Abstract
This journal scan highlights key research articles from cardiovascular journals published between June and October 2025. Happy reading.
Keywords
1.
In the recently published EARLY TAVR trial, there is a benefit of early TAVR compared to clinical surveillance and delayed TAVR in asymptomatic high-gradient severe aortic stenosis (AHGSAS). Elevated cardiac biomarkers in AHGSAS patients are linked to maladaptive remodeling, the onset of symptoms, and poorer outcomes after TAVR. Guidelines suggest TAVR is a reasonable option (Class IIa) when N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels are elevated more than three times the normal range.
With the hypothesis that elevated biomarkers (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) might indicate an early need for TAVR, a subanalysis was conducted within the EARLY TAVR trial. This analysis examined the association between biomarker levels and the risk of the trial’s primary endpoint (death, stroke, and unplanned hospitalization) and secondary endpoints, utilizing Kaplan–Meier curves and Cox proportional hazards models.
Of the 901 patients randomized, 798 (89%) had their biomarkers measured at a core laboratory. Patients were subsequently stratified based on baseline biomarker levels into Tertiles 1, 2, and 3, corresponding to their absolute biomarker concentrations as well as normal versus elevated levels, and classified as 0, 1, or 2 based on the number of elevated biomarkers. The median NT-proBNP level was 287 (ranging from 147 to 601), and hsTrop I was 14.6 (ranging from 10.5 to 21.0). Findings revealed that higher levels of biomarkers were associated with a greater event rate across multiple endpoints. Patients with elevated biomarker levels tended to be older, had worse functional status, and exhibited lower left ventricular ejection fractions.
Contrary to the initial hypothesis, a low hazard ratio (HR) was observed in patients with normal biomarkers at baseline, suggesting that early TAVR provides a greater relative benefit compared to clinical surveillance (CS) and delayed TAVR. An interaction was noted between hsTnT and treatment group concerning death or heart failure hospitalization (P = .04), as well as heart failure hospitalization alone (P = .03), indicating that the relative benefit of early TAVR was more pronounced in patients with normal rather than elevated levels of hs-cTnT at baseline. The relative benefit of TAVR did not differ significantly across the biomarker tertiles. Notably, one-third of patients experienced acute decompensation requiring AVR, even with normal biomarker levels.
For heart failure hospitalization, higher baseline NT-proBNP levels were associated with a numerically greater absolute risk reduction (ARR) with early TAVR compared to those with lower NT-proBNP levels (number needed to treat [NNT] was 11 vs. 32).
The conversion time for TAVR in the surveillance arm was shorter for patients with elevated biomarker levels (315 days vs. 397 days for NT-proBNP and 306 days vs. 347 days for hs-cTnT). Moreover, having both biomarkers elevated was associated with a somewhat shorter conversion time to AVR.
In patients with AHGSAS, NT-proBNP and hs-cTnT levels do not appear to be effective for guiding clinical decision-making regarding the timing of AVR. A single measurement of these biomarkers is insufficient to determine the necessity for TAVR in this population. However, a high level of NT-proBNP indicates an urgent need for TAVR.
Lindman BR, Pibarot P, Schwartz A, et al. Cardiac biomarkers in patients with asymptomatic severe aortic stenosis: analysis from the EARLY TAVR trial. Circulation. 2025;151(22):1550-1564.
2.
Sotatercept, an activin signaling inhibitor, is effective in treating long-standing PAH. However, its effects when given early to patients diagnosed with PAH have not been studied. In a recent trial, patients with World Health Organization Class II and III dyspnea, who were at intermediate to high risk of death and were on double or triple background therapy, were randomly assigned to receive either subcutaneous sotatercept at a dose of 0.3 mg/kg body weight (BW), which could be increased to a target dose of 0.7 mg/kg BW every 21 days, or a placebo. All participants had been diagnosed with PAH less than a year before enrollment.
The primary endpoint of the study was the time to the first event, which included worsening clinical symptoms, a composite of death from any cause, unplanned hospitalization lasting at least 24 h due to worsening PAH, atrial septostomy, lung transplantation, or a decline in exercise performance due to PAH. The trial was stopped early due to the loss of clinical equipoise, as previous trials of the study drugs showed positive results. (Clinical equipoise refers to the ethical principle in medical research that there must be genuine uncertainty regarding the treatments being studied, as determined by experts in the field.)
