Mark C Petrie

Abstract (word count 250) Background and Aims: Phase 3 trials testing whether pharmacologic interventions targeting myocardial fibrosis (MF) improve outcomes require MF measurement that does not rely on tomographic imaging with intravenous contrast. Methods: We developed and externally validated extracellular volume (ECV) prediction models incorporating readily available data (comorbidity and natriuretic peptide variables), excluding tomographic imaging variables. Survival analysis tested associations between predicted ECV and incident outcomes (death or hospitalization for heart failure). We created various sample size estimates for a hypothetical therapeutic clinical trial testing an anti-fibrotic therapy using: a) predicted ECV, b) measured ECV, or c) no ECV. Results: Multivariable models predicting ECV had reasonable discrimination (optimism corrected C-statistic for predicted ECV ≥27% 0.78 (95%CI 90.75–0.80) in the derivation cohort (n=1663) and 0.74 (95%CI 0.71–0.76) in the validation cohort (n=1578)) and reasonable calibration. Predicted ECV associated with adverse outcomes in Cox regression models: ECV ≥27% (binary variable) HR 2.21 (1.84–2.66). For a hypothetical clinical trial with an inclusion criterion of ECV ≥27%, use of predicted ECV (with probability threshold of 0.69 and 80% specificity) compared to measured ECV would obviate the need to perform 3940 CMR scans, at the cost of an additional 3052 participants screened and 705 participants enrolled. Conclusions: Predicted ECV (derived without tomographic imaging) associates with outcomes and efficiently identifies vulnerable patients who might …

In an era focused on value-based healthcare, the quality of healthcare and resource allocation should be underpinned by empirical evidence. Pragmatic clinical trials (pRCTs) are essential in this endeavor, providing randomized controlled trial (RCT) insights that encapsulate real-world effects of interventions. The rising popularity of pRCTs can be attributed to their ability to mirror real-world practices, accommodate larger sample sizes, and provide cost advantages over traditional RCTs. By harmonizing efficacy with effectiveness, pRCTs assist decision-makers in prioritizing interventions that have a substantial public health impact and align with the tenets of value-based health care. An international network for pRCT provides several advantages, including larger and diverse patient populations, access to a broader range of healthcare settings, sharing knowledge and expertise, and overcoming ethical and …

Heart failure with preserved ejection fraction (HFpEF) is increasingly recognised and diagnosed in clinical practice, a trend driven by an ageing population and a rise in contributing comorbidities, such as obesity and diabetes. Representing at least half of all heart failure cases, HFpEF is recognised as a complex clinical syndrome. Its diagnosis and management are challenging due to its diverse pathophysiology, varied epidemiological patterns, and evolving diagnostic and treatment approaches. This Seminar synthesises the latest insights on HFpEF, integrating findings from recent clinical trials, epidemiological research, and the latest guideline recommendations. We delve into the definition, pathogenesis, epidemiology, diagnostic criteria, and management strategies (non-pharmacological and pharmacological) for HFpEF. We highlight ongoing clinical trials and future developments in the field. Specifically, this …

Background The incidence and distribution of acute and chronic dialysis among patients with heart failure (HF), stratified by diabetes, remain uncertain. We hypothesized that with improved survival and rising comorbidities, the demand for dialysis would increase over time. Methods and Results Patients with incident HF, aged 18 to 100 years, between 2002 and 2016, were identified using Danish nationwide registers. Primary outcomes included acute and chronic dialysis initiation, HF‐related hospitalization, and all‐cause mortality. These outcomes were assessed in 2002 to 2006, 2007 to 2011, and 2012 to 2016, stratified by diabetes. We calculated incidence rates (IRs) per 1000 person‐years and hazard ratios (HR) using multivariable Cox regression. Of 115 533 patients with HF, 2734 patients received acute dialysis and 1193 patients received chronic dialysis. The IR was 8.0 per 1000 and 3.5 per 1000 …

