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The article discusses the concept of disease modification in pulmonary arterial hypertension (PAH) and proposes a framework for its definition and evaluation in clinical trials. It defines disease modification as therapy-induced changes in clinical manifestations, disease trajectory, and outcomes due to an effect on the underlying pathophysiology. It proposes a randomized-withdrawal trial design to evaluate disease-modifying therapies effectively.

Aim: The EMPULSE (EMPagliflozin in patients hospitalised with acUte heart faiLure who have been StabilizEd) trial showed that, compared to placebo, the sodium–glucose cotransporter 2 inhibitor empagliflozin (10 mg/day) improved clinical outcomes of patients hospitalized for acute heart failure (HF). We investigated whether efficacy and safety of empagliflozin were consistent across the spectrum of left ventricular ejection fraction (LVEF). Methods and results: A total of 530 patients hospitalized for acute de novo or decompensated HF were included irrespective of LVEF. For the present analysis, patients were classified as HF with reduced (HFrEF, LVEF ≤40%), mildly reduced (HFmrEF, LVEF 41–49%) or preserved (HFpEF, LVEF ≥50%) ejection fraction at baseline. The primary endpoint was a hierarchical outcome of death, worsening HF events (HFE) and quality of life over 90 days, assessed by the win ratio. Secondary endpoints included individual components of the primary endpoint and safety. Out of 523 patients with baseline data, 354 (67.7%) had HFrEF, 54 (10.3%) had HFmrEF and 115 (22.0%) had HFpEF. The clinical benefit (hierarchical composite of all‐cause death, HFE and Kansas City Cardiomyopathy Questionnaire total symptom score) of empagliflozin at 90 days compared to placebo was consistent across LVEF categories (≤40%: win ratio 1.35 [95% confidence interval 1.04, 1.75]; 41–49%: win ratio 1.25 [0.66, 2.37)] and ≥50%: win ratio 1.40 [0.87, 2.23], pinteraction = 0.96) with a favourable safety profile. Results were consistent across individual components of the hierarchical primary endpoint. Conclusion: The clinical benefit of empagliflozin proved consistent across LVEF categories in the EMPULSE trial. These results support early in‐hospital initiation of empagliflozin regardless of LVEF. [ABSTRACT FROM AUTHOR]

Randomized clinical trials are the gold standard for establishing the efficacy and safety of cardiovascular therapies. However, current pivotal trials are expensive, lengthy, and insufficiently diverse. Emerging artificial intelligence (AI) technologies can potentially automate and streamline clinical trial operations. This review describes opportunities to integrate AI throughout a trial's life cycle, including designing the trial, identifying eligible patients, obtaining informed consent, ascertaining physiological and clinical event outcomes, interpreting imaging, and analyzing or disseminating the results. Nevertheless, AI poses risks, including generating inaccurate results, amplifying biases against underrepresented groups, and violating patient privacy. Medical journals and regulators are developing new frameworks to evaluate AI research tools and the data they generate. Given the high-stakes role of randomized trials in medical decision making, AI must be integrated carefully and transparently to protect the validity of trial results. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusion The TRANSFORM‐HF trial found no difference in clinical outcomes between torsemide versus furosemide after hospitalization for heart failure. This analysis aimed to assess the impact of diuretic dosing on the primary and secondary clinical outcomes.This post‐hoc analysis of TRANSFORM‐HF categorized patients into three groups by discharge diuretic dose: (1) ≤40 mg, (2) >40–80 mg, and (3) >80 mg of furosemide equivalents. The associations between discharge dose and 12‐month clinical events, and change in Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ‐CSS), were assessed. Overall, 2379 patients were included, aged 65 years (interquartile range 56–75), 883 (37.1%) women, and 812 (34.2%) Black. Furosemide had adjusted hazard ratios (aHR) for all‐cause mortality of 1.21 (95% confidence interval [CI] 0.91–1.59) for discharge dose group 2 and 1.40 (95% CI 1.04–1.88) for group 3, compared with group 1. For torsemide, aHRs were 1.74 (95% CI 1.32–2.30) for group 2 and 1.58 (95% CI 1.14–2.19) for group 3. No evidence of heterogeneity for the association between increased mortality and higher dose was found by loop diuretic type (pinteraction = 0.17). Higher doses of furosemide and torsemide were associated with increased risk of all‐cause hospitalization and the composite of all‐cause mortality and hospitalization, without evidence of heterogeneity by loop diuretic type (pinteraction > 0.2). Changes in KCCQ‐CSS from baseline at 12 months was similar across dose groups for both drugs.Following hospitalization for heart failure, higher loop diuretic dosing was independently associated with worse clinical and patient‐reported outcomes. The correlation between higher loop diuretic dose and outcomes was consistent, regardless of loop diuretic used. [ABSTRACT FROM AUTHOR]