A total of 320 patients were studied over a duration of 13.2 months. At least one primary endpoint occurred in the sotatercept group compared to the placebo group (10.6% vs. 36.9%, P < .001), with an HR of 0.24. Deterioration in exercise performance due to worsening PAH was observed in 8 patients (5.0%) in the sotatercept group versus 46 patients (28.8%) in the placebo group. Additionally, unplanned hospitalization for worsening PAH occurred in 3 patients (1.9%) in the sotatercept group compared to 14 patients (8.8%) in the placebo group. Death from any cause was reported in seven patients (4.4%) in the sotatercept group and six patients (3.8%) in the placebo group; no cases of atrial septostomy or lung transplantation occurred.
The most common adverse events on use of the drug included epistaxis and telangiectasias, occurring in 31.9% and 26.2% of patients, respectively. Among adults with PAH diagnosed less than 1 year prior, the addition of sotatercept to background therapy resulted in a lower risk of clinical worsening compared to placebo, as demonstrated in the HYPERION trial.
McLaughlin VV, Hoeper MM, Badesch DB, et al. Sotatercept for pulmonary arterial hypertension within the first year after diagnosis. N Engl J Med. 2025;393(16):1599-1611.
3.
a.
This Phase III, multinational, double-blind, randomized, placebo-controlled trial assessed the efficacy and safety of baxdrostat in patients with uncontrolled hypertension (seated systolic blood pressure [SBP] between 140 and 170 mm Hg despite stable treatment with two antihypertensive medications) or resistant hypertension, which involves the use of ≥3 medications, including a diuretic.
A total of 796 patients were recruited and randomly assigned in a 1:1:1 ratio to receive either baxdrostat at doses of 1 or 2 mg, or a placebo, daily for 12 weeks. Baxdrostat, an aldosterone synthase inhibitor, significantly reduced SBP compared to the placebo over the 12 weeks. Specifically, the change in SBP at 12 weeks was −14.5, –15.7, and –5.8 mm Hg, respectively, for the three groups studied.
Notably, 40% of patients receiving either 1 or 2 mg of baxdrostat achieved a reduction in SBP <130 mm Hg, while only 18.7% of patients on placebo reached this target. This blood pressure-lowering effect was sustained throughout the trial, and the drug was deemed safe, with no serious adverse effects reported. Hyperkalemia was observed in 2.3%, 3.0%, and 0.4%, respectively. These findings highlight the impact of elevated aldosterone levels in challenging-to-control hypertension.
Flack JM, Azizi M, Brown JM, et al. Efficacy and safety of baxdrostat in uncontrolled and resistant hypertension. N Engl J Med. 2025;393(14):1363-1374.
b.
Adults with established cardiovascular disease (CVD) or high cardiovascular (CV) risk (defined as a 10-year atherosclerotic cardiovascular disease [ASCVD] risk score >15%, or an estimated glomerular filtration rate [eGFR] of 30-59 mL/min/1.73 m²) and uncontrolled hypertension (SBP of 140-170 mm Hg) were randomized to receive either 300 or 600 mg of zilebesiran, or a placebo, in a ratio of 1:1:1. The study group included patients who exhibited a mean 24-h ambulatory SBP between 130 and 170 mm Hg while on two to four antihypertensive medications.
The median age of the analyzed patients was 67 years, with 45% being female. Prior CVD was seen in 23% and 77% were at high CV risk. At baseline, the average office SBP was 144 mm Hg, and the diastolic blood pressure (DBP) was 80 mm Hg. In terms of ambulatory blood pressure monitoring (ABPM), the mean 24-h SBP and DBP were 142 and 79 mm Hg, respectively. Regarding the medications at baseline, 53%, 36%, and 11% were on two, three, and four antihypertensive medications.
