or usual care with a spirituality intervention. The intervention involved sending daily WhatsApp messages and videos that encouraged optimism, gratitude, and forgiveness, along with brief tasks requiring participants to write messages of gratitude. The study ran for 12 weeks. The results showed that the intervention group had a reduction in systolic blood pressure by 7.6 mm Hg, whereas the control group only had a reduction of 0.55 mm Hg. Additionally, the percentage of change in flow-mediated dilation increased by 4.12% in the intervention group compared with a decrease of 3.34% in the control group. This reduction was larger than that seen in previous non-pharmacological interventions and is beneficial in reducing the risk of cardiac events in patients with hypertension.

DEDICATE DZKH6

TAVR in low-risk AS population

There is an ongoing debate about the advantages of transcatheter aortic valve replacement (TAVR) versus surgical aortic valve replacement (SAVR) in low-risk populations. The results of this trial have shown that TAVR may be more beneficial for patients with symptomatic severe aortic stenosis who are at low to intermediate risk. The incidence of stroke was significantly lower in the TAVR group (only 1.3%) than in the SAVR group, despite the infrequent use of cerebral embolic protection devices. On the other hand, patients who underwent SAVR experienced frequent atrial fibrillation and bleeding. It is worth noting that two-thirds of TAVR procedures used balloon-expandable valves that are particularly beneficial in low-calcium situations. However, it is important to mention that the study did not include patients with bicuspid aortic valve disease.

SMART

TAVR in small annulus: Which valve is better?

The patient prosthesis mismatch is a major concern when it comes to valve replacements. To ensure low gradients post procedure, it is crucial to choose an ideal valve. The small annulus aortic stenosis is a particularly problematic area as it is associated with an increased risk of a permanent pacemaker. The definition of a small annulus, as per multidetector computed tomography, is any measurement less than 430 cm². To address this concern, this trial was conducted to compare the effectiveness of 2 different types of valves in this cohort. The trial included 716 randomized patients, with a mean age of 81 years, out of which 87.3% were women. The 2 types of valves compared were self-expanding and balloon-expanding valves. The suprannular self-expanding valves used included EVOLUT PRO, PRO+, and FX, whereas the balloon-expandable valves used were SAPIEN 3 and SAPIEN 3 ULTRA. At the 12-month mark, the self-expandable valves showed significantly lower gradients than the balloon-expandable valves. However, this difference was no longer observed when gradients were measured invasively. As a result, it is unknown whether the second co-primary outcome in this trial would have been different if gradients were assessed invasively rather than by Doppler at 12 months after the procedure. It is worth noting that the relatively short follow-up in this trial may not have been long enough to detect a difference in the clinical outcomes between the 2 types of valves. Despite this limitation, the results of this trial provide valuable insights into the effectiveness of different types of valves in patients with a small annulus.