Background Obesity and type 2 diabetes are prevalent in patients with heart failure with preserved ejection fraction and are characterized by a high symptom burden. No approved therapies specifically target obesity-related heart failure with preserved ejection fraction in persons with type 2 diabetes. Methods We randomly assigned patients who had heart failure with preserved ejection fraction, a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or more, and type 2 diabetes to receive once-weekly semaglutide (2.4 mg) or placebo for 52 weeks. The primary end points were the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) and the change in body weight. Confirmatory secondary end points included the …

BackgroundIn the Revascularization for Ischemic Ventricular Dysfunction (REVIVED-BCIS2) trial, percutaneous coronary intervention (PCI) did not reduce the incidence of death or hospitalization for heart failure.ObjectivesThis prespecified secondary analysis investigated the effect of PCI on health status measured with the KCCQ combined with the primary outcome in a win ratio.MethodsParticipants with severe ischemic left ventricular dysfunction were randomized to either PCI in addition to optimal medical therapy (PCI) or optimal medical therapy alone (OMT). The primary outcome was a hierarchical composite of all-cause death, HHF and KCCQ overall summary score (OSS) at 24 months analysed using the unmatched win ratio. The key secondary endpoint was a KCCQ-OSS responder analysis.Results347 participants were randomized to PCI and 353 to OMT. Median (IQR) age was 70.0 (63.3 to 76.1) years …

Aims There are few prospective reports of 1‐year outcomes for women with peripartum cardiomyopathy (PPCM). We report findings from the European Society of Cardiology EURObservational Research Programme PPCM Registry. Methods and results The registry enrolled women from 51 countries from 2012 to 2018. Eligibility included: (i) a peripartum state, (ii) signs or symptoms of heart failure, (iii) left ventricular (LV) ejection fraction ≤45%, (iv) exclusion of alternative causes of heart failure. We report mortality, thromboembolism, stroke, rehospitalization, LV recovery and remodelling at 1 year. Differences between regions were compared. One‐year mortality data were available in 535 (71%) women and follow‐up differed across regions. At 1 year, death from any cause occurred in 8.4% of women, with regional variation (Europe 4.9%, Africa 6.5%, Asia‐Pacific 9.2%, Middle East 18.9%; p < 0.001). The …

BackgroundSTEP-HFpEF, a 52 week trial conducted in patients with obesity phenotype of heart failure with preserved ejection fraction (HFpEF) and no type 2 diabetes, examined the effects of once-weekly semaglutide 2.4 mg versus placebo on HF-related symptoms, physical limitations, and exercise function, as well as inflammation and body weight (BW). Except for sodium-glucose co-transporter 2 inhibitors, previous HF therapies have shown differential effects across the spectrum of left ventricular ejection fraction (LVEF). In this pre-specified analysis, we investigated the effects of semaglutide on the primary and key secondary endpoints across the range of LVEF in the STEP-HFpEF Trial.MethodsSTEP-HFpEF randomized 529 participants with symptomatic HF, LVEF ≥45% and body mass index of ≥30 kg/m2 to receive once weekly semaglutide 2.4 mg or placebo. Key exclusion criteria were prior or planned …

Inhibitors Trial to Determine Superiority in Reducing Heart Failure Events After MI] URL: https://clinicaltrials. gov; Unique identifier: NCT02924727) trial investigated whether sacubitril/valsartan improved outcomes compared to ramipril after acute myocardial infarction (MI). 1 Sacubitril/valsartan did not reduce the risk of the primary composite outcome of cardiovascular death, outpatient development of heart failure (HF), or hospitalization for HF compared to ramipril. In the current analysis, we compared the rates of the primary and secondary outcomes in those with pulmonary congestion ([PC] with or without a left ventricular ejection fraction [LVEF]≤ 40%) or without congestion (and LVEF≤ 40%), as well as the treatment effect and safety of sacubitril/valsartan compared with ramipril among these groups.The design and main results of the Institutional Review Board–approved PARADISE-MI trial have been published. 1 …