Aims: Patients hospitalized for acute heart failure (HF) could be enrolled in EMPULSE (NCT04157751) upon haemodynamic stabilization and between 24 h and 5 days after hospital admission. The timing of treatment initiation may influence the efficacy and safety of drugs such as empagliflozin. The aim of this study was to evaluate patient characteristics, clinical events, and treatment effects according to time from admission to randomization. Methods and results: The EMPULSE population was dichotomized by median time from hospital admission to randomization (1–2 days vs. 3–5 days). The primary outcome was a hierarchical composite endpoint of time to all‐cause death, number of HF events, time to first HF event, and a ≥5‐point difference in Kansas City Cardiomyopathy Questionnaire total symptom score change from baseline after 90 days, analysed using the win ratio (WR) method. Patients randomized later (3–5 days, average time 3.9 days; n = 312) had a higher risk of experiencing clinical events than patients randomized earlier (1–2 days, average time 1.7 days; n = 215). The treatment effect favoured empagliflozin versus placebo in patients randomized later (3–5 days: WR 1.69, 95% confidence interval [CI] 1.26–2.25) but was attenuated in patients randomized earlier (1–2 days: WR 1.04, 95% CI 0.74–1.44) (interaction p = 0.029). A similar pattern was observed for the composite of HF hospitalization or cardiovascular death and all‐cause hospitalizations (interaction p < 0.1 for both). The reduction of N‐terminal pro‐B‐type natriuretic peptide levels was more pronounced with empagliflozin among patients randomized later than in patients randomized earlier (interaction p = 0.004). Conclusions: Among patients hospitalized for acute HF enrolled in EMPULSE, those randomized later after hospital admission (3–5 days) experienced greater clinical benefit with empagliflozin than those randomized earlier (1–2 days). These findings should be confirmed in future studies before clinical application. [ABSTRACT FROM AUTHOR]

Clinical trials in pulmonary arterial hypertension (PAH) have led to the approval of several effective treatments that improve symptoms, exercise capacity and clinical outcomes. In phase 3 clinical trials, primary end-points must reflect how a patient "feels, functions or survives". In a rare disease like PAH, with an ever-growing number of treatment options and numerous candidate therapies being studied, future clinical trials are now faced with challenges related to sample size requirements, efficiency and demonstration of incremental benefit on traditional end-points in patients receiving background therapy with multiple drugs. Novel clinical trial end-points, innovative trial designs and statistical approaches and new technologies may be potential solutions to tackle the challenges facing future PAH trials, but these must be acceptable to patients and regulatory bodies while preserving methodological rigour. In this World Symposium on Pulmonary Hypertension task force article, we address emerging trial end-points and designs, biomarkers and surrogate end-point validation, the concept of disease modification, challenges and opportunities to address diversity and representativeness, and the use of new technologies such as artificial intelligence in PAH clinical trials., Competing Interests: Conflict of interest: J. Weatherald declares grants or contracts to their institution from Janssen, Bayer, Merck, AstraZeneca and Sanofi; consulting fees, payment or honoraria to themselves, travel support and paid membership of an Advisory Board from Janssen and Merck; payment for expert testimony from Sprigings Intellectual Property Law; unpaid membership of a Data Safety Monitoring Board drom Université Laval; and unpaid membership of the medical advisory committee of the Pulmonary Hypertension Association of Canada and the scientific medical advisory committee of the Pulmonary Vascular Research Institute. T.R. Fleming declares no competing interests. M.R. Wilkins declares grants or contracts from the British Heart Foundation (RE/18/4/34215 centre support); consulting fees from MorphogenIX (advisory committee), VIVUS (study protocol advisory meeting), Janssen and Kinaset (study advisory boards) and Chiesi, Aerami and Benevolent AI (consultancy); payment for expert testimony from Pennington Marches and Sprigings; support for travel to scientific meetings from Apollo Therapeutics; patents planned, issued or pending (Imperial Innovations: patent submitted for prognostic protein model presented in this manuscript; patent for ZIP12 as a drug target; patent for TSPO as a drug target); membership of an adjudication committee for three clinical trials for Acceleron; membership of study safety committees for GSK and Novartis; a role as a trustee of the Pulmonary Vascular Research Institute; and stock options in W12 Therapeutics. T.M. Cascino delares grants from NHLBI (K12 HL138039) and Johnson & Johnson Innovative Medicine; consulting fees from and participation on a Data Safety Monitoring Board or Advisory Board for Merck; and payment or honoraria from Total CME. M.A. Psotka declares no competing interests. R. Zamanian declares grants to their institution from Gossamer Bio, Merck, United Therapeutics and Janssen; consulting fees from Gossamer Bio, Morphogen IX, Merck and Aerovate; patents planned, issued or pending for FK506 for treatment of pulmonary hypertension; participation on a Data Safety Monitoring Board or Advisory Board for Aerovate; and stock options in REVIVA. W. Seeger declares consulting fees from United Therapeutics, Abivax, Tiakis Biotech AG, Pfizer, Liquidia, Medspray BV and Pieris Pharmaceuticals. N. Galiè declares grants or contracts from Janssen, Actelion and Merck; consulting fees from Janssen, Actelion, Chiesi and Ferrer; payment or honoraria from Janssen, Actelion and Chiesi; support for attending meetings and/or travel from Dompe; and participation on a Data Safety Monitoring Board or Advisory Board from Janssen, Actelion and Ferrer. M. Gomberg-Maitland declares consulting fees from Acceleron/Merck (steering committee), Aerami (until 2023), Janssen (consultancy), JucaBio (steering committee), Keros (steering committee) and United Therapeutics (Jenesis Young Investigator Grant Chairman); support for attending the ERS Congress from Merck; participation on a Data Safety Monitoring board for Acceleron/Merck (until 2023) and Janssen (until 2023); and unpaid roles as Treasurer of ISHLT and a member of the United Therapeutics Scientific Advisory Board., (Copyright ©The authors 2024.)