At the 3-month mark, patients taking 300 and 600 mg of the study drug experienced a 5 and 3.3 mm Hg reduction in SBP, respectively, compared to the placebo group. But neither reduction was statistically significant. At 6 months, the changes in SBP for both doses were –3.9 and –3.6 mm Hg, respectively. However, the change in 24-h ambulatory SBP and nighttime SBP for the same doses of drug were (–5.5, –7.4, –6.6, and –8.2 mm Hg, respectively). Since the primary endpoint did not achieve statistical significance, no claims could be made regarding the significance of secondary outcomes. Notably, a greater reduction in blood pressure was observed in patients using diuretics.
Pagidipati N. KARDIA-3: Zilebesiran as add-on therapy in adults with hypertension and established cardiovascular disease or at high cardiovascular risk. Presented at: HOT LINE 4; August 30, 2025; Madrid, Spain.
4.
Digoxin, derived from foxglove, has historically been a key treatment for heart failure. It is unique among heart failure medications due to its inotropic effects and its ability to decrease heart rate, often referred to as a “poor man’s inotrope.” Importantly, digoxin does not prolong the QT interval, but it has a significant limitation: it has a narrow therapeutic index, making it difficult to predict effective dosing. Low potassium levels (hypokalemia) can exacerbate its toxicity, and due to its renal clearance, caution is advised when using digoxin in patients with impaired renal function.
According to the landmark DIG trial, digoxin reduced hospitalizations by 33%. However, it also led to an increase in deaths from arrhythmias, which negated the overall mortality benefit of the drug. The serum digoxin levels considered beneficial range from 0.8 to 1.0 ng/mL, while the average level in the trial was 0.89 ng/mL. Female patients experienced more adverse events and required lower dosages of the drug. Following this trial, the use of digoxin has significantly declined, prompting changes in heart failure guidelines to recommend its use only in patients with heart failure with reduced ejection fraction (HFrEF) and atrial fibrillation (AF) for rate control.
At the ESC 2025 conference, the DIGIT HF trial—a randomized, placebo-controlled study involving 1,240 heart failure patients (left ventricular ejection fraction [LVEF] ≤40% and New York Heart Association [NYHA] Class III or IV; LVEF ≤30% and NYHA Class II) already receiving guideline-directed medical therapy (GDMT)—found a significant reduction in mortality with digitoxin compared to the placebo over the background GDMT. The starting dose of the drug was 0.07 mg. Over 36 months, there was an 18% decrease in the primary endpoint (HR 0.82, P = .03), with an ARR of 4.6% and an NNT of 22 to prevent one primary endpoint event. Digitoxin has a longer half-life, primarily metabolized in the liver, making it safer to use in patients with renal impairment. It is completely absorbed from the gastrointestinal tract compared to digoxin.
Limitations of the trial—it is underpowered as it could not reach the target number of enrollments, leading to a less precise estimate of the treatment effect. Lack of applicability to digoxin and inconsistent background medical therapy are other limitations. This trial is likely to prompt a reevaluation of the recommendations regarding the use of this cost-effective and beneficial drug.
Bavendiek U, Großhennig A, Schwab J, et al. Digitoxin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2025;393(12):1155-1165.
5.
The recent paradigm shift in diabetes management includes the use of GLP-1 RA and SGLT2i. These medications have shown benefits in improving CV outcomes while also lowering blood glucose levels. Multiple trials have demonstrated the CV benefits of each drug in patients with type 2 diabetes who are at high CV risk. The biological mechanisms underlying the benefits of these drugs differ and may be complementary when used in conjunction.
In this trial, the effects of combining these two agents were evaluated, as no randomized trial had previously been conducted. A total of 9,560 patients with type 2 diabetes and either ASCVD or chronic kidney disease (CKD) were randomized to receive oral semaglutide or a placebo. The study assessed patients based on their baseline use of SGLT2i or their subsequent use during the trial. At baseline, 2,596 patients (26.9%) were using SGLT2i, while 4,718 patients (48.9%) began using the drug during the trial.
The primary outcome measured was the time to the occurrence of significant events such as CV death, nonfatal myocardial infarction, or nonfatal stroke. The safety profile was determined by comparing the incidence of serious adverse events. Patients were followed for an average of 47.5 ± 10.9 months. The risk of primary outcomes was 14% lower in the semaglutide group compared to the placebo group (HR 0.86). For those who took SGLT2i at baseline, the HR was 0.89, while for those who did not, it was 0.84. There was no evidence of variability in the effects of oral semaglutidesemaglutide based on the SGLT2i drugs studied. The adverse effects were similar regardless of SGLT2i use, indicating that the combination was safe for this high-risk population and that the effects of oral semaglutidesemaglutide were independent of concomitant SGLT2i use.