Background Patients with type 2 diabetes are at risk of heart failure hospitalization. As social determinants of health are rarely included in risk models, we validated and recalibrated the WATCH-DM score in a diverse patient-group using their social deprivation index (SDI). Methods We identified US Veterans with type 2 diabetes without heart failure that received outpatient care during 2010 at Veterans Affairs medical centers nationwide, linked them to their SDI using residential ZIP codes and grouped them as SDI <20%, 21% to 40%, 41% to 60%, 61% to 80%, and >80% (higher values represent increased deprivation). Accounting for all-cause mortality, we obtained the incidence for heart failure hospitalization at 5 years follow-up; overall and in each SDI group. We evaluated the WATCH-DM score using the C statistic, the Greenwood Nam D’Agostino test χ2 test and calibration plots and further recalibrated the …

BackgroundEmpagliflozin reduces the risk of heart failure (HF) hospitalizations but not all-cause mortality when started within 14 days of acute myocardial infarction (AMI).ObjectiveTo evaluate the association between left ventricular ejection fraction (LVEF), congestion, or both on outcomes and the impact of empagliflozin in reducing HF risk post-MI.MethodsIn the EMPACT-MI trial, patients were randomized within 14 days of an AMI complicated by either newly reduced LVEF<45%, congestion, or both to empagliflozin 10 mg daily or placebo and followed for a median of 17.9 months.ResultsAmong 6522 patients, the mean baseline LVEF was 41%+9%; 2648 patients (40.6%) presented with LVEF<45% alone, 1483 (22.7%) presented with congestion alone, and 2181 (33.4%) presented with both. Among patients in the placebo arm, multivariable adjusted risk for each 10-point reduction in LVEF included all-cause …

BackgroundPeripartum cardiomyopathy (PPCM) is a global disease with substantial morbidity and mortality. The aim of this study was to analyze to what extent socioeconomic factors were associated with maternal and neonatal outcomes.MethodsIn 2011, >100 national and affiliated member cardiac societies of the European Society of Cardiology (ESC) were contacted to contribute to a global PPCM registry, under the auspices of the ESC EORP Programme. We investigated the characteristics and outcomes of women with PPCM and their babies according to individual and country-level sociodemographic factors (Gini index coefficient [GINI index], health expenditure [HE] and human developmental index [HDI]).Results739 women from 49 countries (Europe [33%], Africa [29%], Asia-Pacific [15%], Middle East [22%]) were enrolled. Low HDI was associated with greater left ventricular (LV) dilatation at time of …

BackgroundIn the STEP-HFpEF (NCT04788511) and STEP-HFpEF DM (NCT04916470) trials, the GLP-1 receptor agonist semaglutide improved symptoms, physical limitations, bodyweight, and exercise function in people with obesity-related heart failure with preserved ejection fraction. In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, we aimed to provide a more definitive assessment of the effects of semaglutide across a range of outcomes and to test whether these effects were consistent across key patient subgroups.MethodsWe conducted a prespecified pooled analysis of individual patient data from STEP-HFpEF and STEP-HFpEF DM, randomised, double-blind, placebo-controlled trials at 129 clinical research sites in 18 countries. In both trials, eligible participants were aged 18 years or older, had heart failure with a left ventricular ejection fraction of at least 45%, a BMI of at …

Aims Subcutaneous (SC) furosemide has potential advantages over intravenous (IV) furosemide by enabling self-administration or administration by a lay caregiver, such as facilitating early discharge, preventing hospitalizations, and in palliative care. A high-concentration, pH-neutral furosemide formulation has been developed for SC administration via a small patch infusor pump. We aimed to compare the bioavailability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of a new SC furosemide formulation with conventional IV furosemide and describe the first use of a bespoke mini-pump to administer this formulation. Methods and results A novel pH-neutral formulation of SC furosemide containing 80 mg furosemide in ∼2.7 mL (infused over 5 h) was investigated. The first study was a PK/PD study of SC furosemide compared with 80 mg IV furosemide administered …