Aims: Despite significant morbidity and mortality, recent advances in cardiogenic shock (CS) management have been associated with increased survival. However, little is known regarding the management of patients who survive CS with heart failure (HF) with reduced left ventricular ejection fraction (LVEF, HFrEF), and the utilization of guideline-directed medical therapy (GDMT) in these patients has not been well described. To fill this gap, we investigated the use of GDMT during an admission for CS and short-term outcomes using the Inova single-centre shock registry., Methods: We investigated the implementation of GDMT for patients who survived an admission for CS with HFrEF using data from our single-centre shock registry from January 2017 to December 2019. Baseline characteristics, discharge clinical status, data on GDMT utilization and 30 day, 6 month and 12 month patient outcomes were collected by retrospective chart review., Results: Among 520 patients hospitalized for CS during the study period, 185 (35.6%) had HFrEF upon survival to discharge. The median age was 64 years [interquartile range (IQR) 56, 70], 72% (n = 133) were male, 22% (n = 40) were Black and 7% (n = 12) were Hispanic. Forty-one per cent of patients (n = 76) presented with shock related to acute myocardial infarction (AMI), while 59% (n = 109) had HF-related CS (HF-CS). The median length of hospital stay was 12 days (IQR 7, 18). At discharge, the proportions of patients on beta-blockers, angiotensin-converting enzyme inhibitors (ACEis)/angiotensin receptor blockers (ARBs)/angiotensin receptor/neprilysin inhibitors (ARNIs) and mineralocorticoid receptor antagonists (MRAs) were 78% (n = 144), 58% (n = 107) and 55% (n = 101), respectively. Utilization of three-drug GDMT was 33.0% (n = 61). Ten per cent of CS survivors with HFrEF (n = 19) were not prescribed any component of GDMT at discharge. Multivariable logistic regression adjusted for baseline GDMT use revealed that patients with lower LVEF and those who transferred to our centre from an outside hospital were more likely to experience GDMT addition (P < 0.05). Patients prescribed at least one additional class of GDMT during admission had higher odds of 6 month and 1 year survival (P < 0.01): On average, 6 month survival odds were 7.1 times greater [confidence interval (CI) 1.9, 28.5] and 1 year survival odds were 6.0 times greater than those who did not have at least one GDMT added (CI 1.9, 20.5)., Conclusions: Most patients who survived CS admission with HFrEF in this single-centre CS registry were not prescribed all classes or goal doses of GDMT at hospital discharge. These findings highlight an urgent need to augment multidisciplinary efforts to enhance the post-discharge medical management and outcomes of patients who survive CS with HFrEF., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)