Before this trial, various studies, including AMPLITUDE-O, HARMONY OUTCOMES, and FLOW, consistently demonstrated the efficacy of GLP-1 RAs, with or without the use of SGLT2i, but the population using both drugs in those trials was only 5.6% to 10.6%. In contrast, the SOUL trial had baseline SGLT2i use in 26.9% of participants, and by the end of the trial, more than 50% were using both drugs. This trial followed patients for an average of 4 years, supporting the safety of the combination treatment.
The oral administration of semaglutide showed a significant reduction in HbA1c from baseline to week 104 compared to placebo. In patients using SGLT2i at baseline, the reduction was –0.66% versus –0.13% for placebo; in those without SGLT2i, the reduction was –0.73% versus –0.16%, with a P value for interaction of 0.44. A higher proportion of patients in the placebo group initiated SGLT2i, and more patients already on semaglutide discontinued their SGLT2i. The initiation and discontinuation of drugs during the trial were not controlled or stratified, which may have affected glycemic control or other aspects of disease progression, possibly influencing HbA1c changes.
Patients using semaglutide experienced a greater decrease in body mass index, with a reduction of –1.5 kg/m² compared to –0.4 kg/m², regardless of SGLT2i use. The occurrence of severe hypoglycemia and ketoacidosis did not differ between groups with or without baseline SGLT2i use. However, it is important to note that the trial was not powered to assess treatment effects related to CV outcomes based on SGLT2i use.
Marx N, Deanfield JE, Mann JFE, et al. Oral semaglutide and cardiovascular outcomes in people with type 2 diabetes, according to SGLT2i use: prespecified analyses of the SOUL randomized trial. Circulation. 2025;151(23):1639-1650.
6.
A rise in intracardiac and PAPs often occurs before clinical signs of congestion in chronic heart failure patients. If not managed promptly, this can lead to hospitalizations for heart failure (HFH). Research indicates that implantable PAP sensors can predict mortality risk and HFH, regardless of ejection fraction. Effective pressure-guided management not only reduces PAP but also improves patients’ quality of life.
A study published in JACC Heart Failure aimed to determine if baseline pulmonary artery diastolic pressure (PAD) and its early changes over 90 days could predict mortality in patients with a CardioMEMS device. This retrospective cohort study in the USA included patients who had the device implanted between 2017 and 2022. Patients were categorized based on PAD measurements as acceptable (<20 mm Hg) or elevated (>20 mm Hg). Cohort A comprised baseline PAD data, while Cohort B focused on changes at 90 days.
In Cohort A (N = 9,579), 64.1% had elevated PAD, averaging 23.1 ± 4.6 mm Hg. Those with acceptable PAD had a significantly lower two-year mortality risk (HR 0.68; P < .001). In Cohort B (N = 8,542), 63.3% had elevated PAD at baseline; 24% improved to acceptable PAD, while 76% remained elevated at 90 days. The overall survival rate in this cohort was 68.3%, with mortality ranging from 20.7% in the persistently acceptable group to 33.1% in the persistently elevated group.
Patients with acceptable PAD were more likely to use angiotensin receptor–neprilysin inhibitor (ARNI) (12.1%) and less likely to use beta-blockers (59.2%). At 90 days, those with elevated PAD had higher usage of loop diuretics (75.2%) and thiazide diuretics (9.5%). This emphasizes the need for aggressive treatment strategies aimed at achieving PAD <20 mm Hg to improve survival.
While this retrospective study provides valuable insights, data on medication adherence, patient profiles, and biomarkers were not evaluated. Ultimately, managing PAD effectively with CardioMEMS is linked to better survival outcomes, highlighting the importance of developing management algorithms targeting elevated PAD.
Zalawadiya S, Abraham J, Rathman L, et al. Early reduction of pulmonary artery pressures is associated with improved mortality among Medicare beneficiaries with heart failure. JACC Heart Fail. 2025;13(10):102589.
Footnotes
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