BackgroundSystemic inflammation has been implicated as a potential risk factor for heart failure (HF) with preserved or mildly reduced ejection fraction (HFpEF, HFmrEF), but little is known regarding the prevalence and clinical correlates of systemic inflammation in patients with prevalent HFpEF/HFmrEF.MethodsWe compared baseline clinical characteristics, laboratory assessments, and vital signs in patients with HFpEF/HFmrEF enrolled in 3 large cardiovascular outcomes trials testing the glucagon like peptide-1 receptor agonist semaglutide, including those with body mass index (BMI) >27 kg/m2 and established cardiovascular (CV) disease (SELECT, NCT03574597), type 2 diabetes (T2D) and chronic kidney disease (CKD; FLOW, NCT03819153), and T2D and atherosclerotic CV disease or CKD (SOUL, NCT03914326). Patients with inflammation (defined as CRP≥2 mg/l) were compared to those without (CRP …

BACKGROUND Patients with heart failure (HF) with preserved ejection fraction (HFpEF) and obesity experience a high burden of symptoms and functional impairment, and a poor quality of life. In the STEP-HFpEF trial (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity), once-weekly semaglutide 2.4 mg improved symptoms, physical limitations, and exercise function, and reduced inflammation and body weight. This prespecified analysis investigated the effects of semaglutide on the primary and confirmatory secondary end points across the range of the Kansas City Cardiomyopathy Questionnaire (KCCQ) scores at baseline and on all key summary and individual KCCQ domains. METHODS STEP-HFpEF randomly assigned 529 participants with symptomatic HF, an ejection fraction of ≥45%, and a body mass index of ≥30 kg/m2 to once-weekly …

Aims Red cell distribution width (RDW) is a strong prognostic marker in patients with heart failure (HF) and reduced ejection fraction and other conditions. However, very little is known about its prognostic significance in HF with preserved ejection fraction. We examined the relationship between RDW and outcomes and the effect of sacubitril/valsartan, compared with valsartan, on RDW and clinical outcomes in PARAGON‐HF. Methods and results PARAGON‐HF enrolled patients with a left ventricular ejection fraction of ≥45%, structural heart disease, and elevated N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP). The primary endpoint was a composite of total HF hospitalizations and cardiovascular deaths. Median RDW at randomization was 14.1% (interquartile range 13.5–15.0%). Patients with higher RDW levels were more often men and had more comorbidity, a higher heart rate and NT‐proBNP …

BackgroundThe terminal cardiac rhythm at the time of death has not been systematically characterised in patients with heart failure (HF). Similarly, contemporary studies do not utilise autopsy data to define cause of death in HF. The relationship between mode of death (eg. sudden), terminal rhythm (TR)(eg. bradyarrhythmia), and autopsy-evidenced cause of death has not been systematically examined. Sudden cardiac deaths (SCDs) are assumed by convention due to ventricular arrhythmias (VAs), and especially so in the presence of an autopsy that is' negative’for specific cause of death.MethodsThe RHYTHM-HF clinical study employed injectable cardiac monitors and autopsies to characterise the mechanism of death in heart failure. Patients were recruited during an index hospitalisation for HF, implanted with an injectable cardiac monitor, and followed up for 2-4 years. Terminal electrocardiographic data was …

MethodsData were pooled for participants with type 2 diabetes and established CV disease or high CV risk in the SUSTAIN 6 and PIONEER 6 trials. Participants received sc semaglutide (0.5 or 1.0 mg)/oral semaglutide (14 mg) or volume-matched placebo; detailed trial descriptions can be found elsewhere. 4, 5

Aims The aims of this study were to assess prescription patterns, dosages, discontinuation rates, and association with prognosis of conventional heart failure medications in patients with transthyretin cardiac amyloidosis (ATTR-CA). Methods and results A retrospective analysis of all consecutive patients diagnosed with ATTR-CA at the National Amyloidosis Centre between 2000 and 2022 identified 2371 patients with ATTR-CA. Prescription of heart failure medications was greater among patients with a more severe cardiac phenotype, comprising beta-blockers in 55.4%, angiotensin-converting enzyme inhibitors (ACEis)/angiotensin II receptor blockers (ARBs) in 57.4%, and mineralocorticoid receptor antagonists (MRAs) in 39.0% of cases. During a median follow-up of 27.8 months (interquartile range 10.6–51.3), 21.7% had beta-blockers discontinued, and 32.9% had ACEi …